Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 239–250
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem
2
Klinefelter syndrome
Anne M. Wikström, Chief Physician a,b,e,
Leo Dunkel, Professor of Pediatrics c,d,*
a HUCH, Hospital for Children and Adolescents, Helsinki University Central Hospital, P.O. Box 281, FI-00029 Helsinki, Finland
b University of Helsinki, Helsinki, Finland
c Department of Pediatrics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio, Finland
d University of Eastern Finland, Kuopio, Finland
Keywords:
Klinefelter syndrome
47,XXY
testicular degeneration
hypogonadism
androgen
androgen deficiency
infertility
* Corresponding author. Department of Pediatr
Tel.: þ358 17 173311; fax: þ358 17 172410.
E-mail addresses: [email protected] (A.M.
e Tel.: þ358 50 4272854; fax: þ358 9 47175888
1521-690X/$ – see front matter � 2010 Elsevier Lt
doi:10.1016/j.beem.2010.09.006
Klinefelter syndrome (KS) is the most common genetic form of
male hypogonadism, but overt phenotype becomes evident only
after puberty. During childhood, and even during early puberty,
pituitary-gonadal function in 47,XXY subjects is relatively normal,
but from midpuberty onwards, FSH and LH levels increase to
hypergonadotropic levels, inhibin B decreases to undetectable
levels, and testosterone levels after some increase plateau at
low-normal levels for healthy adult men. Hence, most adult KS
males display a clear hypergonadotropism with a varying degree of
androgen deficiency; subsequently testosterone substitution
therapy is widely used to prevent symptoms and sequels of
androgen deficiency. Testicular biopsies of prepubertal KS boys
have shown preservation of seminiferous tubules with reduced
numbers of germ cells, but Sertoli and Leydig cells have appeared
normal. The testes in the adult KS male are characterized by
extensive fibrosis and hyalinization of the seminiferous tubules,
and hyperplasia of the interstitium. However, the tubules may
show residual foci of spermatogenesis. Introduction of testicular
sperm extraction (TESE) in combination with intracytoplasmic
sperm injection (ICSI) techniques has allowed non-mosaic KS
males to father children.
� 2010 Elsevier Ltd. All rights reserved.
ics, Kuopio University Hospital, P.O. Box 1777, FI-70211 Kuopio, Finland.
Wikström), [email protected] (L. Dunkel).
.
d. All rights reserved.
mailto:[email protected]
mailto:[email protected]
www.sciencedirect.com/science/journal/1521690X
http://www.elsevier.com/locate/beem
http://dx.doi.org/10.1016/j.beem.2010.09.006
http://dx.doi.org/10.1016/j.beem.2010.09.006
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical Endocrinology & Metabolism 25 (2011) 239–250240
Introduction
Klinefelter syndrome (KS) was first described by Harry F. Klinefelter in 1942 as a clinical entity
characterized by gynecomastia, small testes, absent spe ...
Recupero di spermatozoi nella Sindrome di KlinefelterAdmin Esanum IT
This document summarizes fertility in men with Klinefelter syndrome. It discusses that:
1) Men with Klinefelter syndrome (47,XXY karyotype) typically show azoospermia, though sperm are rarely observed in ejaculate and exceptional spontaneous pregnancies have been reported.
2) With surgical sperm retrieval, sperm have been found in up to 56.7% of cases and used for successful pregnancies via ICSI.
3) There is a higher risk of chromosomal abnormalities in sperm and offspring due to the genetic nature of Klinefelter syndrome, including sex chromosome aneuploidies and increased autosomal aneuploidies.
1 testosterone levels in umbilical cord blood and risk of pyloric stenosispatricia brucellaria
This study examined the relationship between testosterone levels in umbilical cord blood and the risk of infantile hypertrophic pyloric stenosis. The researchers conducted a matched case-control study nested within the Danish National Birth Cohort. They found 46 cases of infantile hypertrophic pyloric stenosis in male infants and measured their umbilical cord blood testosterone levels, comparing them to 150 matched male controls. The study found no significant association between higher testosterone levels at birth and increased risk of infantile hypertrophic pyloric stenosis later in infancy.
This document discusses delayed cord clamping (DCC) versus immediate cord clamping (ICC) and umbilical cord milking (UCM). It notes that DCC allows more blood from the placenta to pass to the newborn, increasing blood volume. ICC results in about 30% of blood staying in the placenta. The document also discusses benefits of DCC such as reduced risk of iron deficiency, increased stem cells, and better outcomes for preterm infants. However, concerns with DCC include delays in resuscitation and risks of postpartum hemorrhage. The evidence and guidelines generally support DCC when possible over ICC or UCM.
Perinatal magnesium administration and the prevention of periventricular leuk...Ross Finesmith M.D.
This study examined the effect of magnesium sulfate (MgSO4) on the development of cystic periventricular leukomalacia (cPVL) in preterm infants. The researchers conducted a retrospective case-control study of 492 preterm infants born between 1992-1994 weighing less than 1750g who survived at least 7 days. They found infants exposed to MgSO4 in utero were less likely to develop cPVL. Specifically, 2 of 18 infants with cPVL were exposed to MgSO4 compared to 14 of 36 controls, indicating MgSO4 exposure is associated with a reduced risk of cPVL. Further analysis confirmed the groups were similar in other variables and preeclampsia alone did
Magnesium Prevents the Cerebral Palsy Precursor in Premature InfantsRoss Finesmith M.D.
To determine if magnesium sulfate has an effect on the development of cystic
periventricular leukomalacia in preterm infants, this retrospective case control study
was conducted. There were 23,382 infants born at three teaching hospitals in the metropolitan New York area from January 1992 to December 1994. Four hundred ninety-two infants met our entrance criteria. Criteria included a birth weight less than 750 g, survival to at least 7 days of life and at least one cranial ultrasound after 7 days of life.
Infants exposed to magnesium sulfate in utero were less likely to develop periventricular
leukomalacia. Two of 18 (11%) infants with periventricular leukomalacia were
exposed to magnesium sulfate in-utero compared to 14 of 36 controls (39%) (p =
0.035) (OR = 0.196, 95% Cl = 0.039-0.988). Pre-eclampsia as an independent factor
was not associated with a reduced risk (p = 0.251) (OR = 0.294, 95% Cl =
0.033-2.65). Preterm infants exposed to antenatal magnesium sulfate were found to
have a reduced risk of developing cystic periventricular leukomalacia.
Lo status materno di vitamina d influisce sulla crescita delle ossa nella pri...Merqurio
This prospective study followed 87 children from birth to 14 months to examine the impact of maternal vitamin D status during pregnancy on the children's bone growth. The children were divided into two groups based on their mother's vitamin D status during pregnancy. While postnatal vitamin D supplementation improved status in both groups, it only partly eliminated differences in bone variables induced during fetal development. Children in the lower prenatal vitamin D group had lower bone mineral content at birth but greater gains, resulting in similar levels at 14 months. Those in the higher prenatal group had a larger bone area at birth, and this difference persisted. Maternal vitamin D status during pregnancy thus influenced long-term bone development in offspring.
Thousands of genes evolved expression in the mammalian uterus during the evolution of pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. The researchers analyzed gene expression data from uterine/endometrial tissues of 14 species, including mammals, a reptile, bird, and frog. They found that over 2,000 genes gained expression in the uterus of early mammals compared to their ancestors. Many of these genes showed enriched expression in decidualized endometrial stromal cells, which differentiate during pregnancy to support fetal development. Ancient transposable elements likely contributed regulatory sequences that mediated the recruitment of these genes and the evolution of uterine gene networks important for pregnancy.
Level of 17-β Estradiol in follicular fluid for patient undergoes IVF as corr...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
Recupero di spermatozoi nella Sindrome di KlinefelterAdmin Esanum IT
This document summarizes fertility in men with Klinefelter syndrome. It discusses that:
1) Men with Klinefelter syndrome (47,XXY karyotype) typically show azoospermia, though sperm are rarely observed in ejaculate and exceptional spontaneous pregnancies have been reported.
2) With surgical sperm retrieval, sperm have been found in up to 56.7% of cases and used for successful pregnancies via ICSI.
3) There is a higher risk of chromosomal abnormalities in sperm and offspring due to the genetic nature of Klinefelter syndrome, including sex chromosome aneuploidies and increased autosomal aneuploidies.
1 testosterone levels in umbilical cord blood and risk of pyloric stenosispatricia brucellaria
This study examined the relationship between testosterone levels in umbilical cord blood and the risk of infantile hypertrophic pyloric stenosis. The researchers conducted a matched case-control study nested within the Danish National Birth Cohort. They found 46 cases of infantile hypertrophic pyloric stenosis in male infants and measured their umbilical cord blood testosterone levels, comparing them to 150 matched male controls. The study found no significant association between higher testosterone levels at birth and increased risk of infantile hypertrophic pyloric stenosis later in infancy.
This document discusses delayed cord clamping (DCC) versus immediate cord clamping (ICC) and umbilical cord milking (UCM). It notes that DCC allows more blood from the placenta to pass to the newborn, increasing blood volume. ICC results in about 30% of blood staying in the placenta. The document also discusses benefits of DCC such as reduced risk of iron deficiency, increased stem cells, and better outcomes for preterm infants. However, concerns with DCC include delays in resuscitation and risks of postpartum hemorrhage. The evidence and guidelines generally support DCC when possible over ICC or UCM.
Perinatal magnesium administration and the prevention of periventricular leuk...Ross Finesmith M.D.
This study examined the effect of magnesium sulfate (MgSO4) on the development of cystic periventricular leukomalacia (cPVL) in preterm infants. The researchers conducted a retrospective case-control study of 492 preterm infants born between 1992-1994 weighing less than 1750g who survived at least 7 days. They found infants exposed to MgSO4 in utero were less likely to develop cPVL. Specifically, 2 of 18 infants with cPVL were exposed to MgSO4 compared to 14 of 36 controls, indicating MgSO4 exposure is associated with a reduced risk of cPVL. Further analysis confirmed the groups were similar in other variables and preeclampsia alone did
Magnesium Prevents the Cerebral Palsy Precursor in Premature InfantsRoss Finesmith M.D.
To determine if magnesium sulfate has an effect on the development of cystic
periventricular leukomalacia in preterm infants, this retrospective case control study
was conducted. There were 23,382 infants born at three teaching hospitals in the metropolitan New York area from January 1992 to December 1994. Four hundred ninety-two infants met our entrance criteria. Criteria included a birth weight less than 750 g, survival to at least 7 days of life and at least one cranial ultrasound after 7 days of life.
Infants exposed to magnesium sulfate in utero were less likely to develop periventricular
leukomalacia. Two of 18 (11%) infants with periventricular leukomalacia were
exposed to magnesium sulfate in-utero compared to 14 of 36 controls (39%) (p =
0.035) (OR = 0.196, 95% Cl = 0.039-0.988). Pre-eclampsia as an independent factor
was not associated with a reduced risk (p = 0.251) (OR = 0.294, 95% Cl =
0.033-2.65). Preterm infants exposed to antenatal magnesium sulfate were found to
have a reduced risk of developing cystic periventricular leukomalacia.
Lo status materno di vitamina d influisce sulla crescita delle ossa nella pri...Merqurio
This prospective study followed 87 children from birth to 14 months to examine the impact of maternal vitamin D status during pregnancy on the children's bone growth. The children were divided into two groups based on their mother's vitamin D status during pregnancy. While postnatal vitamin D supplementation improved status in both groups, it only partly eliminated differences in bone variables induced during fetal development. Children in the lower prenatal vitamin D group had lower bone mineral content at birth but greater gains, resulting in similar levels at 14 months. Those in the higher prenatal group had a larger bone area at birth, and this difference persisted. Maternal vitamin D status during pregnancy thus influenced long-term bone development in offspring.
Thousands of genes evolved expression in the mammalian uterus during the evolution of pregnancy, including genes that mediate maternal-fetal communication and immunotolerance. The researchers analyzed gene expression data from uterine/endometrial tissues of 14 species, including mammals, a reptile, bird, and frog. They found that over 2,000 genes gained expression in the uterus of early mammals compared to their ancestors. Many of these genes showed enriched expression in decidualized endometrial stromal cells, which differentiate during pregnancy to support fetal development. Ancient transposable elements likely contributed regulatory sequences that mediated the recruitment of these genes and the evolution of uterine gene networks important for pregnancy.
Level of 17-β Estradiol in follicular fluid for patient undergoes IVF as corr...iosrjce
IOSR Journal of Dental and Medical Sciences is one of the speciality Journal in Dental Science and Medical Science published by International Organization of Scientific Research (IOSR). The Journal publishes papers of the highest scientific merit and widest possible scope work in all areas related to medical and dental science. The Journal welcome review articles, leading medical and clinical research articles, technical notes, case reports and others.
Efectos fetales de la anestesia espinal maternaAnestesia Dolor
1. Spinal anesthesia is commonly used for cesarean sections due to advantages for the mother such as remaining awake for the birth and facilitating post-op pain relief. However, hypotension is a common side effect that can pose risks to both mother and baby if severe or prolonged.
2. The review found that no single method completely prevents hypotension during spinal anesthesia for c-section but the risk can be reduced through IV fluids, vasopressors like ephedrine or phenylephrine, and leg compression. Even minor hypotension may cause issues for the baby like transient carbon dioxide retention.
3. Fetal oxygenation is dependent on several factors like placental function, uterine and umbilical blood
This document summarizes a review article about the lifecycle of polycystic ovary syndrome (PCOS) from early life through menopause. It finds that:
1) Daughters of women with PCOS show signs of an increased follicle count and mild metabolic abnormalities from infancy, suggesting early genetic and environmental influences.
2) PCOS is often diagnosed in puberty with the onset of hyperandrogenism and menstrual irregularities.
3) During the reproductive years, features of PCOS such as androgen levels and ovarian volume decrease over time, though cardiovascular risks persist after menopause for women who had PCOS.
Clinical presentation and giagnostic sopRolandoDiaz49
This document provides an overview of the clinical presentation and diagnosis of polycystic ovarian syndrome (PCOS). PCOS is a common endocrinopathy in reproductive-aged women, characterized by menstrual irregularities, infertility, hirsutism and obesity. The exact causes are unknown but involve abnormalities in gonadotropin secretion and ovarian function. Diagnosis requires two of three criteria - oligo/anovulation, clinical or biochemical signs of hyperandrogenism, and polycystic ovaries. PCOS presents challenges to diagnose in adolescents and perimenopausal women due to normal hormonal fluctuations during these stages of life.
L6-8.Disorders of the reproductive system.pptxDr Bilal Natiq
In the male, the testis serves two principal functions: synthesis of testosterone by the interstitial Leydig cells under the control of luteinising hormone (LH), and spermatogenesis by Sertoli cells under the control of follicle-stimulating hormone (FSH) (but also requiring adequate testosterone).
Diagnosis and Management of Congenital Adrenal Hyperplasia in the Child and A...Apollo Hospitals
Congenital adrenal hyperplasia is due to 21-hydroxylase deficiency in > 90% of cases. This is a very common
genetic disorder for which biochemical screening is now performed. The classical form occurs in 1:15,000–16,000
live births, while the nonclassical form occurs in 1:1000. Congenital adrenal hyperplasia is the most common cause
of primary adrenal insufficiency in childhood. Undertreatment of the condition leads to acute risk of adrenal crisis and to long-term risk of short adult stature and infertility, whereas overtreatment is associated with short stature, obesity and other effects of hypercortisolism, including, but not limited to, osteoporosis.
1. The document analyzes clinical signs seen on ultrasounds of fetuses suspected of having Osteogenesis Imperfecta (OI) and whether those signs correlate with mutations found in type 1 collagen genes (COL1A1 and COL1A2) after genetic testing.
2. Data from 31 fetuses showed that 53% had mutations in type 1 collagen genes confirming OI. 100% of those cases showed bowed long bones and multiple fractures on ultrasound.
3. The results suggest that fractures and bowed long bones are the most common clinical signs seen on ultrasound in fetuses later diagnosed with OI through genetic testing.
This document summarizes several studies related to preeclampsia and eclampsia. One study found that supplementing VEGF-121 helped reduce symptoms of preeclampsia in mice by promoting angiogenesis. Another study discovered higher levels of nephrin and podocalyxin in the urine of women with preeclampsia, suggesting these slit proteins were being shed from the kidneys allowing other proteins to pass through. A third study in mice found both genetic and environmental factors like diet contributed to the development of preeclampsia symptoms, demonstrating it has multifaceted causes. A final study examined cerebral autoregulation in women with preeclampsia versus healthy pregnancies to better understand the progression from preeclampsia to
This document summarizes several studies on factors related to bronchopulmonary dysplasia (BPD) in preterm infants. One study found that maternal smoking during pregnancy doubled the odds of BPD in infants, and was also associated with prolonged ventilation and late respiratory disease. Another study found that endothelial cell dysfunction in umbilical vein cells was associated with BPD or death in extremely preterm infants. A third study found that infants treated with caffeine in the neonatal period had better lung function at 11 years of age compared to placebo, mediated by caffeine's ability to reduce rates of BPD.
De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with...Apollo Hospitals
The common cause of mental impairment and the wide range of physical abnormalities is balanced chromosome rearrangement. As such, it is difficult to interpret, posing as a diagnostic challenge in human development. We present a unique case report with a denovo autosomal-balanced reciprocal translocation involving chromosomal regions 4q and 20q.The etiology of the translocation, i.e. 46,XX,t (4;20)(q28;q11) was detected by conventional high-resolution Giemsa-Trypsin-Giemsabanding technique. Parents non-consanguineous, with 2 healthy children. To the best of our knowledge this is the first case reported so far with the balanced reciprocal translocation involving 4q and 20q associated with the delayed milestone development.
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
This document summarizes a study investigating neuroepithelial/ependymal denudation in human fetuses with meningomyelocele (MMC, also known as spina bifida). The study found that neuroepithelial/ependymal denudation can occur before the development of hydrocephalus and Chiari II malformation. Specifically, the study observed neuroepithelial/ependymal denudation in the telencephalon and aqueduct of fetuses between 16-34 weeks gestation, even in the absence of hydrocephalus. Later in gestation between 37-40 weeks, neuroepithelial/ependymal denudation coincided with the presence of both hydro
Oral probiotics reduce the incidence and severity of necrotizingShirlye Cahuaya
This study evaluated the efficacy of probiotics in reducing necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. 367 VLBW infants were enrolled and randomized to receive either Infloran (Lactobacillus acidophilus and Bifidobacterium infantis) with breast milk or breast milk alone. The incidence of death or NEC (> stage 2) and NEC alone was significantly lower in the probiotics group compared to the control group. There were no cases of severe NEC (Bell stage 3) in the probiotics group. The incidence of culture-proven sepsis was also lower in the probiotics group. No adverse effects were observed with the
Oral probiotics reduce the incidence and severity of necrotizingmarlonluisf
This study evaluated the effectiveness of probiotics in reducing necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. 367 VLBW infants were randomly assigned to receive breast milk with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis or breast milk alone. The probiotic group had a significantly lower incidence of NEC and death compared to the control group. No adverse effects from the probiotics were observed. The probiotics were effective in reducing the incidence and severity of NEC in VLBW infants when administered with breast milk.
Early gestational alcohol exposure in mice alters hippocampal gene expression and DNA methylation, leading to changes in brain structure. The study found 23 genes and 3 microRNAs with altered expression in the hippocampus of adolescent offspring exposed to alcohol during early gestation. DNA methylation was also altered in CpG islands upstream of three candidate genes. Expression of two of these genes was also upregulated in the main olfactory epithelium and bone marrow of exposed offspring, supporting the hypothesis that early epigenetic changes affect multiple tissue types. Magnetic resonance imaging found asymmetries in brain structures of adult exposed offspring, including enlarged left hippocampus and smaller left olfactory bulb. The results suggest early alcohol exposure induces long-term epigenetic and
This study presents growth charts for Wolf-Hirschhorn syndrome (WHS) from birth to 4 years of age based on data from 101 children with WHS. The growth charts show severe growth retardation in WHS, with heights, weights, and head circumferences consistently below -3 to -4.5 standard deviations from normal growth charts. No catch-up growth was observed. The study recommends using these WHS-specific growth charts rather than standard charts to monitor growth and health in children with this rare genetic syndrome.
Puberty in girls is a period of profound biological, morphological, and psychological changes between childhood and adulthood that leads to maturity and fertility. Key changes include breast development, pubic and underarm hair growth, increased height, and menstruation occurring between ages 10-16 with peak onset at 13 years. Precocious puberty refers to signs of secondary sex characteristics before age 8 or menstruation before 10. It can be central, involving normal progression of puberty starting too soon, or peripheral, caused by excess sex hormones from problems in ovaries, adrenal glands or pituitary gland. Diagnosis involves assessing growth, bone age, hormone levels and ruling out tumors or other lesions. Prognosis is generally good with
This study aimed to evaluate predictors of umbilical artery acidemia in term neonates with low 5-minute Apgar scores. The researchers analyzed data from over 27,000 term singleton births over a 13-year period. They identified 94 neonates with 5-minute Apgar scores under 7, of which 33 showed evidence of umbilical artery acidemia. Logistic regression found that intrauterine vascular disease was independently associated with umbilical artery acidemia, whereas intrauterine infection and acute intrapartum events were not significantly associated. Umbilical artery acidemia was present in 38% of term babies with low Apgar scores, and was predominantly linked to chronic antepartum vascular problems
Recent Trends in Pubertal Timing and Current Management of Precocious Puberty...Apollo Hospitals
Precocious puberty is defined as the development of pubertal signs at a younger age than the accepted lower limits for the onset of puberty. In girls, breast development before the age of 8 years, appearance of sexual pubic hair before the age of 8 years or beginning menses before the age of 9.5 years is traditionally considered as precocious puberty. This is accompanied by rapid growth rate, advanced skeletal maturation and increased levels of gonadotropins and/or sex steroids.
Problem 1
Problem 2 (two screen shots)
Problem 3 (two screen shots)
Problem 4 (three screen shots)
Problem 5 (one screen shot)
Problem 6 (six screenshots plus a data table)
.
Problem 20-1A Production cost flow and measurement; journal entrie.docxChantellPantoja184
Problem 20-1A Production cost flow and measurement; journal entries L.O. P1, P2, P3, P4
[The following information applies to the questions displayed below.]
Edison Company manufactures wool blankets and accounts for product costs using process costing. The following information is available regarding its May inventories.
Beginning
Inventory
Ending
Inventory
Raw materials inventory
$
60,000
$
41,000
Goods in process inventory
449,000
521,500
Finished goods inventory
610,000
342,001
The following additional information describes the company's production activities for May.
Raw materials purchases (on credit)
$
250,000
Factory payroll cost (paid in cash)
1,850,300
Other overhead cost (Other Accounts credited)
82,000
Materials used
Direct
$
200,500
Indirect
50,000
Labor used
Direct
$
1,060,300
Indirect
790,000
Overhead rate as a percent of direct labor
115
%
Sales (on credit)
$
3,000,000
The predetermined overhead rate was computed at the beginning of the year as 115% of direct labor cost.
\\\\\
rev: 11_02_2011
references
1.
value:
2.00 points
Problem 20-1A Part 1
Required:
1(a)
Compute the cost of products transferred from production to finished goods. (Omit the "$" sign in your response.)
Cost of products transferred
$
1(b)
Compute the cost of goods sold. (Omit the "$" sign in your response.)
Cost of goods sold
$
rev: 10_31_2011
check my workeBook Links (4)references
2.
value:
5.00 points
Problem 20-1A Part 2
2(a)
Prepare journal entry dated May 31 to record the raw materials purchases. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(b)
Prepare journal entry dated May 31 to record the direct materials usage. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(c)
Prepare journal entry dated May 31 to record the indirect materials usage. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(d)
Prepare journal entry dated May 31 to record the payroll costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(e)
Prepare journal entry dated May 31 to record the direct labor costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(f)
Prepare journal entry dated May 31 to record the indirect labor costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(g)
Prepare journal entry dated May 31 to record the other overhead costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(h)
Prepare journal entry dated May 31 to record the overhead applied. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(i)
Prepare journal entry dated May 31 to record the goods transferred from production to finished goods.(Omit the "$" sign in yo.
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3. The results suggest that fractures and bowed long bones are the most common clinical signs seen on ultrasound in fetuses later diagnosed with OI through genetic testing.
This document summarizes several studies related to preeclampsia and eclampsia. One study found that supplementing VEGF-121 helped reduce symptoms of preeclampsia in mice by promoting angiogenesis. Another study discovered higher levels of nephrin and podocalyxin in the urine of women with preeclampsia, suggesting these slit proteins were being shed from the kidneys allowing other proteins to pass through. A third study in mice found both genetic and environmental factors like diet contributed to the development of preeclampsia symptoms, demonstrating it has multifaceted causes. A final study examined cerebral autoregulation in women with preeclampsia versus healthy pregnancies to better understand the progression from preeclampsia to
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De novo reciprocal translocation t(4;20) (q28;q11) associated in a child with...Apollo Hospitals
The common cause of mental impairment and the wide range of physical abnormalities is balanced chromosome rearrangement. As such, it is difficult to interpret, posing as a diagnostic challenge in human development. We present a unique case report with a denovo autosomal-balanced reciprocal translocation involving chromosomal regions 4q and 20q.The etiology of the translocation, i.e. 46,XX,t (4;20)(q28;q11) was detected by conventional high-resolution Giemsa-Trypsin-Giemsabanding technique. Parents non-consanguineous, with 2 healthy children. To the best of our knowledge this is the first case reported so far with the balanced reciprocal translocation involving 4q and 20q associated with the delayed milestone development.
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
This document summarizes a study investigating neuroepithelial/ependymal denudation in human fetuses with meningomyelocele (MMC, also known as spina bifida). The study found that neuroepithelial/ependymal denudation can occur before the development of hydrocephalus and Chiari II malformation. Specifically, the study observed neuroepithelial/ependymal denudation in the telencephalon and aqueduct of fetuses between 16-34 weeks gestation, even in the absence of hydrocephalus. Later in gestation between 37-40 weeks, neuroepithelial/ependymal denudation coincided with the presence of both hydro
Oral probiotics reduce the incidence and severity of necrotizingShirlye Cahuaya
This study evaluated the efficacy of probiotics in reducing necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. 367 VLBW infants were enrolled and randomized to receive either Infloran (Lactobacillus acidophilus and Bifidobacterium infantis) with breast milk or breast milk alone. The incidence of death or NEC (> stage 2) and NEC alone was significantly lower in the probiotics group compared to the control group. There were no cases of severe NEC (Bell stage 3) in the probiotics group. The incidence of culture-proven sepsis was also lower in the probiotics group. No adverse effects were observed with the
Oral probiotics reduce the incidence and severity of necrotizingmarlonluisf
This study evaluated the effectiveness of probiotics in reducing necrotizing enterocolitis (NEC) in very low birth weight (VLBW) infants. 367 VLBW infants were randomly assigned to receive breast milk with the probiotics Lactobacillus acidophilus and Bifidobacterium infantis or breast milk alone. The probiotic group had a significantly lower incidence of NEC and death compared to the control group. No adverse effects from the probiotics were observed. The probiotics were effective in reducing the incidence and severity of NEC in VLBW infants when administered with breast milk.
Early gestational alcohol exposure in mice alters hippocampal gene expression and DNA methylation, leading to changes in brain structure. The study found 23 genes and 3 microRNAs with altered expression in the hippocampus of adolescent offspring exposed to alcohol during early gestation. DNA methylation was also altered in CpG islands upstream of three candidate genes. Expression of two of these genes was also upregulated in the main olfactory epithelium and bone marrow of exposed offspring, supporting the hypothesis that early epigenetic changes affect multiple tissue types. Magnetic resonance imaging found asymmetries in brain structures of adult exposed offspring, including enlarged left hippocampus and smaller left olfactory bulb. The results suggest early alcohol exposure induces long-term epigenetic and
This study presents growth charts for Wolf-Hirschhorn syndrome (WHS) from birth to 4 years of age based on data from 101 children with WHS. The growth charts show severe growth retardation in WHS, with heights, weights, and head circumferences consistently below -3 to -4.5 standard deviations from normal growth charts. No catch-up growth was observed. The study recommends using these WHS-specific growth charts rather than standard charts to monitor growth and health in children with this rare genetic syndrome.
Puberty in girls is a period of profound biological, morphological, and psychological changes between childhood and adulthood that leads to maturity and fertility. Key changes include breast development, pubic and underarm hair growth, increased height, and menstruation occurring between ages 10-16 with peak onset at 13 years. Precocious puberty refers to signs of secondary sex characteristics before age 8 or menstruation before 10. It can be central, involving normal progression of puberty starting too soon, or peripheral, caused by excess sex hormones from problems in ovaries, adrenal glands or pituitary gland. Diagnosis involves assessing growth, bone age, hormone levels and ruling out tumors or other lesions. Prognosis is generally good with
This study aimed to evaluate predictors of umbilical artery acidemia in term neonates with low 5-minute Apgar scores. The researchers analyzed data from over 27,000 term singleton births over a 13-year period. They identified 94 neonates with 5-minute Apgar scores under 7, of which 33 showed evidence of umbilical artery acidemia. Logistic regression found that intrauterine vascular disease was independently associated with umbilical artery acidemia, whereas intrauterine infection and acute intrapartum events were not significantly associated. Umbilical artery acidemia was present in 38% of term babies with low Apgar scores, and was predominantly linked to chronic antepartum vascular problems
Recent Trends in Pubertal Timing and Current Management of Precocious Puberty...Apollo Hospitals
Precocious puberty is defined as the development of pubertal signs at a younger age than the accepted lower limits for the onset of puberty. In girls, breast development before the age of 8 years, appearance of sexual pubic hair before the age of 8 years or beginning menses before the age of 9.5 years is traditionally considered as precocious puberty. This is accompanied by rapid growth rate, advanced skeletal maturation and increased levels of gonadotropins and/or sex steroids.
Similar to Best Practice & Research Clinical Endocrinology & Metabolism 2 (20)
Problem 1
Problem 2 (two screen shots)
Problem 3 (two screen shots)
Problem 4 (three screen shots)
Problem 5 (one screen shot)
Problem 6 (six screenshots plus a data table)
.
Problem 20-1A Production cost flow and measurement; journal entrie.docxChantellPantoja184
Problem 20-1A Production cost flow and measurement; journal entries L.O. P1, P2, P3, P4
[The following information applies to the questions displayed below.]
Edison Company manufactures wool blankets and accounts for product costs using process costing. The following information is available regarding its May inventories.
Beginning
Inventory
Ending
Inventory
Raw materials inventory
$
60,000
$
41,000
Goods in process inventory
449,000
521,500
Finished goods inventory
610,000
342,001
The following additional information describes the company's production activities for May.
Raw materials purchases (on credit)
$
250,000
Factory payroll cost (paid in cash)
1,850,300
Other overhead cost (Other Accounts credited)
82,000
Materials used
Direct
$
200,500
Indirect
50,000
Labor used
Direct
$
1,060,300
Indirect
790,000
Overhead rate as a percent of direct labor
115
%
Sales (on credit)
$
3,000,000
The predetermined overhead rate was computed at the beginning of the year as 115% of direct labor cost.
\\\\\
rev: 11_02_2011
references
1.
value:
2.00 points
Problem 20-1A Part 1
Required:
1(a)
Compute the cost of products transferred from production to finished goods. (Omit the "$" sign in your response.)
Cost of products transferred
$
1(b)
Compute the cost of goods sold. (Omit the "$" sign in your response.)
Cost of goods sold
$
rev: 10_31_2011
check my workeBook Links (4)references
2.
value:
5.00 points
Problem 20-1A Part 2
2(a)
Prepare journal entry dated May 31 to record the raw materials purchases. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(b)
Prepare journal entry dated May 31 to record the direct materials usage. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(c)
Prepare journal entry dated May 31 to record the indirect materials usage. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(d)
Prepare journal entry dated May 31 to record the payroll costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(e)
Prepare journal entry dated May 31 to record the direct labor costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(f)
Prepare journal entry dated May 31 to record the indirect labor costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(g)
Prepare journal entry dated May 31 to record the other overhead costs. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(h)
Prepare journal entry dated May 31 to record the overhead applied. (Omit the "$" sign in your response.)
Date
General Journal
Debit
Credit
May 31
2(i)
Prepare journal entry dated May 31 to record the goods transferred from production to finished goods.(Omit the "$" sign in yo.
Problem 2 Obtain Io.Let x be the current through j2, ..docxChantellPantoja184
Problem 2: Obtain Io.
Let x be the current through j2, .
Let .
.
.
.
………..1.
…………2.
.
.
…………3.
……………….4.
Solving these 4 equations we can get .
.
Problem 1:Find currents I1, I2, and I3
Problem 2: Obtain Io
Problem 3:Obtain io
.
Problem 1On April 1, 20X4, Rojas purchased land by giving $100,000.docxChantellPantoja184
Problem 1On April 1, 20X4, Rojas purchased land by giving $100,000 in cash and executing a $400,000 note payable to the former owner. The note bears interest at 10% per annum, with interest being payable annually on March 31 of each year. Rojas is also required to make a $100,000 payment toward the note's principal on every March 31.(a)Prepare the appropriate journal entry to record the land purchase on April 1, 20X4.(b)Prepare the appropriate journal entry to record the year-end interest accrual on December 31, 20X4.(c)Prepare the appropriate journal entry to record the payment of interest and principal on March 31, 20X5.(d)Prepare the appropriate journal entry to record the year-end interest accrual on December 31, 20X5.(e)Prepare the appropriate journal entry to record the payment of interest and principal on March 31, 20X6.
&R&"Myriad Web Pro,Bold"&20B-13.01
B-13.01
Worksheet 1(a), (b), (c), (d), (e)GENERAL JOURNALDateAccountsDebitCredit04-01-X412-31-X403-31-X512-31-X503-31-X6
&L&"Myriad Web Pro,Bold"&12Name:
Date: Section: &R&"Myriad Web Pro,Bold"&20B-13.01
B-13.01
Problem 2Ace Brick company issued $100,000 of 5-year bonds. The bonds were issued at par on January 1, 20X1, and bear interest at a rate of 8% per annum, payable semiannually.(a)Prepare the journal entry to record the bond issue on January, 20X1.(b)Prepare the journal entry that Ace would record on each interest date.(c)Prepare the journal entry that Ace would record at maturity of the bonds.
&R&"Myriad Web Pro,Bold"&20B-13.06
B-13.06
Worksheet 2(a)(b)(c)GENERAL JOURNAL DateAccountsDebitCreditIssueInterestMaturity
&L&"Myriad Web Pro,Bold"&12Name:
Date: Section: &R&"Myriad Web Pro,Bold"&20B-13.06
B-13.06
Problem 3Erik Food Supply Company issued $100,000 of face amount of 4-year bonds on January 1, 20X1. The bonds were issued at 98, and bear interest at a stated rate of 8% per annum, payable semiannually. The discount is amortized by the straight-line method.(a)Prepare the journal entry to record the initial issuance on January, 20X1.(b)Prepare the journal entry that Erik would record on each interest date.(c)Prepare the journal entry that Erik would record at maturity of the bonds.
&R&"Myriad Web Pro,Bold"&20B-13.08
B-13.08
Worksheet 3(a)(b)(c)GENERAL JOURNAL DateAccountsDebitCreditIssueInterestMaturity
&L&"Myriad Web Pro,Bold"&12Name:
Date: Section: &R&"Myriad Web Pro,Bold"&20B-13.08
B-13.08
Problem 4Horton Micro Chip Company issued $100,000 of face amount of 6-year bonds on January 1, 20X1. The bonds were issed at 103, and bear interest at a stated rate of 8% per annum, payable semiannually. The premium is amortized by the straight-line method.(a)Prepare the journal entry to record the initial issue on January, 20X1.(b)Prepare the journal entry that Horton would record on each interest date.(c)Prepare the journal entry that Horton would record at maturity of the bonds.
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Problem 17-1 Dividends and Taxes [LO2]Dark Day, Inc., has declar.docxChantellPantoja184
Problem 17-1 Dividends and Taxes [LO2]
Dark Day, Inc., has declared a $5.60 per share dividend. Suppose capital gains are not taxed, but dividends are taxed at 15 percent. New IRS regulations require that taxes be withheld at the time the dividend is paid. Dark Day sells for $94.10 per share, and the stock is about to go ex-dividend.
What do you think the ex-dividend price will be? (Round your answer to 2 decimal places. (e.g., 32.16))
Ex-dividend price
$
Problem 17-2 Stock Dividends [LO3]
The owners’ equity accounts for Alexander International are shown here:
Common stock ($0.60 par value)
$
45,000
Capital surplus
340,000
Retained earnings
748,120
Total owners’ equity
$
1,133,120
a-1
If Alexander stock currently sells for $30 per share and a 10 percent stock dividend is declared, how many new shares will be distributed?
New shares issued
a-2
Show how the equity accounts would change.
Common stock
$
Capital surplus
Retained earnings
Total owners’ equity
$
b-1
If instead Alexander declared a 20 percent stock dividend, how many new shares will be distributed?
New shares issued
b-2
Show how the equity accounts would change. (Negative amount should be indicated by a minus sign.)
Common stock
$
Capital surplus
Retained earnings
Total owners’ equity
$
Problem 17-3 Stock Splits [LO3]
The owners' equity accounts for Alexander International are shown here.
Common stock ($0.50 par value)
$
35,000
Capital surplus
320,000
Retained earnings
708,120
Total owners’ equity
$
1,063,120
a-1
If Alexander declares a five-for-one stock split, how many shares are outstanding now?
New shares outstanding
a-2
What is the new par value per share? (Round your answer to 3 decimal places. (e.g., 32.161))
New par value
$ per share
b-1
If Alexander declares a one-for-seven reverse stock split, how many shares are outstanding now?
New shares outstanding
b-2
What is the new par value per share? (Round your answer to 2 decimal places. (e.g., 32.16))
New par value
$ per share
Problem 17-4 Stock Splits and Stock Dividends [LO3]
Red Rocks Corporation (RRC) currently has 485,000 shares of stock outstanding that sell for $40 per share. Assuming no market imperfections or tax effects exist, what will the share price be after:
a.
RRC has a four-for-three stock split? (Round your answer to 2 decimal places. (e.g., 32.16))
New share price
$
b.
RRC has a 15 percent stock dividend? (Round your answer to 2 decimal places. (e.g., 32.16))
New share price
$
c.
RRC has a 54.5 percent stock dividend? (Round your answer to 2 decimal places. (e.g., 32.16))
New share price
$
d.
RRC has a two-for-seven reverse stock split? (Round your answer to 2 decimal places. (e.g., 32.16))
New share price
$
Determine the new number of shares outstanding in parts (a) through (d).
a.
New shares outstanding
b.
New shares o.
Problem 1Problem 1 - Constant-Growth Common StockWhat is the value.docxChantellPantoja184
Problem 1Problem 1 - Constant-Growth Common StockWhat is the value of a common stock if the firm's earnings and dividends are growing annually at 10%, the current dividend is $1.32,and investors require a 15% return on investment?What is the stock's rate of return if the market price of the stock is $35?
Problem 2Problem 2 - Preferred Stock Price and ReturnA firm has preferred stock outstanding with a $1,000 par value and a $40 annual dividend with no maturity. If the required rate of return is 9%, what is the price of the preferred stock?The market price of a firm's preferred stock is $24 and pays an annual dividend of $2.50. If the stock's par value is $1,000 and it has no maturity, what is the return on the preferred stock?
Problem 3Problem 3 - Bond Valuation and YieldA bond has a par value of $1,000, pays $50 semiannually and has a maturity of 10 years.If the bond earns 12% per year, what is the price of the bond?RateNperPMTFVTypePVWhat is the yield to maturity for the bond?NperPMTPVFVTypeRateWhat would be the bond's price if the rate earned declined to 8% per year?RateNperPMTFVTypePVIf the maturity period is reduced to 5 years and the required rate of return is 8%, what would be the price of the bond?RateNperPMTFVTypePVWhat is the yield to maturity for the bond when the maturity is 5 years and the required rate of return is 8%?NperPMTPVFVTypeRateWhat generalizations about bond prices, interest rates and maturity periods can be made based on the calculations made above?
Problem 4Problem 4 - Callable BondsThe following bonds have a par value of $1,000 and the required rate of return is 10%.Bond XY: 5¼ percent coupon, with interest paid annually for 20 yearsBond AB: 14 percent coupon, with interest paid annually for 20 yearsWhat is each bond's current market price?Bond XYBond ABRateNperPMTFVTypePVIf current interest rates are 9%, which bond would you expect to be called? Explain.
Exercise 10-5
During the month of March, Olinger Company’s employees earned wages of $69,500. Withholdings related to these wages were $5,317 for Social Security (FICA), $8,145 for federal income tax, $3,366 for state income tax, and $434 for union dues. The company incurred no cost related to these earnings for federal unemployment tax but incurred $760 for state unemployment tax.
Prepare the necessary March 31 journal entry to record salaries and wages expense and salaries and wages payable. Assume that wages earned during March will be paid during April. (Credit account titles are automatically indented when amount is entered. Do not indent manually.)
Date
Account Titles and Explanation
Debit
Credit
Mar. 31
SHOW LIST OF ACCOUNTS
LINK TO TEXT
Prepare the entry to record the company’s payroll tax expense. (Credit account titles are automatically indented when amount is entered. Do not indent manually.)
Date
Account Titles and Explanation
Debit
Credit
Mar. 31
===========================================
E.
Problem 1Prescott, Inc., manufactures bookcases and uses an activi.docxChantellPantoja184
Problem 1Prescott, Inc., manufactures bookcases and uses an activity-based costing system. Prescott's activity areas and related data follows:ActivityBudgeted Cost
of ActivityAllocation BaseCost Allocation
RateMaterials handling$230,000Number of parts$0.50Assembly3,200,000Direct labor hours16.00Finishing180,000Number of finished
units4.50Prescott produced two styles of bookcases in October: the standard bookcase and an unfinished bookcase, which has fewer parts and requires no finishing. The totals for quantities, direct
materials costs, and other data follow:ProductTotal Units
ProducedTotal Direct
Materials CostsTotal Direct
Labor CostsTotal Number
of PartsTotal Assembling
Direct Labor HoursStandard bookcase3,000$36,000$45,0009,0004,500Unfinished bookcase3,50035,00035,0007,0003,500Requirements:1. Compute the manufacturing product cost per unit of each type of bookcase.2. Suppose that pre-manufacturing activities, such as product design, were assigned to the standard bookcases at $7 each, and to the unfinished bookcases at $2 each. Similar analyses
were conducted of post-manufacturing activities such as distribution, marketing, and customer service. The post-manufacturing costs were $22 per standard bookcase and $14 per
unfinished bookcase. Compute the full product costs per unit.3. Which product costs are reported in the external financial statements? Which costs are used for management decision making? Explain the difference.4. What price should Prescott's managers set for unfinished bookcases to earn $15 per bookcase?
Problem 2Corbertt Pharmaceuticals manufactures an over-the-counter allergy medication. The company sells both large commercial containers of 1,000 capsules to health-care facilities
and travel packs of 20 capsules to shops in airports, train stations, and hotels. The following information has been developed to determine if an activity-based costing system
would be beneficial:ActivityEstimated Indirect Activity
CostsAllocation BaseEstimated Quantity of
Allocation BaseMaterials handling$95,000Kilos19,000 kilosPackaging219,000Machine hours5,475 hoursQuality assurance124,500Samples2,075 samplesTotal indirect costs$438,500Other production information includes the following:Commercial ContainersTravel PacksUnits produced3,500 containers57,000 packsWeight in kilos14,0005,700Machine hours2,625570Number of samples700855Requirements:1. Compute the cost allocation rate for each activity.2. Use the activity-based cost allocation rates to compute the activity costs per unit of the commercial containers and the travel packs. (Hint: First compute the total activity
cost allocated to each product line, and then compute the cost per unit.)3. Corbertt's original single-allocation-base costing system allocated indirect costs to produce at $157 per machine hour. Compute the total indirect costs allocated to the
commercial containers and to the travel packs under the original system. Then compute the indirect cost per unit for ea.
Problem 1Preston Recliners manufactures leather recliners and uses.docxChantellPantoja184
Problem 1Preston Recliners manufactures leather recliners and uses flexible budgeting and a standard cost system. Preston allocates overhead based on yards of direct materials. The company's performance report includes the following selected data:Static Budget
(1,000 recliners)Actual Results
(980 recliners)Sales (1,000 recliners X $495)$495,000 (980 recliners X $475)$465,500Variable manufacturing costs: Direct materials (6,000 yds @ $8.80/yard)52,800 (6,150 yds @ $8.60/yard)52,890 Direct labor (10,000 hrs @ $9.20/hour)92,000 (9,600 hrs @ $9.30/hour)89,280Variable overhead (6,000 yds @ $5.00/yard)30,000 (6,510 yds @ $6.40/yard)39,360Fixed manufacturing costs: Fixed overhead60,00062,000Total cost of goods sold$234,800$243,530Gross profit$260,200$221,970Requirements:1. Prepare a flexible budget based on the actual number of recliners sold.2. Compute the price variance and the efficiency variance for direct materials and for direct labor. For manufacturing overhead, compute the variable overhead spending, variable overhead efficiency, fixed overhead spending, and fixed overhead volume variances.3. Have Preston's managers done a good job or a poor job controlling materials, labor, and overhead costs? Why?4. Describe how Preston's managers can benefit from the standard costing system.
Problem 2AllTalk Technologies manufactures capacitors for cellular base stations and other communications applications. The company's January 2012 flexible budget income statement shows output levels of 6,500, 8,000, and 10,000 units. The static budget was based on expected sales of 8,000 units.ALLTALK TECHNOLOGIES
Flexible Budget Income Statement
Month Ended January 31, 2012Per UnitBy Units (Capacitors)6,5008,00010,000Sales revenue$24$156,000$192,000$240,000Variable expenses$1065,00080,000100,000Contribution margin$91,000$112,000$140,000Fixed expenses53,00053,00053,000Operating income$38,000$59,000$87,000The company sold 10,000 units during January, and its actual operating income was as follows:ALLTALK TECHNOLOGIES
Income Statement
Month Ended January 31, 2012Sales revenue$246,000Variable expenses104,500Contribution margin$141,500Fixed expenses54,000Operating income$87,500Requirements:1. Prepare an income statement performance report for January.2. What was the effect on AllTalk's operating income of selling 2,000 units more than the static budget level of sales?3. What is AllTalk's static budget variance? Explain why the income statement performance report provides more useful information to AllTalk's managers than the simple static budget variance. What insights can AllTalk's managers draw from this performance report?
Problem 3Java manufacturers coffee mugs that it sells to other companies for customizing with their own logos. Java prepares flexible budgets and uses a standard cost system to control manufacturing costs. The standard unit.
Problem 1Pro Forma Income Statement and Balance SheetBelow is the .docxChantellPantoja184
Problem 1Pro Forma Income Statement and Balance SheetBelow is the income statement and balance sheet for Blue Bill Corporation for 2013. Based on the historical statements and theadditional information provided, construct the firm's pro forma income statement and balance sheet for 2014.Blue Bill CorporationIncome StatementFor the year ended 2013Projected201220132014Revenue$60,000$63,000Cost of goods sold42,00044,100Gross margin18,00018,900SG&A expense6,0006,300Depreciation expense1,8002,000Earnings Before Interest and Taxes (EBIT)10,20010,600Interest expense1,5001,800Taxable income8,7008,800Income Tax Expense3,0453,080Net income5,6555,720Dividends750800To retained earnings$4,905$4,920Additional income statement information:Sales will increase by 5% in 2014 from 2013 levels.COGS and SG&A will be the average percent of sales for the last 2 years.Depreciation expense will increase to $2,200.Interest expense will be $1,900.The tax rate is 35%.Dividend payout will increase to $850.Blue Bill CorporationBalance SheetDecember 31, 2013Projected20132014Current assetsCash$8,000Accounts receivable3,150Inventory9,450Total current assets20,600Property, plant, and equipment (PP&E)28,500Accumulated depreciation16,400Net PP&E12,100Total assets$32,700Current liabilitesAccounts payable$3,780Bank loan (10%)3,200Other current liabilities1,250Total current liabilities8,230Long-term debt (12%)4,800Common stock1,250Retained earnings18,420Total liabilities and equity$32,700Additional balance sheet information:The minimum cash balance is 12% of sales.Working capital accounts (accounts receivable, accounts payable, and inventory) will be the same percent of sales in 2014 as they were in 2013.$8,350 of new PP&E will be purchased in 2014.Other current liabilities will be 3% of sales in 2014.There will be no changes in the common stock or long-term debt accounts.The plug figure (the last number entered that makes the balance sheet balance) is bank loan.
1
Rough Draft
Rough Draft
Rasmussen College
Metro Dental Care is a dental office that provides affordable, convenient, and high quality of care to patients. As a patient at Metro, I personally believe that Metro Dental Care is one of the best dental clinics around, and that’s why I have chosen this company. Metro Dental Care measures their results by recording patient satisfaction.
Managing financial reports, and the quality of service they provide to their customers. Furthermore, the dentists and staff at Metro Dental Care know how important your smile is. Their mission statement states “We pride ourselves in making your smile look great so you not only look good, but feel confident with your smile.”
Metro Dental Care offers convenience for their patients with more than 40 offices throughout the Minneapolis and St. Paul metro area offering flexible hours including early morning, evening and Saturday appointments. Whether you work or live Metro Dental Care has a location near you. Metro Dental .
Problem 2-1PROBLEM 2-1Solution Legend= Value given in problemGiven.docxChantellPantoja184
This document provides a solution to Problem 2-1. It begins by listing the values given in the problem statement. The document then likely shows the step-by-step work and calculations to arrive at the solution for Problem 2-1, ending with the final answer.
PROBLEM 14-6AProblem 14-6A Norwoods Borrowings1. Total amount of .docxChantellPantoja184
PROBLEM 14-6AProblem 14-6A: Norwoods Borrowings1. Total amount of each installment payment.Present value of an ordinary annuity$200,000Interest per period(i)0.08Number of periods(n)5Total amount of each installment payment($50,091.29)Therefore the total amount of each installment payment is $ 50,091.292.Norwoods Amortization TablePeriod Ending DateBeginning balance Interest expenseNotes PayableCash paymentEnding Balance10/31/15$200,000.00$16,000.00$34,091.29$50,091.29$165,908.7110/31/16$165,909.00$13,272.72$36,818.57$50,091.29$129,090.4310/31/17$129,090.43$10,327.23$39,764.06$50,091.29$89,326.3710/31/18$89,326.37$7,146.11$42,945.18$50,091.29$46,381.1910/31/19$46,381.19$3,710.50$46,380.79$50,091.29$0.403.a) Accrued interest as December 31st 2015Accrued interest expense = $200,000*8%*2/12= $2,666.67. Thus the journal entry is as shown below:DescriptionDr($)Cr($)interest expense $2,666.67 Interest payable $2,666.67b) The first annual payment on the note.Ten more months of interest has accrued $200,000*8%*10/12 =$13,333.33 accrued interest .Therefore the journal entry is as shown below:DescriptionDr($)Cr($)Notes payable$34,091.29interest expense$13,333.33interest payable$2,666.67 Cash$50,091.29
PROBLEM 14-7AProblem 14-7AQuestion 1a) Debt to equity ratiosPulaski CompanyScott Company Total liabilities$360,000.00$240,000.00Total Equity$500,000.00$200,000.00Debt-Equity Ratio0.721.2Question 2The debt to equity ratio measures the amount of debt a company uses has to finance its business for every dollar of equity it has. A higher debt to equity ratio implies that a company uses more debt than equity for financing. In this case, the debt to equity ratio for Pulaski Company is 0.72 which is less than 1 implying that the stockholder's equity exceeds the amount of debt borrowed. Thus Pulaski Company may not likely suffer from risks brought about by huge amount of debts in the capital structure. On the other hand, the debt to equity ratio of Scott Company is 1.2 which is greater than 1 implying that the debt exceeds the totalamount stockholders equity. Huge debts is associated with a lot of risks. First, there is the risk of defaulting whereby the company may be unable to repay its debt and therefore leading to bankruptcy. Second, a company may find it difficult to obtain additional funding from creditors.This is because the creditors prefer companies with low debt to equity ratio. Finally, there is the risks of violating the debt covenants. A covenant is an agreement that requires a company to maintain adequate financial ratio levels. Too much borrowings may violate this covenant. Since ScottCompany has a higher debt to equity ratio, it may experience these risks which may eventually lead to the company being declared bankrupt .
PROBLEM 14-6BProblem 14-6B: Gordon Enterprises Borrowings1. Total amount of each installment payment.Present value of an ordi.
Problem 13-3AThe stockholders’ equity accounts of Ashley Corpo.docxChantellPantoja184
Problem 13-3A
The stockholders’ equity accounts of Ashley Corporation on January 1, 2012, were as follows.
Preferred Stock (8%, $49 par, cumulative, 10,200 shares authorized)
$ 387,100
Common Stock ($1 stated value, 1,937,100 shares authorized)
1,408,700
Paid-in Capital in Excess of Par—Preferred Stock
123,200
Paid-in Capital in Excess of Stated Value—Common Stock
1,496,800
Retained Earnings
1,814,400
Treasury Stock (10,300 common shares)
51,500
During 2012, the corporation had the following transactions and events pertaining to its stockholders’ equity.
Feb. 1
Issued 24,100 shares of common stock for $123,900.
Apr. 14
Sold 6,000 shares of treasury stock—common for $33,800.
Sept. 3
Issued 5,100 shares of common stock for a patent valued at $35,700.
Nov. 10
Purchased 1,100 shares of common stock for the treasury at a cost of $5,700.
Dec. 31
Determined that net income for the year was $456,600.
No dividends were declared during the year.
(a)
Journalize the transactions and the closing entry for net income. (Credit account titles are automatically indented when amount is entered. Do not indent manually.)
Date
Account Titles and Explanation
Debit
Credit
Feb. 1
Apr. 14
Sept. 3
Nov. 10
Dec. 31
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Problem 12-9AYour answer is partially correct. Try again..docxChantellPantoja184
Problem 12-9A
Your answer is partially correct. Try again.
Condensed financial data of Odgers Inc. follow.
ODGERS INC.Comparative Balance Sheets
December 31
Assets
2014
2013
Cash
$ 131,704
$ 78,892
Accounts receivable
143,114
61,940
Inventory
183,375
167,646
Prepaid expenses
46,292
42,380
Long-term investments
224,940
177,670
Plant assets
464,550
395,275
Accumulated depreciation
(81,500
)
(84,760
)
Total
$1,112,475
$839,043
Liabilities and Stockholders’ Equity
Accounts payable
$ 166,260
$ 109,699
Accrued expenses payable
26,895
34,230
Bonds payable
179,300
237,980
Common stock
358,600
285,250
Retained earnings
381,420
171,884
Total
$1,112,475
$839,043
ODGERS INC.Income Statement Data
For the Year Ended December 31, 2014
Sales revenue
$633,190
Less:
Cost of goods sold
$220,800
Operating expenses, excluding depreciation
20,228
Depreciation expense
75,795
Income tax expense
44,466
Interest expense
7,710
Loss on disposal of plant assets
12,225
381,224
Net income
$ 251,966
Additional information:
1.
New plant assets costing $163,000 were purchased for cash during the year.
2.
Old plant assets having an original cost of $93,725 and accumulated depreciation of $79,055 were sold for $2,445 cash.
3.
Bonds payable matured and were paid off at face value for cash.
4.
A cash dividend of $42,430 was declared and paid during the year.
Prepare a statement of cash flows using the indirect method. (Show amounts that decrease cash flow with either a - sign e.g. -15,000 or in parenthesis e.g. (15,000).)
ODGERS INC.Statement of Cash Flows
For the Year Ended December 31, 2014
$
Adjustments to reconcile net income to
$
$
Problem 12-10A
Condensed financial data of Odgers Inc. follow.
ODGERS INC.Comparative Balance Sheets
December 31
Assets
2014
2013
Cash
$ 151,904
$ 90,992
Accounts receivable
165,064
71,440
Inventory
211,500
193,358
Prepaid expenses
53,392
48,880
Long-term investments
259,440
204,920
Plant assets
535,800
455,900
Accumulated depreciation
(94,000
)
(97,760
)
Total
$1,283,100
$967,730
Liabilities and Stockholders’ Equity
Accounts payable
$ 191,760
$ 126,524
Accrued expenses payable
31,020
39,480
Bonds payable
206,800
274,480
Common stock
413,600
329,000
Retained earnings
439,920
198,246
Total
$1,283,100
$967,730
ODGERS INC.Income Statement Data
For the Year Ended December 31, 2014
Sales revenue
$730,305
Less:
Cost of goods sold
$254,665
Operating expenses, excluding depreciation
23,331
Depreciation expense
87,420
Income taxes
51,286
Interest expense
8,892
Loss on disposal of plant assets
14,100
439,694
Net income
$ 290,611
Additional information:
1.
New plant assets costing $188,000 were purchased for c.
Problem 1123456Xf122437455763715813910106Name DateTopic.docxChantellPantoja184
Problem 1123456Xf122437455763715813910106
Name: Date:
Topic One: Mean, Variance, and Standard Deviation
Please type your answer in the cell beside the question.
5. The following is the heart rate for 10 randomly selected patients on the unit. Find the mean, variance, and standard deviation of the data using the descriptive statistics option in the data analysis toolpak.
75, 80, 62, 97, 107, 59, 76, 83, 84, 69
6. The following is a frequency distribution fo the number of times patience use the call light in a days time. X is the number of times the call light is used and f is the frequency (meaning the number of patients). Create a histogram of the data.
Sheet2
Sheet3
EXERCISE 11 USING STATISTICS TO DESCRIBE A STUDY SAMPLE
STATISTICAL TECHNIQUE IN REVIEW
Most studies describe the subjects that comprise the study sample. This description of the sample is called the sample characteristics which may be presented in a table or the narrative of the article. The sample characteristics are often presented for each of the groups in a study (i.e. experimental and control groups). Descriptive statistics are used to generate sample characteristics, and the type of statistic used depends on the level of measurement of the demographic variables included in a study (Burns & Grove, 2007). For example, measuring gender produces nominal level data that can be described using frequencies, percentages, and mode. Measuring educational level usually produces ordinal data that can be described using frequencies, percentages, mode, median, and range. Obtaining each subject's specific age is an example of ratio data that can be described using mean, range, and standard deviation. Interval and ratio data are analyzed with the same type of statistics and are usually referred to as interval/ratio level data in this text.
RESEARCH ARTICLE
Source: Troy, N. W., & Dalgas-Pelish, P. (2003). The effectiveness of a self-care intervention for the management of postpartum fatigue. Applied Nursing Research, 16 (1), 38–45.
Introduction
Troy and Dalgas-Pelish (2003) conducted a quasi-experimental study to determine the effectiveness of a self-care intervention (Tiredness Management Guide [TMG]) on postpartum fatigue. The study subjects included 68 primiparous mothers, who were randomly assigned to either the experimental group (32 subjects) or the control group (36 subjects) using a computer program. The results of the study indicated that the TMG was effective in reducing levels of morning postpartum fatigue from the 2nd to 4th weeks postpartum. These researchers recommend that “mothers need to be informed that they will probably experience postpartum fatigue and be taught to assess and manage this phenomenon” (Troy & Dalgas-Pelish, 2003, pp. 44-5).
Relevant Study Results
“A total of 80 women were initially enrolled [in the study] … twelve of these women dropped out of the study resulting in a final sample of 68.” (Troy & Dalgas-Pelish, 2003, p. 39). The researchers presen.
Problem 1. For the truss and loading shown below, calculate th.docxChantellPantoja184
Problem 1. For the truss and loading shown below, calculate the horizontal
displacement of point "D" using the method of virtual work. Show ALL your work!
HW No. 8 - Part 1
Solution
HW FA15 2 Page 1
Problem 1 Continued
Member L (in.) N (lb) N (in) NnL
HW No. 8 - Part 1
.
Problem 1 (30 marks)Review enough information about .docxChantellPantoja184
Problem 1 (30 marks)
Review enough information about Trinidad Drilling Ltd. to propose a vision and strategic objectives for the company. Develop a balanced scorecard that will help the company achieve this vision and monitor how well it is accomplishing its strategic objectives. Include a strategy map in table format that shows objectives and performance measures, with arrows illustrating hypothesized cause-and -effect relationships. Provide rationale for your strategy map. The body of your report should not exceed 1,000 words. Cite material you used to prepare the response and provide references in an appendix.
Problem 2 (20 marks)
Ajax Auto Upholstery Ltd. manufactures upholstered products for automobiles, vans, and trucks. Among the various Ajax plants around Canada is the Owlseye plant located in rural Alberta.
The chief financial officer has just received a report indicating that Ajax could purchase the entire annual output of the Owlseye plant from a foreign supplier for $37 million per year.
The budgeted operating costs (in thousands) for the Owlseye plant’s for the coming year is as follows:
Materials $15,000
Labor
Direct $12,000
Supervision 4,000
Indirect plant 5,000 19,000
Overhead
Depreciation – plant 6,000
Utilities, property tax, maintenance 2,000
Pension expense 4,500
Plant manager and staff 2,500
Corporate headquarters overhead allocation 3,000 18,000
Total budgeted costs $52,000
If material purchase orders are cancelled as a consequence of the plant closing, termination charges would amount to 10 percent of the annual cost of direct materials in the first year (zero thereafter).
A clause in the Ajax union contract requires the company to provide employment assistance to its former employees for 12 months after a plant closes. The estimated cost to administer this service if the Owlseye plant closes would be $2 million. $3.6 million of next year’s pension expense would continue indefinitely whether or not the plant remains open. About $900,000 of labour would still be required in the first year after closure to decommission the plant. After that, the plant would be sold for an estimated $1 million. Utilities, property taxes, and maintenance costs would remain unchanged in the first year after closure, but disappear when the plant is sold.
The plant manager and her staff would be somewhat affected by the closing of the Owlseye plant. Some managers would still be responsible for managing three other plants. As a result, total management salaries would be about 50% of the current level, starting at closure and remaining into the future.
Required:
Assume you are the company’s chief financial officer. Perform a five-year financial analysis and make a recommendation whether to close the Owlseye plant on this basis. Provide support for and cautions about your recommendation with organized, clearly-labeled data. Use bullet points where appropriate.
Problem 3 (16 marks)
Br.
Problem 1 (10 points) Note that an eigenvector cannot be zero.docxChantellPantoja184
Problem 1 (10 points): Note that an eigenvector cannot be zero, but an eigenvalue can
be 0. Suppose that 0 is an eigenvalue of A. What does it say about A? (Hint: One of the
most important properties of a matrix is whether or not it is invertible. Think about the
Invertible Matrix Theorem and all the ‘good things’ of dealing with invertible matrices)
Problem 5: (20 points): The figure below shows a network of one-way streets with
traffic flowing in the directions indicated. The flow rate along the streets are measured
as the average number of vehicles per hour.
a) Set up a mathematical model whose solution provides the unknown flow rates
b) Solve the model for the unknown flow rates
c) If the flow rates along the road A to B must be reduced for construction, what is
the minimum flow that is required to keep traffic flowing on all roads?
Problem 6 (20 points): Problem 7 (9 points): Prove that if A and B are matrices of the same
size, then tr(A+B)=tr(A)+tr(B)
Given:
Goal:
Proof:
Problem 7 (20 points)*: In the 1990, the northern spotted owl became the center of a
nationwide controversy over the use and misuse of the majestic forests in the Pacific
Northwest. Environmentalists convinced the federal government that the owl was
threatened with extinction if logging continued in the old-growth forests (with trees over
200 years old), where the owls prefer to live. The timber industry, anticipating the loss of
30,000 to 100,000 jobs as a result of new government restrictions on logging, argued that
the owl should not be classified as a “threatened species” and cited a number of published
scientific reports to support its case.
Caught in the crossfire of the two lobbying groups, mathematical ecologists
intensified their drive to understand the population dynamics of the spotted owl. The life
cycle of a spotted owl divides naturally into three stages: juvenile (up to 1 year old),
subadult (1 to 2 years), and adult (over 2 years). The owls mate for life during the subadult
and adult stages, begin to breed as adults, and live for up to 20 years. Each owl pair
requires about 1,000 hectares (4 square miles) for its own home territory. A critical time in
the life cycle is when the juveniles leave the nest. To survive and become a subadult, a
juvenile must successfully find a new home range (and usually a mate).
A first step in studying the population dynamics is to model the population at yearly
intervals, at times denoted by 𝑘𝑘 = 0,1,2, …. Usually, one assumes that there is a 1:1 ratio of
males to females in each life stage and counts only the females. The population at year 𝑘𝑘
can be described by a vector 𝒙𝒙𝒌𝒌 = (𝑗𝑗𝑘𝑘 , 𝑠𝑠𝑘𝑘 , 𝑎𝑎𝑘𝑘 ), where 𝑗𝑗𝑘𝑘 , 𝑠𝑠𝑘𝑘 , and 𝑎𝑎𝑘𝑘 are the numbers of
females in the juvenile, subadult, and adult stages, respectively. Using actual field data from
demographic studies, a rese
Probation and Parole 3Running head Probation and Parole.docxChantellPantoja184
Probation and Parole 3
Running head: Probation and Parole
Probation and Parole
Student Name
Allied American University
Author Note
This paper was prepared for Probation and Parole, Module 8 Check Your Understanding taught by [INSERT INSTRUCTOR’S NAME].
Directions: Respond to the following questions using complete sentences. Your answer should be at least 1 paragraph in length, which must be composed of three to five sentences.
1. What is meant by intermediate punishments and what programs are included in this category?
2. How do intermediate punishments serve to keep down prison populations?
3. Why has electronic monitoring proven so popular?
4. What is meant by shock probation/parole?
5. What are the essential features of the boot camp program?
6. Why has intensive supervision been a public relations success?
7. What are the criticisms of boot camp programs?
8. What has research revealed with respect to intensive supervision?
9. What are the criticisms of electronic monitoring in probation and parole?
10. What are the criticisms leveled at intensive supervision?
11. What are the purposes of and services offered by a day reporting center?
12. Why would heroin addicts who have no intention of giving up drug use voluntarily enter a drug treatment program? What are the advantages of using methadone to treat heroin addicts?
13. Why is behavior modification difficult to use in treating drug abusers?
14. What are the characteristics of chemical dependency (CD) programs?
15. What are the primary characteristics of the therapeutic community (TC) approach for treating drug abusers?
16. What are criticisms of the Alcoholics Anonymous approach?
17. What are the problems inherent in drug testing?
18. What are the typical characteristics of sex offenders? How have sex offender laws affected P/P supervision?
19. What are the pros and cons of restitution and charging offenders fees in probation or parole?
20. What are the problems encountered in using the interstate compact?
.
Problem 1(a) Complete the following ANOVA table based on 20 obs.docxChantellPantoja184
Problem 1:
(a) Complete the following ANOVA table based on 20 observations for the regression equation
(a) Is the overall regression significant? Fill in the missing values in the table.
Source DF SS MS F
Regression ___ 350 ____ ____
Error ___ _____
Total 500
(b) Suppose that you have computed the following sequential sums of squares due to regression:
Regressor Variables in Model SS Regression
………………………………………. 300
……………………………………… 250
…………………………………….. 340
……………………………………. 325
Fill in the missing values in the following “computer output”:
Source DF Partial SS F-value Pr>F
……………………………………………………………………………………….. 0.1245
………………………………………………………………………………………. 0.3841
………………………………………………………………………………………. 0.0042
………………………………………………………………………………………. 0.0401
Problem 2:
The time required for a merchandise to stock a grocery store shelf with a soft drink product as well as the number of cases of product stocked are given below. Consider a linear regression of delivery time against number of cases.
X=number of cases
Y=delivery time
Delivery time number of cases Hat diagonals
1.41 4 0.5077
2.96 6 0.3907
6.04 14 0.2013
7.57 19 0.3092
9.38 24 0.5912
Observations used L.S. Model
4,6,14,19,24
6,14,19,24
4,14,19,24
4,14,19,24
4,6,14,24
4,6,14,19
(a)
Calculate the PRESS statistic for the model .
(b) Calculate the regular residual for the model above. Then, compare these residuals with the PRESS residuals for this model.
Exercises from the Text
Use SAS whenever possible to do these exercises:
# 3.4 on p 122
# 3.5
# 3.8
# 3.15
# 3.21
# 3.27
# 3.28
# 3.31
# 3.38
# 3.39
Example with SAS on Sequential and Partial Sum of Squares
Data Weather;
Title 'Lows and Highs from N&O Jan 28,29,30 1992';
Title2 'using actual numbers (yesterday values)';
input city $ hi2 lo2 yhi ylo thi tlo;
* Mon Tues Wed ;
cards;
seattle 51 44 52 44 59 47
.
.
.
;
proc reg; model thi = yhi hi2 tlo ylo lo2/ss1 ss2;
test tlo=0, ylo=0, lo2=0;
/*-----------------------------------------------
| Showing sequential and partial sums of squares|
| Note t**2 = F relationship for partial F. By |
| hand, construct F to leave out .
Probe 140 SPrecipitation in inchesTemperature in F.docxChantellPantoja184
Probe 1
40 S
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 26.8
Precip 27.1
MAT(F) 59.8
Probe 2
6 S
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 69.2
Precip 124.6
MAT(F) 77.9
Probe 3
57 S
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 21.5
Precip 38.7
MAT(F) 43.5
Probe 4
38 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 30.3
Precip 16.5
MAT(F) 53.6
Probe 5
55 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 21.3
Precip 28.1
MAT(F) 40.6
Probe 6
43 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 25.4
Precip 14.4
MAT(F) 47.2
Probe 7
42 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 17.3
Precip 31.2
MAT(F) 26.0
Probe 8
42 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 29.6
Precip 38.8
MAT(F) 51.6
Probe 9
18 S
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 66.1
Precip 74.8
MAT(F) 77.7
Probe 10
58 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 16.5
Precip 24.8
MAT(F) 36.9
Probe 11
26 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 47.6
Precip 3.8
MAT(F) 70.1
Probe 12
29 N
Precipitation in inches
Temperature in F
J F M A M J J A S O N D
2
4
6
8
10
12
0
10
20
30
40
50
60
70
80
90
POTET 44.0
Precip 47.3
MAT(F) 63.2
Probe 4
Probe 2
Probe 10
Probe 5
Probe 6
Probe 7
Probe 11
Probe 12
Probe 8
Probe 9
Probe 3
Probe 1
Map 1
20 N
40 N
60 N
80 N
0
20 S
40 S
60 S
0
1000
miles
Geography 204
Koppen Climate Classification Guidelines
If POTET exceeds Precip then B
BW = POTET more than 2x Precip
(desert)
h = mean annual temp > 18 C (64.4 F)
k = mean annual temp < 18 C (64.4 F)
BS = POTET less than 2x Precip
(steppe)
h = mean annual t.
it describes the bony anatomy including the femoral head , acetabulum, labrum . also discusses the capsule , ligaments . muscle that act on the hip joint and the range of motion are outlined. factors affecting hip joint stability and weight transmission through the joint are summarized.
Reimagining Your Library Space: How to Increase the Vibes in Your Library No ...Diana Rendina
Librarians are leading the way in creating future-ready citizens – now we need to update our spaces to match. In this session, attendees will get inspiration for transforming their library spaces. You’ll learn how to survey students and patrons, create a focus group, and use design thinking to brainstorm ideas for your space. We’ll discuss budget friendly ways to change your space as well as how to find funding. No matter where you’re at, you’ll find ideas for reimagining your space in this session.
A workshop hosted by the South African Journal of Science aimed at postgraduate students and early career researchers with little or no experience in writing and publishing journal articles.
Walmart Business+ and Spark Good for Nonprofits.pdfTechSoup
"Learn about all the ways Walmart supports nonprofit organizations.
You will hear from Liz Willett, the Head of Nonprofits, and hear about what Walmart is doing to help nonprofits, including Walmart Business and Spark Good. Walmart Business+ is a new offer for nonprofits that offers discounts and also streamlines nonprofits order and expense tracking, saving time and money.
The webinar may also give some examples on how nonprofits can best leverage Walmart Business+.
The event will cover the following::
Walmart Business + (https://business.walmart.com/plus) is a new shopping experience for nonprofits, schools, and local business customers that connects an exclusive online shopping experience to stores. Benefits include free delivery and shipping, a 'Spend Analytics” feature, special discounts, deals and tax-exempt shopping.
Special TechSoup offer for a free 180 days membership, and up to $150 in discounts on eligible orders.
Spark Good (walmart.com/sparkgood) is a charitable platform that enables nonprofits to receive donations directly from customers and associates.
Answers about how you can do more with Walmart!"
This document provides an overview of wound healing, its functions, stages, mechanisms, factors affecting it, and complications.
A wound is a break in the integrity of the skin or tissues, which may be associated with disruption of the structure and function.
Healing is the body’s response to injury in an attempt to restore normal structure and functions.
Healing can occur in two ways: Regeneration and Repair
There are 4 phases of wound healing: hemostasis, inflammation, proliferation, and remodeling. This document also describes the mechanism of wound healing. Factors that affect healing include infection, uncontrolled diabetes, poor nutrition, age, anemia, the presence of foreign bodies, etc.
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Best Practice & Research Clinical Endocrinology & Metabolism 2
1. Best Practice & Research Clinical Endocrinology & Metabolism
25 (2011) 239–250
Contents lists available at ScienceDirect
Best Practice & Research Clinical
Endocrinology & Metabolism
journal homepage: www.elsevier.com/locate/beem
2
Klinefelter syndrome
Anne M. Wikström, Chief Physician a,b,e,
Leo Dunkel, Professor of Pediatrics c,d,*
a HUCH, Hospital for Children and Adolescents, Helsinki
University Central Hospital, P.O. Box 281, FI-00029 Helsinki,
Finland
b University of Helsinki, Helsinki, Finland
c Department of Pediatrics, Kuopio University Hospital, P.O.
Box 1777, FI-70211 Kuopio, Finland
d University of Eastern Finland, Kuopio, Finland
Keywords:
Klinefelter syndrome
47,XXY
testicular degeneration
hypogonadism
androgen
androgen deficiency
infertility
* Corresponding author. Department of Pediatr
Tel.: þ358 17 173311; fax: þ358 17 172410.
2. E-mail addresses: [email protected] (A.M.
e Tel.: þ358 50 4272854; fax: þ358 9 47175888
1521-690X/$ – see front matter � 2010 Elsevier Lt
doi:10.1016/j.beem.2010.09.006
Klinefelter syndrome (KS) is the most common genetic form of
male hypogonadism, but overt phenotype becomes evident only
after puberty. During childhood, and even during early puberty,
pituitary-gonadal function in 47,XXY subjects is relatively
normal,
but from midpuberty onwards, FSH and LH levels increase to
hypergonadotropic levels, inhibin B decreases to undetectable
levels, and testosterone levels after some increase plateau at
low-normal levels for healthy adult men. Hence, most adult KS
males display a clear hypergonadotropism with a varying degree
of
androgen deficiency; subsequently testosterone substitution
therapy is widely used to prevent symptoms and sequels of
androgen deficiency. Testicular biopsies of prepubertal KS boys
have shown preservation of seminiferous tubules with reduced
numbers of germ cells, but Sertoli and Leydig cells have
appeared
normal. The testes in the adult KS male are characterized by
extensive fibrosis and hyalinization of the seminiferous tubules,
and hyperplasia of the interstitium. However, the tubules may
show residual foci of spermatogenesis. Introduction of testicular
sperm extraction (TESE) in combination with intracytoplasmic
sperm injection (ICSI) techniques has allowed non-mosaic KS
males to father children.
� 2010 Elsevier Ltd. All rights reserved.
ics, Kuopio University Hospital, P.O. Box 1777, FI-70211
Kuopio, Finland.
Wikström), [email protected] (L. Dunkel).
.
3. d. All rights reserved.
mailto:[email protected]
mailto:[email protected]
www.sciencedirect.com/science/journal/1521690X
http://www.elsevier.com/locate/beem
http://dx.doi.org/10.1016/j.beem.2010.09.006
http://dx.doi.org/10.1016/j.beem.2010.09.006
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250240
Introduction
Klinefelter syndrome (KS) was first described by Harry F.
Klinefelter in 1942 as a clinical entity
characterized by gynecomastia, small testes, absent
spermatogenesis, normal to moderately reduced
Leydig cell function, and increased secretion of FSH.1 The
disorder in 1959 was found to be caused by
a supernumerary X chromosome.2 Today, studies indicate that
some 80% of KS males have the
karyotype 47,XXY and 20%, higher-grade chromosome
aneuploidies, 46,XY/47,XXY mosaicism, or
structurally abnormal X chromosomes.3 With an estimated
prevalence of about 1 in 600 newborn
males, KS is the most common sex-chromosome abnormality.4
It is among the most frequent genetic
causes of human infertility, occurring in 11% of azoospermic
men and 4% of infertile men.5 The classical
phenotype of KS is widely recognized, but many affected
subjects present only with very discrete
symptoms (Table 1). Consequently, the disorder is
underdiagnosed; only approximately one-fourth of
adult males with KS receive diagnoses, and fewer than 10% of
4. the expected number are diagnosed
before puberty.4,6
Many of the clinical findings in KS may be attributed to the
hypogonadism typical for this syndrome,
but some are instead caused directly by the chromosome
abnormality. KS is diagnosed prenatally by
routine amnioscentesis quite rarely, because the association
with advanced maternal age is weak3,7,
and at birth most 47,XXY neonates appear normal.8,9 During
childhood, the KS boy often presents with
speech development delay, learning disabilities or behavioral
problems.6,10 Consequently, child
neurologists or child psychiatrists, who perform chromosome
analysis, along with fragile X screening,
often make the diagnosis. The tall stature typical of KS results
from a notable increase in height velocity
between ages 5 and 8 years owing to a greater leg-growth, but
otherwise identifying any differences
between KS boys and normal boys in physical appearance is
very difficult.11 Furthermore, neither
magnitude nor timing of the pubertal growth spurt differs from
that of normal boys.11–13 Only after
puberty do small, firm testes and variable symptoms of
androgen deficiency characterize the KS males
most often detected among patients with azoospermia visiting
infertility clinics.6
Function of hypothalamic-pituitary-testicular axis during
development
Fetal and neonatal periods
When prenatal testosterone was investigated in amniotic fluid
obtained at antenatal diagnoses
between 16 and 20 weeks of gestation from 20,XXY fetuses and
from XY and XX controls of the same
5. age14, no significant difference was evident between the two
male groups; both had significantly
higher levels than the XX fetuses.
At birth there already may be some impairment of Leydig cell
function. Cord-blood testosterone was
significantly lower in two 47,XXY infants and in one
46,XY/XXY than in three control infants.15
Table 1
Clinical features (%) of adult patients with Klinefelter
syndrome.3,38,81
Small testes (<4–6 mL) >95
Infertility >99
Azoospermia >95
Decreased facial hair 60–80
Decreased pubic hair 30–60
Abdominal adiposity 50
Gynecomastia 38–75
Varicose veins 40
Decreased libido and potency 70
Decreased muscle strength 70
The metabolic syndrome 46
Type 2 diabetes 10–39
Osteopenia and osteoporosis 40 þ 10
Mitral valve prolapse �55
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250 241
However, in another study comparing testosterone levels of six
KS infants to levels in a large cohort of
normal infants, no significant difference appeared.8 Lahlou et
al. compared reproductive hormone
levels during the postnatal hormonal activation of the
6. reproductive axis (i.e. minipuberty) in 18
prenatally diagnosed 47,XXY boys to those in 215 healthy
boys.16 The KS infants’ timing of peak serum
testosterone was similar to healthy infants’, but levels in the KS
boys, were significantly lower from
birth to 8 months. However, their serum LH, FSH, inhibin B and
anti-Müllerian hormone (AMH) levels
were normal. Another study found, in 11 of 12 KS boys under
age 6 months, lower than normal serum
testosterone levels but normal gonadotropin levels.9 In contrast,
Aksglaede et al. found high normal
concentrations of testosterone and elevated levels LH and FSH
in 10 KS infants aged 3.1 months when
compared to healthy controls.17 Hence, no indisputable
hypoandrogenism appears during infancy in KS
subjects.
Childhood and adolescence
Prepubertal 47,XXY boys are characterized by normal serum
levels of testosterone, FSH, LH, and
inhibin B until onset of puberty12,18–23, and their serum
testosterone responses to human chorionic
gonadotropin (hCG) stimulation are normal.21,22 During
puberty, after an initial normal adolescent
increase, serum testosterone concentrations plateau and remain
subsequently within the low-normal
range throughout puberty.18,20–22,24 Such testosterone levels
seem sufficient to allow in KS boys normal
onset and progression of puberty (Fig. 1) and development of
satisfactory secondary sexual
characteristics.11,18,21,22
Insulin-like factor 3 (INSL3) is a peptide hormone secreted in
an LH-dependent manner by fetal and
fully differentiated Leydig cells.25–27 It is only weakly
7. expressed in immature prepubertal Leydig cells
and in Leydig cells that have become hypertrophic or
transformed.27 Hence, INSL3 is suggested to be
more sensitive than testosterone to Leydig cell dysfunction and
differentiation status. In healthy boys,
puberty is associated with a marked increase in INSL3 levels
that occurs concomitantly with significant
increases in LH levels (Fig. 2).20,28 In KS boys, no significant
difference in comparison with healthy boys
in INSL3 levels emerges in assessment by bone age or Tanner
pubertal stages, but from midpuberty
onwards, despite stimulation by high LH levels, a leveling-off
in INSL3 concentrations occurs (Fig. 2).
Serum estradiol (E2) levels are already high in early pubertal
47,XXY boys and remain high, irre-
spective of the presence or absence of gynecomastia.12,18,21 A
tendency for higher E2/testosterone ratios
also occur in pubertal KS boys, but their serum SHBG levels
decrease normally.18
Serum levels of inhibin B are considered to reflect Sertoli cell
function during prepuberty and to
become germ cell-dependent during midpuberty.29 Onset of
male puberty is normally associated with
increasing serum concentration of inhibin B, and already by
pubertal stage 2, is the adult serum level of
serum inhibin B reached.30,31 In patients with KS, inhibin B
similarly showed progressive increase
before the clinical onset of puberty, but this initial rise is
followed by a rapid suppression accompanied
by a simultaneous increase in serum testosterone.19,23 Thus, a
strong, inverse non-linear correlation
appear in KS boys between serum inhibin B and testosterone
levels.19 In healthy subjects, serum
concentrations of AMH, another Sertoli cell marker, remain
8. high throughout childhood and wane
during normal male puberty concomitantly with rising
testosterone levels and onset of meiosis in
spermatogenesis.32–34 Despite their lack of active
spermatogenesis, in KS subjects this decrease in AMH
levels also occurs.16,19 From midpuberty (at about age 13)
onwards, KS subjects show a gradual increase
in FSH and LH concentrations to hypergonadotropic levels; FSH
levels increasing somewhat earlier and
more markedly than do LH levels.18,19,21,22,35 At the same
time, the responses of both FSH and LH to
gonadotropin-releasing hormone (GnRH) stimulation become
exaggerated.18,21,22,36,37 These obser-
vations coincide with decreasing inhibin B and AMH levels, and
leveling-offs in testosterone and INSL3
levels, and thus indicate a diminished testicular inhibition of
gonadotropin secretion.
Adulthood
Adult KS patients are characterized by hypergonadotropic
hypogonadism. Concentrations of LH and
FSH are high; FSH is usually higher, and little overlap occurs
with normal individuals.3,38 In 65–85% of
adult KS patients, serum testosterone concentrations are below
normal, but some may show levels
A B
C
Age (yr)
P-stage
10. 9 10 11 12 13 14 15 16 17
Testicular volume (mL)
Fig. 1. Pubic hair (A) and genital stage (B) development
according to Tanner, and testicular volumes (C) by age in boys
with
Klinefelter syndrome, for details see.18 Shaded rectangles ¼
mean age � 2 SD for healthy Finnish boys.82 Gray area ¼ range
of the
volume of the right testis in healthy pubertal Swiss boys.83
0
.4
.8
1.2
10 11 12 13 14 15
INSL3 (ng/mL)
0
4
8
12
16
20
11. 10 11 12 13 14 15
LH (IU/L)
0
4
8
12
16
10 11 12 13 14 15
T (nmol/L)
Age (yr)Healthy boys KS
Fig. 2. Mean (�SD) plasma insulin-like factor 3 (INSL3), LH,
and testosterone (T) concentrations by age in boys with
Klinefelter
syndrome compared to healthy boys, for details see Ref. [20].
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250242
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250 243
within the normal range.3,38 On average, serum concentrations
of E2 and SHBG are higher than
normal.3 Serum inhibin B levels in most adult KS subjects are
12. undetectable23,39,40, and adult KS patients
have serum INSL3 concentrations significantly below
normal.25,26
Morphological degeneration of the testis
Fetal and neonatal periods
The degenerative process may start even during fetal life, as
studies of aborted fetuses at gestational
ages 18–22 weeks have shown.41,42 A reduced number of germ
cells and an increased proportion of
tubules devoid of germ cells are visible in the testicular
biopsies of midterm 47,XXY fetuses, whereas
the density and number of seminiferous tubules and
mesenchymal structures appear normal.41 Two
case reports presented normal testicular histology in 47,XXY
fetuses aborted at 17 and 20 weeks.43,44
Mikamo et al.45 showed, over the first year of life, a
progressive diminution in the number of
spermatogonia from 24 to 0.1% of control value. The number
and appearance of immature Sertoli cells
appeared normal, as did interstitial tissue. In one 13-day-old
47,XXY infant, germ cells appeared in
only 23% of seminiferous tubules, and the number of
spermatogonia was reduced.46 Numerous germ
cells and immature Sertoli cells, and Leydig cells that appeared
normal were evident in a testicular
biopsy of a 4-week-old KS infant undergoing surgery for
inguinal hernia8, but a quantitative assay
indicated a reduced number of spermatogonia. The one-month-
old 47,XXY infant in the group of KS
boys studied by Müller et al. showed a normal germ cell count
in his biopsy despite bilateral
undescended testes.47
13. Childhood and adolescence
Ferguson-Smith, reporting in 1959 on eight mentally retarded
prepubertal chromatin-positive KS
boys, aged 7–1248, noted reduced size of the seminiferous
tubules and a reduced number or complete
absence of spermatogonia. A minority of the tubules was
normal, containing a normal amount of
spermatogonia; the majority was smaller tubules with
undifferentiated Sertoli cells.48 Müller et al.,
studying testicular biopsies of 11 KS boys between the neonatal
period and 13 years of age47, found no
germ cells in nine KS boys older than two years. It should,
however, be noted in that study all boys were
cryptorchid47, a condition which also reduces germ cell
number.49
Histomorphometric and immunohistochemical analyses reveal
that in early adolescence the
majority of boys with KS have germ cells in their testes.19,50
The number of spermatogonia, especially
adult dark spermatogonia is, however, markedly reduced, and
the depletion of these cells accelerated
with the activation of the pituitary-gonadal axis at the onset of
puberty (Fig. 3).19,50 In prepubertal KS
boys, the focal nature of the degeneratio n process is already
evident, since the few seminiferous
tubules containing spermatogonia are surrounded by Sertoli cell
only (SCO) tubules (Fig. 3D). Germ cell
differentiation is not delayed in KS boys; gonocytes mature into
spermatogonia without significant
delay, but a careful review of serial sections revealed no
pachytene spermatocytes.50 This indicates that
in KS, germ cell differentiation is – at least partially – arrested
at the spermatogonium or early primary
14. spermatocyte stage. It seems that in KS, spermatogonia have
difficulty entering meiosis; instead they
proceed at onset of puberty to apoptosis.
In KS immature Sertoli cells are incapable during puberty of
transforming into the adult mature cell
type.19 Immunoexpression of inhibin a-subunit indicates
degeneration of the Sertoli cells, as also seen
in electron microscopy of biopsies.19,50 Inhibin B synthesis is
obviously altered in subjects with KS,
since both subunits are expressed in the Sertoli cells, even when
serum inhibin B is unmeasurable.50
With age, fibrosis and hyalinization of the interstitium and
peritubular connective tissue increases,
and already in 12- to 14-year-old KS boys huge hyperplastic
Leydig cells can be visible in testicular
biopsies.19
In normal males, androgen receptor (AR) expression first
appears in Sertoli cell nuclei just before
the onset of puberty but before final maturation of the Sertoli
cells, concomitant with rising concen-
trations of FSH and testosterone.51 In the absence of androgens,
AR is located in the cytoplasm.52 KS
boys have, in contrast to age-matched controls, constant AR
expression in their Sertoli cell cytoplasm.50
Fig. 3. Testicular biopsies of adolescent boys with Klinefelter
syndrome displaying the progression of testicular degeneration
during
puberty. (A) KS boy, age 10.7 years, with spermatogonia; (B)
13.7-year-old with no spermatogonia, and (C) 14-year-old with
extensive degeneration. The focal nature of the degeneration is
15. obvious in (D) seminiferous tubules with spermatogonia stained
with MAGE-A4 surrounded by Sertoli cell only tubules in a 10-
year-old patient. Ap; pale adult spermatogonia; Ad; dark adult
spermatogonia. See Refs. [19,50] for details.
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250244
Furthermore, they have a smaller proportion of Sertoli cell
nuclei expressing AR than do controls.50
Older KS boys display a strong cytoplasmic AR staining in
Leydig cells, which may be a sign of
impaired function of hypertrophied Leydig cells, as also
suggested by high serum LH levels and low
testosterone and INSL3 levels.18–20,50
In summary, these results characterizing the testicular
degeneration process in the testes of
adolescent KS boys confirm that this process accelerates at the
onset of puberty.
Adulthood
Histology of the testes in the adult KS patient is characterized
by extensive fibrosis and
hyalinization of the seminiferous tubules, absence of
spermatogenesis, and hyperplasia of Leydig
cells and interstitium.1,53 The patchy nature of the testicular
histology, with more – and less-
affected areas, has been described.54,55 The seminiferous
tubules can be divided into two types
according to Sertoli cell morphology, the first containing small
immature Sertoli cells and the
second type larger and more differentiated ones.56 Later studies
of the cytological features of
these immature Sertoli cells have suggested a lower activity
16. than that of mature Sertoli cells,
probably resulting in impaired protein synthesis.57 Regadera et
al. showed in their immunohis-
tochemical and quantitative study that 78.9 � 9.1% of the
Leydig cells were normal in adult KS
males compared to 96.0 � 10.0% in control men, and in KS the
functional activity of the Leydig
cells was reduced.58
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250 245
Genetic mechanisms of gonadal failure
Apart from normal inter-individual genetic variation, several
genetic mechanisms may explain
the clinical features and variability of the phenotype in KS. In
principal, gene-dosage effects and
the parental origin of the supernumerary X chromosome in
conjunction with (possibly skewed)
X-chromosome inactivation, may play significant roles.
In females, one of the X chromosomes is inactivated to achieve
dosage-compensation, and probably
likewise in KS. Genes from the pseudoautosomal regions
(PARs) and an additional 15% of other genes,
however, escape X inactivation and are putatively contributing
to the KS phenotype. Therefore, the KS
phenotype may reflect increased gene dosage originating either
from two active copies of these strictly
X linked genes or from three active copies of the X–Y
homologous genes of the PAR. For instance, in KS
longleggedness is already evident from early childhood despite
normal circulating concentrations of
IGF-I and IGFBP-3, suggesting that hypogonadism in puberty
17. and young adulthood cannot solely
explain tall stature and long extremities. Excessive expression
of growth-related genes (e.g. the trip-
licate of the SHOX gene of the PAR of X chromosome) is one
explanation put forward.
The supernumerary X chromosome is paternal in 40–60% and
maternal in 40–60% of KS cases.3,7,59
KS boys with additional paternal X chromosome seem to have
later onset and slower progression of
puberty.60 However, some studies have suggested that parental
origin of the extra X chromosome has
no evident effect on the phenotypes of KS males.61–63 Data
from several small patient series suggest
that X-chromosome isodisomy/heterodisomy and X-chromosome
inactivation pattern have no impact
on the phenotype60,62,63, although these issues require
detailed studies in larger patient series.
The AR gene on the X chromosome may play a particular role in
differences in the KS phenotype. The
N-terminal domain of exon 1 of the AR gene contains a highly
polymorphic CAG repeat, the length of
which is inversely associated with activity of the receptor.64 A
positive correlation exists with body
height and presence of gynecomastia, but an inverse association
with bone density, social status,
testicular volume, and even with response to androgen
substitution.65 In another study, however, the
only parameter associated with CAG repeat length was penile
length; the correlation was inverse.63 In
addition, KS boys with a longer CAG repeat show later onset
and slower progression of puberty and
slower testicular degeneration process.60 These findings are in
agreement with diminished AR
18. response to androgens when the AR gene has a longer CAG
repeat. Recently, in healthy elderly men
increased estrogen rather than decreased androgen action was
associated with longer androgen
receptor CAG repeats.66Thus also increased estrogen action can
play a role in the variation of KS
phenotype.
Among genes on the X chromosome, a large number belong to
the cancer-testis antigen family and
are expressed in testicular germs cells.67,68 Mroz et al. showed
that X-reactivation occurs during germ
cell development in the XXY mouse, and it is assumed that for
the survival of germ cells in the mature
testis the proper X-chromosome dose is crucial.69 Hence,
molecular mechanisms induced by an altered
dose of X-encoded genes in testicular cells may, during puberty,
initiate the degeneration process in the
testes of boys with KS.
Testosterone substitution therapy in KS
When serum testosterone concentrations in KS patients become
low, lifelong substitution therapy
is indicated to prevent symptoms and consequences of androgen
deficiency, and subsequently to
improve quality of life. Beneficial effects of testosterone
therapy in hypogonadal men have been
demonstrated in several studies.3,38
KS subjects might benefit from testosterone supplementation
during the first 2–3 months of life7,
although we still lack evaluation of the role of the minipuberty
as a predictor of testicular insufficiency
in KS. Any such treatment should be performed only in
controlled, randomized clinical trials. The KS
19. boys have sufficient testosterone levels to allow normal onset
and progression of puberty11,18,21,22, but
development of a relative testosterone deficiency from
midpuberty onwards is obvious. For instance,
leveling-off of INSL3 levels and exaggerated responses to
GnRH stimulation indicate Leydig cell
dysfunction.18,20 This is also in agreement with
histomorphometric and immunohistochemical anal-
yses: Leydig cell hyperplasia and fibrosis of the interstitium
develop with age, and immunoexpression
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250246
of AR indicate diminished androgen action.19,50 Consequently,
although it seems that androgen
supplementation in KS boys from midpuberty onwards is
necessary, to date, placebo-controlled studies
showing the benefits of early testosterone substitution are
lacking, especially regarding the positive
effects of early testosterone therapy on cognitive and behavioral
parameters.
That sperm retrieval rate appeared to be lower in KS men who
previously received exogenous
testosterone causes an argument against the routine treatment of
KS males with testosterone.70
Actually, during spermatogenesis testosterone causes a marked
inhibition of spermatogonial matu-
ration.71 Concern for the maintenance of fertility potential in
young KS men must be balanced against
the potential benefits of testosterone replacement.
Fertility in KS
20. KS subjects are traditionally described as infertile. Semen
analysis most often reveals azoospermia;
in a cohort of 131 KS males, only 8.4% had spermatozoa in
their ejaculate.3 Some spermatogonia in KS
subjects are capable of completing the spermatogenic process
leading to formation of mature sper-
matozoa, but with an increased risk for genetically imbalanced
spermatozoa.72 Consequently, because
of the risk for producing a chromosomal abnormality both on
sex chromosomes and autosomes
(chromosomes 18 and 21) in the offspring, most investigators
recommend professional genetic
counseling and standard prenatal diagnosis techniques.72,73
Most often the only hope for biological paternity in KS couples
is TESE combined with ICSI. To date,
more than 100 healthy children have been reported born after
ICSI with testicular sperm from non-
mosaic KS men. The initial success rate of TESE in adult
47,XXY males in small series has been 40–50%.3
A new technique, “microdissection TESE”, has shown
significantly better sperm recovery rates
compared to conventional TESE, sperm recovery rates as high
as 70% have been achieved70, and
therefore this technique should be favored instead of TESE74.
Live birth rates of 20–46% have been
reported once sperm are obtained.70,72 In the KS male, the only
predictive factor for successful sperm
recovery seems to be the testicular histopathology75, but even
with no sperm in histological sections,
TESE has proven successful.70,77 Neither testicular
ultrasonography, extensive chromosome analysis,
degree of virilization, testicular volume, nor serum testosterone,
FSH, LH, nor inhibin B level is
21. predictive for outcome of TESE75,76; thus even patients with
unmeasurable inhibin B levels have
undergone successful TESE.77 It is to be noted, however, that
results from only few centres have been
published thus far, and there is a possibility of a positive
publication bias, i.e. centres with less
impressive success rates have not been able to report their data.
In boys with KS, the fact that the number of adult dark
spermatogonia – of fundamental importance
for development of male fertility49 – is markedly reduced
indicates a severely impaired fertility
potential even before puberty.19 Cryopreservation of semen
samples containing very low numbers of
spermatozoa from KS boys in early puberty is possible and
should be offered to appropriate patients
before the start of testosterone supplementation. The expected
success rate is, however, exceedingl y
low, since the onset of puberty initiates a marked acceleration
in germ cell depletion, and one must also
take into account the limited ability of boys to provide semen
samples during early puberty. Another
option would be TESE, if the biopsy sample contains haploid
germ cells. The possible future use for
infertility treatments of cryopreserved testicular samples
containing spermatogonia but not more
mature germ cells would require in vitro maturation of
spermatogonia into mature spermatozoa or at
least into late/elongated spermatids. Recent studies indicate that
human testicular tissue can be
cultured for at least up to 3 weeks without essential loss of
spermatogonia.78,79 Early results also
suggest that meiosis and spermatogenesis may resume under
culture conditions, yielding normal
spermatids with some fertilization potential.79 However, at
present this option for fertility preservation
22. in boys before spermarche remains entirely experimental.
Summary
Placebo-controlled studies are vital to determine the role of
hypogonadism in aggravating the
47,XXY phenotype, because all the characteristics of the KS
phenotype cannot be ascribed to the
relative androgen deficiency; other factors such as the excess of
X-chromosome genes probably also
A.M. Wikström, L. Dunkel / Best Practice & Research Clinical
Endocrinology & Metabolism 25 (2011) 239–250 247
have some impact. Whether the defect in the 47,XXY testis is
intrinsic to germ cells or is due to
inability of the Sertoli cells to support normal germ cell
development is not fully resolved, although
recent data on mice show that there is intrinsic capability of
donor XY germ cells to develop into
haploid germ cells in XXY environment.80 Furthermore, we do
not know whether the Leydig cell
failure is a consequence of germ cell depletion and Sertoli cell
injury or is intrinsic to Leydig cells.
Molecular mechanisms behind the testicular degeneration in KS
have remained a mystery and require
further elucidation.
Practice points
� The testicular degeneration process in the testes of KS boys
accelerates at the onset of
puberty.
� Concern for the maintenance of fertility potential in young
KS men must be balanced against
23. the potential benefits of testosterone replacement.
� Cryopreservation of semen samples containing very low
numbers of spermatozoa from KS
boys in early puberty is possible and should be offered to
appropriate patients before the start
of testosterone supplementation.
� The only option for biological paternity in most KS couples
is TESE combined with ICSI.
� The only predictive factor for successful sperm recovery
seems to be the testicular histopa-
thology, but even with no sperm in biopsy specimens, TESE has
proven successful.
� Professional genetic counseling and standard prenatal
diagnosis techniques are recom-
mended, because of the risk for chromosomal abnormality both
on sex chromosomes and
autosomes in the offspring.
Research agenda
� The role of the postnatal testicular activation as a predictor
of testicular insufficiency has
remained unresolved.
� Induction of an altered dose of X-encoded genes in testicular
cells is a hypothetical mecha-
nism accelerating germ cell loss and testicular degeneration
during puberty.
� Studies with larger number of patients are needed to
substantiate if X-chromosome
isodisomy/heterodisomy and X-chromosome inactivation pattern
have an impact on the KS
24. phenotype.
� Placebo-controlled studies showing the benefits of early
testosterone substitution are
lacking, especially regarding the positive effects of early
testosterone therapy on cognitive
and behavioral parameters.
� The possible future use for infertility treatments of
cryopreserved testicular samples would
require development of in vitro maturation techniques of
immature germ cells into
spermatids.
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Klinefelter syndromeIntroductionFunction of hypothalamic-
pituitary-testicular axis during developmentFetal and neonatal
periodsChildhood and adolescenceAdulthoodMorphological
degeneration of the testisFetal and neonatal periodsChildhood
and adolescenceAdulthoodGenetic mechanisms of gonadal
failureTestosterone substitution therapy in KSFertility in
KSSummaryReferences
140 | Reprod Med Biol. 2019;18:140–
150.wileyonlinelibrary.com/journal/rmb
1 | I N T R O D U C T I O N
In 1942, Klinefelter and Albright reported that nine men had a
“Syndrome characterized by gynecomastia, aspermatogenesis
without Leydigism and increased excretion of
follicle‐ stimulating
hormone”.1 Karyotype analysis elucidated that this syndrome
was
caused by an extra X chromosome (XXY). The classic form
(nonmo‐
saic type) of Klinefelter syndrome (KS) is observed in one per
660
births, with up to 3%‐ 4% occurring in infertile men and
10%‐ 12%
occurring in nonobstructive azoospermia (NOA). A study on the
KS
37. prevalence in Japan found a lower prevalence at 60 per 100
000,2
indicating the presence of racial differences. KS is the most
common
sex chromosome abnormality associated with male
infertility,3,4 and
men with KS have been shown to be potentially fertile by using
a
testicular sperm and intracytoplasmic sperm injection (ICSI)
proto‐
col.6 Approximately 85% of KS cases are due to a single
aberrant X
chromosome (47,XXY), whereas the remaining 15% display
multiple
aneuploidies (48,XXXY; 48,XXYY; 49,XXXXY), causing the
devel‐
opment of more severe phenotypes, which are usually diagnosed
during prenatal and infantile periods as abnormalities of the
external
Received: 3 October 2018 | Revised: 7 November 2018 |
Accepted: 11 November 2018
DOI: 10.1002/rmb2.12261
R E V I E W A R T I C L E
Klinefelter syndrome: From pediatrics to geriatrics
Koji Shiraishi | Hideyasu Matsuyama
This is an open access article under the terms of the Creative
Commons Attribution‐ NonCommercial License, which permits
use, distribution and reproduction
in any medium, provided the original work is properly cited and
39. however, low testosterone levels after micro‐ TESE will lower
the general health and
quality of life. KS men face a number of comorbidities, such as
malignancies, meta‐
bolic syndrome, diabetes, cardiovascular disease, bone disease,
and immune dis‐
eases, which ultimately results in increased mortality rates.
Conclusion: A deeper understanding of the pathophysiology of
KS and the histories
of KS patients before they seek infertility treatment, during
which discussions with
multidisciplinary teams are sometimes needed, will help to
properly treat these
patients.
K E Y W O R D S
comorbidity, Klinefelter syndrome, microdissection testicular
sperm extraction,
nonobstructive azoospermia, pediatrics, testosterone
www.wileyonlinelibrary.com/journal/rmb
mailto:
https://orcid.org/0000-0002-3278-7747
http://creativecommons.org/licenses/by-nc/4.0/
mailto:[email protected]
| 141SHIRAISHI And MATSUYAMA
genitalia.7 A structurally abnormal X chromosome (eg,
47,iXq,Y) or
mosaicisms (eg, 47,XXY/46,XY) are also included in KS. The
origin
of the aberrant X chromosome in KS, of either paternal or
maternal
40. origin, and how the presence of a supernumerary X chromosome
causes the phenotype and morbidity in KS are not fully
understood.
The multiple aneuploidies causing the abnormalities of external
genitalia and children with KS with severe intellectual and
behav‐
ioral problems are relatively rare compared with other cases of
male
infertility, usually NOA. These are symptoms often present
among
men with KS, and in most of the cases, lead to its diagnosis
during
the workup for infertility. Less than 10% of these patients are
di‐
agnosed before puberty.3 On the other hand, we should not
forget
that KS is also responsible for general comorbidities related to
met‐
abolic and psychological disorders and risks of specific
malignancies,
which, in part, are caused by low testosterone in KS patients.
As
microdissection testicular sperm extraction (micro‐ TESE) has
been
shown to be an ideal sperm retrieval method8 used by many
urolo‐
gists and, in Japan, gynecologists, the chances of
low‐ testosterone‐
related symptoms and comorbidities are increasing. The
testicular
size is significantly smaller and serum testosterone levels are
lower
in KS patients compared to those in other NOA cases; thus, a
post‐
micro‐ TESE decline in testosterone is enhanced in KS
41. patients.9
Unfortunately, we often see many KS patients who claim to
have
impaired sexual function, general fatigue, and comorbidities
after
micro‐ TESE, and they are not properly followed up after
micro‐ TESE
irrespective of the results of sperm retrieval. Diagnosing KS
should
be the beginning of a strict follow‐ up of general health;
however,
reproductive medicine has caused new and severely low levels
of
testosterone in men with KS in the era of assisted reproductive
tech‐
nologies (ART).
Data related to infertility treatment are apt to be focused on the
sperm retrieval of KS. The purposes of this review are to
understand
the background pathophysiology of KS patients, including how
they
grew up, which symptoms occurred before they were treated for
infertility, what information is available after their infertility
treat‐
ment, and finally how they should be managed for lifelong
basis.
2 | K S A N D I N F E R T I L I T Y T R E AT M E N T
For a long time, KS was considered to be an absolute infertility
condi‐
tion once diagnosed. In 1996, Tournaye et al10 reported a
successful
testicular sperm retrieval by conventional TESE in men with
KS. One
42. year later, Palermo et al6 reported the first pregnancy and live
birth
resulting from a KS father after TESE/ICSI. A recent review
reported
by Majzoub et al11 indicated that publications from many
different
centers documented sperm retrieval rates (SRRs) in KS adults of
ap‐
proximately 50%‐ 70%, which are higher than those of general
NOA
cases, and reported excellent pregnancy rates and healthy 46,XY
or
46,XX offspring. A recent meta‐ analysis has shown an overall
SRR of
approximately 40%, ranging from 1% to 50%, in both
conventional
TESE and micro‐ TESE.12 These results indicate that
micro‐ TESE, but
not conventional TESE, is an ideal method to retrieve sperm
from
men with KS. A survey conducted on Dutch patients reported
that
the majority of KS patients and their partners would like to have
a
positive attitude toward TESE/ICSI to conceive a child.13
The age at micro‐ TESE is the only parameter to predict
success‐
ful sperm retrieval. Okada et al14 reported that the SRR was
81% in
patients 25‐ 29 years of age, 73% in patients 30‐ 34 years of
age, 25%
in patients 35‐ 39 years of age, and 22% in men 40‐ 44 years of
age,
and proposed that micro‐ TESE should be performed before 35
43. years
of age in men with KS. Data from the Cornell group showed
that
the SRR in men with KS was 71% in the 22‐ to 30‐ year
age‐ group,
86% in the 31‐ to 35‐ year age‐ group, and 50% in the 36‐ to
50‐ year
age‐ group. In fact, age affects the SRR, but the data are not
bleak.
The hormonal pattern and testicular volume have been advo‐
cated as possible prognostic factors for successful SRR in KS
pa‐
tients.5,15,16 Rohayem et al18 reported that the combination of
total
serum testosterone above 7.5 nmol/L and LH levels below 17.5
U/L
resulted in higher retrieval rates of spermatozoa by
micro‐ TESE in
both adolescents and adults with KS. Similar results were more
re‐
cently reported by Cissen et al19 Interestingly, Rohayem et al18
did
not document any clinical difference in nonmosaic KS patients
with
or without spermatozoa in their seminal fluid. The lack of
prognostic
value of the FSH levels might be related to the low inhibin B
levels
(which is almost undetectable during early puberty) in all
patients
with KS, which does not allow for the negative feedback of FSH
secretion.20
It should be recognized that postoperative testicular damage
leading to a decrease in testicular function has been described
44. as
a complication of micro‐ TESE. The transient but statistically
signifi‐
cant decrease in testosterone levels indicates that men are at
risk of
developing hypogonadism after micro‐ TESE, but there is
insufficient
evidence for whether patients actually experience clinical
symptoms
in the case of decreased serum testosterone levels. One apparent
parameter to predict post‐ micro‐ TESE hypogonadism is KS,9
and a
recent meta‐ analysis has shown that men with KS and men with
NOA
had the strongest decreases in total testosterone levels at 6
months
after TESE.21 The largest disaster regarding this issue is that a
ma‐
jority of men with KS are not properly followed up after
micro‐ TESE,
which will be addressed in another section in this review.
3 | P R E N ATA L , I N FA N T I L E , A N D
P E D I AT R I C P E R I O D S
The opportunity for physicians to diagnose and manage KS may
occur even during the prenatal period, as the diagnosis is
sometimes
established by prenatal genetic information. The recent
develop‐
ment of noninvasive prenatal screening is anticipated to
increase
the number of couples seeking counseling; however, a
discussion on
whether to abort has never occurred in KS cases.
45. Studies in KS infants have found that the postnataltempo‐
rary surge in gonadotropins (“mini‐ puberty”) may be
accompanied
by low testosterone levels22,23 or normal testosterone
levels.24,25
Simultaneously, FSH levels increase at 2‐ 3 months after birth,
142 | SHIRAISHI And MATSUYAMA
followed by a subsequent rapid decline.25 This early exposure
of an‐
drogens is severely disturbed with an increase in the number of
X
chromosomes. Genital anomalies (micropenis, undescended
testis,
bifid scrotum, and hypospadia) might present at birth, but
whether
they are due to the effects of supernumerary X chromosome(s)
or
androgen deficiency during the fetal period remains
undetermined.
Figure 1 shows a case of a KS baby with 49,XXXXY that was
referred
to us for the evaluation of sex development disorders. He
under‐
went bilateral orchiopexy and two‐ stage hypospadia repair, and
he
can now void at standing position. On the other hand,
individuals
with mosaic KS tend to present with milder symptoms.
Basically, testosterone‐ related symptoms do not occur during
infancy or early pediatric periods. Signs and symptoms
appearing
46. during this period, such as longer legs, disturbance of speech
and
cognition,adaptation problems, attention deficits, and social
skill
impairments,26,27 have been attributed to the genetic
abnormality
rather than to hypogonadism. As a result, men with KS are
prone
to learning difficulties, and their academic and professional
status
achievements are reported to be inferior to those without KS28;
however, this finding has not been fully investigated, and men
with
KS who visit our infertility clinic, of course they are only
limited cases
of KS, are always highly educated and talented. The
management
of children with KS warrants the collaboration of a
multidisciplinary
team consisting of pediatricians as well as behavioral specialists
to
ameliorate the developmental defects in early life.29 In
addition, an
echocardiographic study should be performed to reveal
congenital
cardiovascular abnormalities.30
Although multidisciplinary treatment for each child with KS
should be administered and testosterone may not play a major
role
in the treatment of KS during this period, there are some
anticipated
benefits of testosterone replacement therapy (TRT) on the
improve‐
ment of the energy level, attention span, mood, and cardiac
health
47. of young KS patients.31,32 Recently, two reports have indicated
that
early TRT may be beneficial for developmental and behavioral
issues
in boys with KS without serious adverse effects.33,34 However,
there
is concern that TRT might cause obstructive sleep apnea and
venous
thromboembolism.35,36 In addition, there is evidence that TRT
in
boys with KS is not as effective as that observed in males with a
nor‐
mal karyotype, at least regarding body proportions and bone
min‐
eral density (BMD).37,38 Studies that apply population‐ based
genetic
screening should be performed to investigate a proper
evaluation
of the costs and benefits of such an approach in KS patients.39
Randomized controlled trials are also needed to evaluate the
efficacy
of TRT on different aspects of the symptoms, to determine
optimal
dose regimens and, most importantly, to prevent the impairment
of spermatogenesis or to stimulate future spermatogenesis in
boys
with KS.40 In this situation, psychological aspects regarding
their
future reproductive function should be taken into consideration
to
avoid negative impacts on reproductive health, and follow ‐ up
should
be performed by a specialized team consisting of pediatricians,
adult
endocrinologists/andrologists, and psychologists during the
48. transi‐
tion from pediatric and adolescent periods to adulthood.
4 | A D O L E S C E N T P E R I O D
Although the onset of puberty in KS patients occurs at the same
time as that in normal boys, hypogonadism remains silent until
pu‐
bertal onset because testosterone levels are usually sufficient
for
satisfactory development of the body and genitalia.41,42
Additionally,
the severity of low‐ testosterone‐ related symptoms is mild in
KS pa‐
tients during the adolescent period, unlike in male
hypogonadotropic
hypogonadism. Furthermore, the negative feedback elevation of
LH
activates aromatase, resulting in an increase in estradiol, which
may
contribute to the development of gynecomastia.43 At puberty,
only
a few patients notice overt hypogonadism signs, such as poor
muscle
development, a short penis, and a lack of or sparse pubic,
axillary,
and facial hair. Low‐ to‐ normal testosterone levels contribute
to the
development of tall stature and disturb the ratio between the
upper
and lower skeletal segments.44 On the other hand, Bojesen et al
re‐
ported that 65%‐ 85% of KS patients present overt
hypogonadism
after the age of 25,45 and this number might differ among
countries
49. and according to the circumstances surrounding KS patients.
Along with LH, FSH is increased via the negative feedback
mech‐
anism of testosterone, estradiol, and inhibin B, whichultimately
cause the hypergonadotropic levels observed in adult KS
patients.46
Additionally, we suspect that some disturbances in testicular
devel‐
opment occur during this period. The testes of KS adolescents
can
develop to a volume of 6 mL due to the proliferation and
maturation
of Sertoli and Leydig cells,47 which is considered to be normal
ini‐
tial testicular development. Rising intratesticular testosterone
levels
are subsequently followed by an accelerating decline in germ
cells,
F I G U R E 1 Photographs of proximal
hypospadias and penoscrotal disposition
in a newborn with a 49,XXXXY karyotype
are shown (A). The scrotum is raised, and
a small penis is observed (B). This patient
was managed with bilateral orchiopexy
and a 2‐ stage hypospadias repair with a
simultaneous correction of a penoscrotal
transposition repair
| 143SHIRAISHI And MATSUYAMA
hyalinization of the tubules, degeneration of Sertoli cells, and
hyper‐
50. plasia of Leydig cells,47 resulting in the loss of testicular
volume and
a decrease in serum testosterone levels. It is still unclear why
the rise
in serum or intratesticular testosterone during puberty is
associated
with accelerated destruction of the seminiferous tubules during
this
period.48 Lue et al49 suggested that germ cell defects occurred
sec‐
ondary to a defect in spermatogonial migration during the
postnatal
period and not the prenatal period in XXY mice. On the other
hand,
normal spermatogenesis in KS can potentially be explained by
the
following three mechanisms: (a) Occult intratesticular
mosaicism in
which 46,XY spermatogonia are able to differentiate normally
into
mature sperm50; (b) Spermatogenesis arising from 47,XXY
sper‐
matogonia. It has previously been demonstrated that 47,XXY
sper‐
matogonia and spermatocytes are able to enter the
spermatogenic
process, leading to the formation of mature sperm51; and (c)
Active
repair of testicular stem cell renewal via the silencing or loss of
the
extra X chromosomes.52 This phenomenon causes the presence
of
ejaculate sperm during the adolescent period in some KS
patients,
which leads to the hypothesis that SRR by TESE might be
superior
51. during the adolescent period rather than in the adult period to
pre‐
serve future fertility potential.
5 | I S T E S E D U R I N G A D O L E S C E N C E
E F F E C T I V E I N K S PAT I E N T S ?
Limited data suggest that sperm production in men with KS, as
de‐
termined by the results of TESE, is rapidly impaired after a
certain
age (approximately 35 years of age), and it might be better to
retrieve
sperm as soon as the diagnosis is made. This suggestion was
gener‐
ated from data reported by Okada et al.14 In their study, the
SRR in
25 patients >35 years of age was only 23%. On the other hand,
data
from Cornell University showed that the SRR in men with KS
was
71% in the 22‐ to 30‐ year age‐ group, 86% in the 31‐ to
35‐ year age‐
group, and 50% in the 36‐ to 50‐ year age‐ group. In our
experience,
the SRR in 84 men with KS was 61% (11/18) in the 21‐ to
30‐ year
age‐ group, 55% (21/38) in the 31‐ to 35‐ year age‐ group,
52% (14/27)
in the 36‐ to 50‐ year age‐ group, and 100% (1/1) in
52‐ year‐ old men.
Based on these results, spermatogenesis in men with KS
declines
gradually and not rapidly. Taking these results together with the
biological information that progressive hyalinization of
seminiferous
52. tubules is observed after puberty in men with KS,47,48 it has
been
suggested that performing earlier TESE procedures might result
in
better SRR results.17 A meta‐ analysis has shown that
successful SRR
in KS patients is independent of age.12
Several studies have reported the presence of sperm by ejacula ‐
tion in adolescents and young adults with KS,15,53,54 and these
sperm
should be cryopreserved for future treatment. However,
problems
arise in KS adolescents who have never performed masturbation
or
whose semen analysis results in azoospermia. In this situation,
TESE
is an option for evaluating spermatogenesis and sperm retrieval.
In
2001, Damani et al56 first reported the results of TESE in a
15‐ year‐
old adolescent to preserve fertility before TRT for the
symptoms of
hypogonadism. In 2004, Wikstrom et al47 performed a
single‐ site
testis biopsy for histologic analysis in 14 adolescents with KS,
which
is the same procedure used for conventional TESE, and reported
that
no mature sperm were observed in any tissue sections. In this
study,
a few types of Ap and Ad spermatogonia were found in seven
boys
aged 10‐ 12.5 years, whereas no spermatogonia of any type
were
53. detected in the other seven boys aged 11.7‐ 14 years, and they
con‐
cluded that diploid germ cells vanished in early puberty in boys
with
KS.47 In 2012, Gies et al54 reported data from testicular biopsy
in
seven boys aged 10.2‐ 15.6 years, and they could not find any
mature
sperm; however, they could identify spermatogonia upon
histologic
analysis in four of the boys. In 2013, Rives et al57 published
their
results in five adolescents with KS who underwent bilateral
conven‐
tional TESE and noted that sperm were found in a 16‐ year‐ old
boy,
elongated spermatids and spermatocytes were found in a
15.5‐ year‐
old boy, and no germ cells were found in the remaining three
boys
aged 15‐ 16.5 years. In the same year, Van Saen et al reported
that
no mature sperm were found in adolescents boys with KS, but
72%
(5/7) of the patients, boys with KS from 13 to 16 years of age,
pre‐
sented with spermatogonia. The overall number of
spermatogonia
in the boys with KS was significantly reduced compared with
that in
normal adolescent boys.58,59
The micro‐ TESE procedure performed in adolescent boys with
KS was first performed by a Cornell group and reported by
Mehta
et al in 2013. Ten KS patients aged 14‐ 22 years underwent
54. micro‐
TESE, and mature sperm were found in seven patients (SRR:
70%).60
A subsequent publication from the same institution showed a
65%
retrieval rate in 127 KS adult men, which was the same rate of
suc‐
cess for adolescents and adults.61 Plotten et al62 investigated
the
largest series to date comparing SRRs at the same institution for
young KS patients aged 15‐ 23 years and adult KS patients
more
than 23 years of age and found SRRs of 52% and 62%,
respectively,
which were not significantly different. In the same year,
Rohayem et
al18 reported the results of micro‐ TESE in 50 adolescents from
13
to 19 years of age, and the SRR was 38% (19/50). Their result
was
interesting because the SRR was 10% (1/10) in the subgroup of
ado‐
lescents between 11 and 14 years of age, whereas in the
adolescents
between 15 and 19 years of age, the SRR was much higher at
45%
(18/40).18 Most recently, Nahata et al55 reported a 50% SRR in
10
adolescent boys with KS between 15 and 23 years of age and
indi‐
cated no distinct pattern or prediction based on the clinical data.
The
accumulated data from these publications showed that total
SRRs by
conventional TESE were 30% (15/50) and 42.6% (29/68) by
micro‐
55. TESE, which is summarized in Figure 2. It is clear that
micro‐ TESE has
a substantial advantage for retrieving sperm, but the risks and
ben‐
efits of the procedure must be considered. Information related
to
reproductive outcomes is still lacking; for example, the ICSI
results
related to using frozen sperm, how many KS patients have
successful
sperm retrieval, how many KS patients are married, and how
many
KS patients could have a child born live have not been
determined.
Experimentally, there are several options for cryopreservatio n
of
spermatogenic stem cells from either a testicular cell suspension
or
testicular tissue. However, there are no reports of inducing
haploid
144 | SHIRAISHI And MATSUYAMA
cells in vitro using 47,XXY spermatogonia. In summary,
fertility pres‐
ervation techniques for adolescent boys with KS are still
experi‐
mental, and use of the cryopreserved material when the boys
reach
adulthood cannot be guaranteed.
One dilemma in the management of adolescent KS patients is
the negative effect of TRT on spermatogenesis.TRT has
previously
56. been reported to have a negative impact on the future fertility of
KS
patients, as an SRR of 20% was observed in five adults with
KS.63
In contrast, Plotton et al62 found no negative influence of TRT
on
sperm retrieval in 41 KS patients and reported an SRR by
micro‐ TESE
in 9/17 (52.9%) men with previous TRT and a positive TESE in
14/24
(59.1%) men with KS who never had TRT. TRT was stopped 9
months
prior to micro‐ TESE. Another study included 10 KS
adolescents who
received continuous topical testosterone replacement and/or an
aromatase inhibitor and found mature sperm by micro‐ TESE in
seven
of 10 participants (70%).60 Considering these results together,
TRT
is unlikely to have a permanent negative impact on
spermatogenesis,
but larger studies and other medical treatment (eg,
gonadotropins,
clomiphene, other aromatase inhibitors) are warranted to
confirm
these findings.
Most importantly, we must consider how patients and their
fam‐
ilies feel about fertility preservation, especially in cases in
which
micro‐ TESE needs to be performed. A psychosocial
investigation
clearly demonstrates a high incidence of negative feelings
toward
infertility and its effect on overall life satisfaction and
57. well‐ being.64
Two other studies have shown that reproductive function is not
an
issue of awareness in adolescent boys with KS, whereas their
parents
and physicians appreciate fertility preservation at a young
age.57,65
The influence of a TESE procedure on the psychological health
of
adolescents with KS has not been investigated, and further
studies
are warranted.
6 | P O S T I N F E R T I L I T Y M A N A G E M E N T:
D I A G N O S I S O F K S I S A P R O X Y O F G E N E
R A L
H E A LT H
A 26‐ year‐ old man with KS was referred to our clinic and
com‐
plained of decreased libido and general fatigue. His testicular
size
was 0.5 mL bilaterally, and his total testosterone concentration
was
15 ng/dL. He underwent micro‐ TESE at an IVF clinic 6 months
prior
to visit at our clinic, and his preoperative total testosterone
level was
276 ng/dL. Unfortunately, no sperm were found in his testes,
and his
management was stopped at the clinic. At our hospital, he
started
TRT every 3 weeks, and his symptoms were dramatically
improved.
This type of case is not rare but rather very common in our
58. urology
department. What are the problems in this case?
In addition to reproductive medicine, many urologists in Japan
are engaged in general urology as well as nephrology,
hemodialy‐
sis, and renal transplant, which enables a quick start to the
manage‐
ment of comorbidities, such as hypertension, diabetes,
dyslipidemia,
and hyperuricemia, in most men with KS after infertility
treatment
F I G U R E 2 The numbers of patients
and sperm retrieval rates in adolescents
who underwent conventional (A) and
micro‐ testicular sperm extraction (B)
procedures are shown. The closed bar
indicates no sperm retrieval, and the open
bar indicates successful sperm retrieval
0
5
10
15
20
0
10
20
59. 30
40
9, 10 11, 12 13, 14 15, 16 17-19 years 13, 14
15, 16 17-19 years
N
u
m
b
er
o
f
p
at
ie
n
ts
N
u
m
b
er
o
f
60. p
at
ie
n
ts
SRR: 0% 0% 14% 21% 65% SRR:
15% 50% 48%
(A) (B) ESET-orciMESET lanoitnevnoC
F I G U R E 3 The symptoms of and
strategies for managing Klinefelter
syndrome on a lifelong basis and the roles
of those who should participate in the
management
| 145SHIRAISHI And MATSUYAMA
(Figure 3). If micro‐ TESE is performed at an IVF clinic by
either a
urologist or gynecologist, patients are recommended to visit the
urology/andrology or endocrinology department as soon as
possible
for follow‐ up for an extended period. In other words,
micro‐ TESE
induces new and severely low testosterone levels in recipients.
Furthermore, we must make every effort to improve our ability
to
diagnose KS. The high frequency of mild KS phenotypes
explains, at
61. least in part, why a majority of the patients remain
undiagnosed.66
A distinct racial difference in the prevalence of KS and the
patterns
of symptoms during the pediatric and adolescent periods are
still
unclear; in our experience, the BMIs of men with KS who
visited an
infertility clinic are obviously low (approximately 23) compared
with
T A B L E 1 Comorbidity of Klinefelter syndrome (KS)
Findings References
Cancer
Extragonadal germ cell tumors Nonseminomatous subtype
Nichols (1987)103
Younger than non‐ KS
Breast cancer 4‐ to 60‐ fold compared with non‐ KS Swerdlow
et al (2005)94
Brinton (2011)75
Sasco et al (1993)74
Gomez‐ Raposo et al (2010)76
Younger than non‐ KS
Metabolism
Obesity, metabolic syndrome Abdominal fat is increased
Bojesen et al (2006)90
Aksglaede (2008)104
Laaksonen (2014)105
62. Pasquali et al (2013)38
4‐ to 5‐ fold compared with non‐ KS
Odds ratio of 2.3 with low testosterone
Effect of TRT on BMI is controversial
Diabetes 8%‐ 50% in Western countries Takeuchi (1999)106
Lichiardopol (2004)107
Swerdlow et al (2005)94
Bojesen et al (2006)90
Pasquali et al (2013)38
3.9%‐ 4.1% in Japan
HR of 2.21 for T1D and 3.71 for T2D
Prediabetes is more frequent
No effect of TRT
Cardiovascular disease
Congenital abnormalities Mitral valve prolapse Fricke (1981,
1984)108,109
Pasquali et al (2013)38Diastolic dysfunction
Conduction defects Short QTc interval Jorgensen (2015)93
Liu (2010)110
Lai (2009)111
Atrial fibrillation
Thrombosis Hazard ratio of 3.6 to 5.7 for pulmonary thrombosis
Bojesen et al (2006)90
63. Swerdlow et al (2005)94
Campbell et al (1981)96
Hazard ratio of 6.6 to 7.9 for deep vein thrombosis
Bone disease
Osteoporosis/fracture Decreased bone mineral density Bojesen
et al (2006)90
Swerdlow et al (2005)94
Bojesen and Gravholt (2011)68
Ferlin et al (2015)98
Femur fracture
8‐ fold increase compared with non‐ KS
Low levels of 25‐ OH vitamin D
Immunological diseases
Autoimmune diseases 13‐ fold increase in systemic lupus
erythematosus
compared with non‐ KS
Scofield (2008)112
El‐ Mansoury (2005)113
Sawalha et al (2009)100
Rovensky et al (2010)101
Seminog et al (2015)102
Rheumatic diseases
Addison's disease
Diabetes mellitus type 1
64. Multiple sclerosis
Acquired hypothyroidism
Sjogren's syndrome
TRT, testosterone replacement therapy.
146 | SHIRAISHI And MATSUYAMA
those described in data from the United States and Europe
(approx‐
imately 24‐ 30). Investigations regarding the patterns of
comorbidity
and the TRT treatment regimen for KS patients from Japan and
Asian
countries are warranted.
Based on data from epidemiological studies, KS is associated
with increased morbidity and mortality althoughall the
information
collected regarding KS is derived from diagnosed cases
comprising
only approximately 25% of the expected affected number of
pa‐
tients.3,66 In other words, the diagnosis of KS at the time of
infertility
treatment is a special opportunity to evaluate their general
health,
and patients and medical providers should begin follow‐ up and
the
management of comorbidities. Multidisciplinary management is
needed for lifelong follow‐ up (Figure 3).
65. Comorbidities associated with KS, such as metabolic syndrome,
diabetes, osteoporosis, and cardiovascular diseases, often
appear
in adulthood, with many of the patients being of reproductive
age;
these comorbidities increase with age,67 which is ultimately
related
to a significant increase in mortality risk. Actually, men with
KS re‐
quire more frequent hospitalization, and the life span of KS
patients
appears to be shorter by approximately 2.1 years compared to
that of
the general population.68 The main comorbidity associated with
in‐
creased mortality risk is the increased prevalence of type 2
diabetes
and thrombosis/embolism disorders, both of which are risk
factors
of cardiovascular events.69 Other conditions increasing the
morbid‐
ity of men with KS are osteoporosis and bone fractures as well
as
the higher prevalence of specific types of cancer and
immunological
diseases (Table 1). The reason for this impaired mortality is not
well
understood, and further investigations are needed to clarify
whether
it is due to the syndrome per se or is mainly a consequence of
low
testosterone levels. A number of reports show that low
testosterone
is a biomarker for increased mortality in normal healthy men.70
66. In addition to the comorbidities mentioned above, the loss of
mus‐
cle and a depressed mood due to low testosterone are not
directly
related to mortality but are associated with a markedly
decreased
quality of life.71 Of note, from observational studies, some
positive
effects of TRT in KS have been reported, including decreased
fatigue,
less irritability, and improved libido, muscle strength, and
sleep.72,73
The general consensus indicates that most men with KS should
be
offered TRT around the time of puberty with a target
testosterone
level in the high normal range.45 However, no randomized
placebo‐
controlled trials have been performed to date to verify this
recom‐
mendation, and data on future spermatogenesis remain
unknown.
As a result, the timing of the initiation and the dose of TRT in
KS
patients remain topics for further investigation. Specifically, a
study
on treatment during the pediatric period showed promising
results
for improving behavior and neurodevelopment,33 and this
treatment
could have an overall positive effect on social integration
during the
pediatric and adolescent periods and, presumably, also in adult
life.
6.1 | KS and cancer
67. Breast cancer andgerm cell tumors, especially extragonadal
tumors,
occur more frequently in KS patients than in the general
population
(Table 1). Several meta‐ analyses concerning the prevalence of
male
breast cancer have shown the incidence of breast cancer in KS
to
be increased 4‐ to 30‐ fold compared with that in normal
men,74,75
which supports that KS is the strongest independent risk factor
for
breast cancer in males.76 The mean age of breast cancer onset
in KS
patients is 58 years,77 which is earlier than that of normal
healthy
men (67 years of age).78 The early diagnosis of breast cancer
requires
monthly breast self‐ examination and a periodic physical
examination
by a specialized physician.75 A markedly increased prevalence
of
germ cell tumors in KS patients has been confirmed in
pathology‐
based studies,79 and nonseminomatous tumors are the major
patho‐
logical type. Additionally, the diagnosis occurs at a younger age
in KS
patients than in normal healthy men. A recent Italian
consensus80
suggests a biannual chest X‐ ray to address the risk of
extragonadal
germ cell tumors.
68. On the other hand, the prevalence of prostate cancer and the
associated mortality have been reported to be lower in KS
patients
than in normal healthy men.79,81 The reason for these lower
rates
may be because the presence of hypogonadism does not
stimulate
the growth of prostate cancer cells, whereas recent studies cast
doubt on the correlation between intraprostatic testosterone
lev‐
els and the carcinogenesis and progression of prostate cancer.82
Interestingly, the level of prostate‐ specific antigen, a marker of
pros‐
tate cancer, stays below the normal range regardless of the
presence
of TRT.83
6.2 | KS and diabetes
In the general population, a clear relationship between the
serum
testosterone concentration and insulin sensitivity has been re‐
ported.84,85 Low testosterone levels are associated with
increased
insulin resistance,86 and the onset of insulin resistance may be
influ‐
enced by testosterone levels.87,88 Serum testosterone levels are
in‐
dependently associated with insulin resistance, suggesting that
low
testosterone might be responsible for diabetes (in this review,
type 2
diabetes),89 and a 5‐ fold increase in metabolic syndrome38 has
been
observed in men with KS. After a diabetes diagnosis,
atheroscle‐
69. rosis progressively follows, requiring the evaluation of
endothelial
function.
We expect and hope for a high efficacy of TRT on glucose me‐
tabolism. Some studies have reported that the actual treatment
for
low testosterone improves metabolic risk factors and insulin
resis‐
tance in some individuals, but not all studies have shown
positive
results.90 Unfortunately, KS is a condition in which TRT does
not
have positive effects on glucose metabolism.91 In a study
reported
by Pasquali et al38 that included 48 men with KS and 21 men
with
hypogonadotropic hypogonadism who were all treated with TRT
for
3 years, KS patients were more insulin resistant, had increased
body
fat and lower levels of HDL, and showed an increased
prevalence of
metabolic syndrome than those with hypogonadotropic
hypogonad‐
ism treated with TRT. Compared to other types of
hypogonadism,
TRT has not been shown to improve metabolic syndrome or
diabetes
in KS patients,38,91 indicating either a potential hormonal
resistance,
| 147SHIRAISHI And MATSUYAMA
70. consistent with the accompanying elevated gonadotropins,80 an
increased aromatization,92 or more simply, that testosterone is
not
involved in the glucose metabolism of KS, and more complex
and un‐
revealed mechanisms exist that are associated with KS and
glucose
metabolism. However, information regarding the effect of TRT
on
glucose metabolism in Japanese men with KS is lacking, and
investi‐
gations are needed to determine optimal therapeutic regimens
and
follow‐ up schedules for Japanese patients.
6.3 | KS and cardiovascular disease
A number of reports indicate that KS is closely associated with
CVD
and abnormalities in electrocardiography and cardiopulmonary
ex‐
ercise tests (reviewed in Salzano et al30). There are no
standardized
guidelines for the follow‐ up of men with KS. In addition to the
current
guidelines of TRT for hypogonadism, including T, PSA, and
hematocrit
evaluation,93 KS patients should be followed up for related
comor‐
bidities, especially for CVD. Because CVD is the most
life‐ threatening
comorbidity, the initial evaluation has been proposed to include
risk
assessment for metabolic syndrome and thromboembolic disease
as
well as echocardiography.30 AS structural and functional
71. cardiovas‐
cular abnormalities, a shorter QTc interval in KS patients
compared
with that in controls,94 and a 55% prevalence of mitral valve
prolapse
was found in 22 patients with KS. Data from large
registry‐ based
studies95 indicate that men with KS are at an increased risk of
throm‐
boembolic events. One reason for this increased risk is that the
vis‐
cosity of blood in KS patients is high, causing the formation of
venous
thromboembolism.96 In addition, Campbell et al found that the
risks
of pulmonary embolism and deep venous thrombosis were 5‐ 20
times
higher in KS patients than in normal healthy men.97 The
updated AUA
guideline for the evaluation and management of testosterone
defi‐
ciency indicates that whether TRT increases or decreases the
risk of
cardiovascular events cannot be definitively stated. This
guideline
also indicates that there is no definitive evidence linking TRT
to a
higher incidence of venous thromboembolic events.98
Obviously, this
guideline is for general hypogonadal men, and data on men with
KS
are needed for future investigations.
6.4 | KS and bone disease
Klinefelter syndrome patients also face an increased prevalence
72. of bone disorders, particularly reduced BMD. A study found
that
42.5% of KS patients had a combination of osteoporosis and
os‐
teopenia, which was 8‐ fold higher than the incidence in men
with
a normal karyotype.99 Reduced BMD is caused by increased
bone
turnover and is accompanied by an increased risk of bone frac‐
tures, especially in the femoral area. Unlike fractures that occur
in aging males, men with KS are more active, and the influence
of
fractures on their body and socioeconomic aspects are more se‐
rious. Furthermore, decreased BMD and fractures affecting
mor‐
bidity and mortality 68,95 have long been associated with KS.
The
mechanism of decreased BMD changes upon normal aging
because
the hypogonadism that occurs during the critical pubertal stages
of bone development accompanying low physical exercise
capacity
and muscle strength is present in KS patients. TRT has been
shown
to improve BMD,100 but vitamin D repletion has been demon‐
strated to be superior to TRT for improving BMD; KS patients
are
more prone to 25‐ OH vitamin D fluctuations than normal
men.99
Practically, biannual assessments of BMD and 25‐ OH vitamin
D
levels to evaluate the risk of osteoporosis are recommended.80
6.5 | KS and immune diseases
73. The association between KS and immune diseases, including
rheu‐
matoid arthritis (RA), systemic lupus erythematosus (SLE),
idiopathic
juvenile arthritis, psoriatic arthritis,
polymyositis/dermatomyositis,
systemic sclerosis, and mixed connective tissue disease, has
long
been described101,102; however, there has been no systematic
evi‐
dence or rationale to account for the link. A retrospective study
has
demonstrated that compared to that of normal healthy men, men
with KS have a significantly increased risk of developing
Sjogren’s
syndrome (risk ratio: 19.3), SLE (risk ratio: 18.1), Addison’s
disease
(risk ratio: 11.7), type 1 diabetes mellitus (risk ratio: 6.1),
multiple
sclerosis (risk ratio: 4.3), RA (risk ratio: 3.3), and acquired
hypothy‐
roidism (risk ratio: 2.7) .
7 | C O N C L U S I O N
The incidence of KS syndrome is 1:600, and the majori ty of
patients
in Japan are diagnosed upon a male infertility evaluation by
medi‐
cal providers, especially gynecologists and urologists. Finding
sperm
via micro‐ TESE is only one consideration for men with KS
among a
number of comorbidities that are found during adulthood,
especially
after infertility treatment. In other words, patients need lifelong
74. care
and often need a multidisciplinary team that includes general
prac‐
titioners, psychologists, speech therapists, and endocrinologists
in addition to urologists and gynecologists. Additionally,
infertility
specialists should understand the pathophysiology and previous
his‐
tories of KS patients before they visit the IVF clinic, and
discussions
with general practitioners and pediatricians are sometimes
needed
to properly treat these patients. Again, KS should be managed
from
the infantile and pediatric periods to the geriatric period.
D I S C L O S U R E S
Conflict of interest: The authors declare no conflict of interest.
Human
rights statement and informed consent: This article does not
contain
any study with human participants that have been performed by
any of the authors. Animal studies: This article does not contain
any
study with animal participants that have been performed by any
of
the authors.
O R C I D
Koji Shiraishi https://orcid.org/0000‐ 0002‐ 3278‐ 7747
https://orcid.org/0000-0002-3278-7747
https://orcid.org/0000-0002-3278-7747
75. 148 | SHIRAISHI And MATSUYAMA
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