BRM is a successful biopharmaceutical company formed in 1996 by Dennis Guberski and Dr. Arthur Like of the University of Massachusetts Medical School (UMass). Over the course of 20 years the founders developed proprietary diabetes research models under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). BRM licensed this intellectual property portfolio from UMass in 1998 and since that time has used these proprietary tools to become one of the leading sources of customized preclinical contract research specializing in type 1 and type 2 diabetes.
This is a comprehensive review of the physiology and pathophysiology of iron deficiency anemia and the evolution of its treatment with parenteral iron to the current recommendations. In our practice, in an attempt to minimize allogenic blood transfusions, we optimize preoperatively patients with iron deficiency anemia by means if intravenous iron replacement.
Harnessing the Power of Nutrition to Complement Brain Tumor CareJeanne M Wallace PhD
Presentation by Jeanne M. Wallace, PhD, CNC, at the 1st Annual Brains Matter conference (Sept 2012 in Seattle), sponsored by the Chris Elliott Foundation. Learn how nutrition can play a powerful role to influence the terrain (environment) surrounding cancer cells. Discover foods that can "talk" to your genes, suppressing oncogenes and turning on tumor suppressor genes. Explore simple diet and lifestyle changes you can make to nourish your wellness when facing a brain tumor diagnosis.
Serum Vitamin D Deficiency is Associated with NASH in AdultsJames Nelson
The aim of this study was to determine the relationship of serum vitamin D levels to histologic features of NAFLD, and associated demographic, clinical, and laboratory data in the well characterized NASH CRN cohort.
Considering the mechanisms behind cancer cachexia-anorexia can inform wiser n...Jeanne M Wallace PhD
Unwanted weight loss and lack of interest in food drives many cancer patients to conventional canned nutrition formulas like Ensure, but these may actually foster the oncogenic process. This article outlines the underlying physiology of cachexia and compares various feeding formulas including holistic nutrition options.
Modulating Oncometabolic Syndrome: Integrative Diet & Nutrition to Complement...Jeanne M Wallace PhD
Presentation by Jeanne M. Wallace, PhD, CNC, at CMBM's Food as Medicine conference, Indianapolis 2013. Oncometabolic Syndrome is a cluster of metabolic factors that influence the growth and progression of cancer. Standard lab testing can be used to assess nutritional factors that may influence cancer outcomes, tailor a protocol to an individual's unique needs, and evaluate the efficacy of the nutrition intervention in modulating these factors.
Radiation Therapy: Nutritional Strategies to Improve OutcomesJeanne M Wallace PhD
Presentation by Jeanne M. Wallace, PhD, CNC, at "Integrative Cancer Medicine: Clinical Applications of Cancer Strategies" conference April 26-29, 2013, Scottsdale AZ. Explore the mechanisms of tumor resistance to radiation therapy. Review diet, lifestyle, nutritional and botanical strategies for bolstering therapeutic efficacy. Employ selective radioprotectors to lessen injury to healthy tissues. Take into consideration the unfavorable consequences of radiotherapy, which can potentially increase the oncogenic potential of surviving tumor cells, and develop a plan for blocking these pathways. Cases will be presented from 15 yrs experience of the Nutritional Solutions team in counseling clients undergoing radiation therapy for Glioblastoma multiforme brain tumors, colorectal, head-and-neck, breast and gynecologic cancers.
1) Vitamin D plays an important role in muscle strength and performance, especially in the elderly. Studies show that treatment with vitamin D can increase the size and number of type II muscle fibers which are important for strength.
2) Maintaining serum 25(OH)D levels of at least 75 nmol/L through vitamin D3 supplementation of 800-1000 IU per day can reduce the risk of falls and fractures in older adults as well as lower the risk of other chronic diseases.
3) According to studies, a significant portion of the United States population has serum 25(OH)D levels below recommended levels for optimal health benefits. Certain groups like blacks, the elderly, and northerners are particularly
This is a comprehensive review of the physiology and pathophysiology of iron deficiency anemia and the evolution of its treatment with parenteral iron to the current recommendations. In our practice, in an attempt to minimize allogenic blood transfusions, we optimize preoperatively patients with iron deficiency anemia by means if intravenous iron replacement.
Harnessing the Power of Nutrition to Complement Brain Tumor CareJeanne M Wallace PhD
Presentation by Jeanne M. Wallace, PhD, CNC, at the 1st Annual Brains Matter conference (Sept 2012 in Seattle), sponsored by the Chris Elliott Foundation. Learn how nutrition can play a powerful role to influence the terrain (environment) surrounding cancer cells. Discover foods that can "talk" to your genes, suppressing oncogenes and turning on tumor suppressor genes. Explore simple diet and lifestyle changes you can make to nourish your wellness when facing a brain tumor diagnosis.
Serum Vitamin D Deficiency is Associated with NASH in AdultsJames Nelson
The aim of this study was to determine the relationship of serum vitamin D levels to histologic features of NAFLD, and associated demographic, clinical, and laboratory data in the well characterized NASH CRN cohort.
Considering the mechanisms behind cancer cachexia-anorexia can inform wiser n...Jeanne M Wallace PhD
Unwanted weight loss and lack of interest in food drives many cancer patients to conventional canned nutrition formulas like Ensure, but these may actually foster the oncogenic process. This article outlines the underlying physiology of cachexia and compares various feeding formulas including holistic nutrition options.
Modulating Oncometabolic Syndrome: Integrative Diet & Nutrition to Complement...Jeanne M Wallace PhD
Presentation by Jeanne M. Wallace, PhD, CNC, at CMBM's Food as Medicine conference, Indianapolis 2013. Oncometabolic Syndrome is a cluster of metabolic factors that influence the growth and progression of cancer. Standard lab testing can be used to assess nutritional factors that may influence cancer outcomes, tailor a protocol to an individual's unique needs, and evaluate the efficacy of the nutrition intervention in modulating these factors.
Radiation Therapy: Nutritional Strategies to Improve OutcomesJeanne M Wallace PhD
Presentation by Jeanne M. Wallace, PhD, CNC, at "Integrative Cancer Medicine: Clinical Applications of Cancer Strategies" conference April 26-29, 2013, Scottsdale AZ. Explore the mechanisms of tumor resistance to radiation therapy. Review diet, lifestyle, nutritional and botanical strategies for bolstering therapeutic efficacy. Employ selective radioprotectors to lessen injury to healthy tissues. Take into consideration the unfavorable consequences of radiotherapy, which can potentially increase the oncogenic potential of surviving tumor cells, and develop a plan for blocking these pathways. Cases will be presented from 15 yrs experience of the Nutritional Solutions team in counseling clients undergoing radiation therapy for Glioblastoma multiforme brain tumors, colorectal, head-and-neck, breast and gynecologic cancers.
1) Vitamin D plays an important role in muscle strength and performance, especially in the elderly. Studies show that treatment with vitamin D can increase the size and number of type II muscle fibers which are important for strength.
2) Maintaining serum 25(OH)D levels of at least 75 nmol/L through vitamin D3 supplementation of 800-1000 IU per day can reduce the risk of falls and fractures in older adults as well as lower the risk of other chronic diseases.
3) According to studies, a significant portion of the United States population has serum 25(OH)D levels below recommended levels for optimal health benefits. Certain groups like blacks, the elderly, and northerners are particularly
This document describes a case of a novel form of glycogen storage disease (GSD) found in a 62-year-old female patient. Genetic screening revealed a variant in the AGL gene encoding glycogen debranching enzyme, resulting in an amino acid substitution that is believed to impair the enzyme's glucosyltransferase activity specifically in muscle tissue. This causes symptoms like exercise-induced muscle cramps and fatigue consistent with a rare type of GSD IIIc affecting only muscle. The patient responded well to a high-protein diet and carnitine supplementation, representing a newly identified variant of GSD IIId.
This document summarizes the background and qualifications of Dr. Gwei-Bian Gao, a cardiologist and diabetes specialist. It lists his medical education, areas of specialty training, positions held at major hospitals, awards for diabetes care quality, and current practice at Muh-Kang Clinic in Kaohsiung, Taiwan. The clinic focuses on cardiology, pulmonology, endocrinology, and diabetes management. Recent clinical trials show that SGLT2 inhibitors can protect cardiac and renal function in patients with type 2 diabetes.
The document discusses diabetes mellitus and fracture risk. It notes that type 2 diabetes affects over 700,000 people in the Netherlands and is associated with higher bone mineral density but also more rapid bone loss over time. While type 2 diabetes is initially linked to higher bone density due to factors like higher body weight, studies have shown those with type 2 diabetes have a 1.7 times higher risk of hip fractures and 1.2 times higher risk of any fracture after adjusting for characteristics like age, body mass index and bone mineral density. The increased fracture risk in type 2 diabetes may be due to factors beyond bone mineral density, such as changes in bone microarchitecture, turnover and material properties from excess glucose.
Ckd-MBD & osteoporosis the management dilemma Ayman Seddik
This document discusses the management of chronic kidney disease-mineral and bone disorder (CKD-MBD) and osteoporosis in elderly patients. It outlines that CKD-MBD and osteoporosis are common in elderly populations and impact mortality and morbidity. Management is based on the stage of CKD and involves controlling serum phosphorus and calcium levels, using phosphate binders to treat hyperphosphatemia, and treating abnormal PTH levels. Guidelines recommend treating bone disease with bisphosphonates and other osteoporosis medications according to the condition and stage of CKD. The risks and benefits of different treatment options must be considered based on each patient's situation.
This clinical trial compared the efficacy and safety of two doses of ferrous bisglycinate chelate (60mg once daily and 60mg twice daily) to ferrous ascorbate (100mg once daily) in treating iron deficiency anemia in women. Over 8 weeks, all three treatments significantly increased hemoglobin levels from baseline with no significant differences between groups. Adverse events occurred in 9-13% of subjects across the groups, mostly gastrointestinal disorders, with no serious adverse events reported. The study demonstrated that ferrous bisglycinate chelate at both doses and ferrous ascorbate were effective and well-tolerated treatments for iron deficiency anemia.
The document discusses drug-induced osteoporosis, focusing on glucocorticoids, aromatase inhibitors, androgen deprivation therapy, Depo-provera, proton pump inhibitors, and selective serotonin reuptake inhibitors. It summarizes their effects on bone loss and fracture risk, mechanisms of action, and treatment approaches. Key findings include rapid bone loss associated with glucocorticoid use, increased fracture risk from aromatase inhibitors and androgen deprivation therapy for cancer patients, and conflicting data on fracture risk from proton pump inhibitor use.
intravenous iron sucrose is a ray of hope for treating iron defeciency anemia which is still a major problem in india. It circumvents the problem of compliance and its large safety encourages its routine use in antenatal care and is highly suitable for treating postpartum anemia...
Musculoskeletal Complications of Cancer and its TreatmentsInsideScientific
Cancer frequently associates with the occurrence of cachexia, a debilitating syndrome responsible for reduced tolerance to anticancer therapies, as well as increased morbidity and mortality. Dr. Bonetto's group reported that animals bearing cancers not only show reduced skeletal muscle mass and strength, but also dramatic bone loss, despite the absence of bone metastases. Their latest findings revealed that muscle and bone depletion may also occur as a direct consequence of anticancer treatments (i.e., chemotherapy). There is now substantial agreement on the fact that abnormalities of the so-called ‘muscle-bone crosstalk’ may contribute to the onset of cachexia secondary to cancer or chemotherapy. Clinical and experimental observations also suggest that pharmacological bone preservation may concurrently benefit muscle mass in animal models, burn patients and osteoporotic women.
In this webinar Dr. Bonetto will present evidence that bone preservation directly impacts muscle size and function in cachexia, thus also contributing to unraveling novel pathogenetic mechanisms and opening new avenues for treatment.
The document discusses collagen type I and II supplements for treating rheumatic diseases. Clinical trials showed that collagen type II significantly reduced symptoms of osteoarthritis, and collagen type I reduced symptoms in patients with rheumatoid arthritis and systemic sclerosis, with no serious adverse effects reported. A randomized controlled trial found that collagen type I (Colafit) significantly decreased pain and functional impairment in patients with knee osteoarthritis, compared to placebo.
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...My Healthy Waist
By Ulf Smith, MD, PhD, Professor of Internal Medicine, The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
Impact of obesity on cardiometabolic risk: Will we lose the battle?My Healthy Waist
1. Obesity and related conditions like diabetes pose a growing threat to cardiovascular health and mortality. Risk factors like obesity, physical inactivity and diabetes accounted for thousands of additional deaths in the UK from 1981-2000.
2. Studies show obesity is independently associated with coronary endothelial dysfunction and a more malignant form of coronary artery disease. Even modest excess weight increases the risk of acute conditions like unstable angina and myocardial infarction.
3. Visceral abdominal fat is metabolically active and secretes inflammatory proteins that can promote atherosclerosis. Losing weight and reducing inflammation may help lower cardiovascular risk.
treating anemia is a big challenge.oral iron therapy do not adequately treat IDA. IV ferric carboxy maltose (FCM)effectively treats IDA by circumventing the problem compliance of oral iron therapy.
The document discusses the strong link between erectile dysfunction (ED) and cardiovascular disease, as ED is correlated with reduced nitric oxide (NO) production and endothelial dysfunction. It recommends 10 steps to improve vascular health and ED, including exercise, a healthy diet low in sugar and fat, antioxidants, fish oil, and lifestyle changes like stress reduction and weight control
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...My Healthy Waist
By Jean-Pierre Després, PhD, FAHA, Scientific Director, International Chair on Cardiometabolic Risk, Professor, Division of Kinesiology, Université Laval, Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada.
The document discusses 6 case reports of patients who underwent genetic testing to identify pathogenic variants contributing to their conditions. The cases include patients with mitochondrial disease, gastrointestinal dysmotility, cardiomyopathy, abnormal movements, and Leigh disease. Next-generation sequencing identified likely pathogenic variants in genes involved in mitochondrial function, metabolism, and neurological pathways. Identifying causative genetic variants allowed for improved treatment and management of the patients' conditions.
1) Inhibition of bone formation plays a crucial role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP).
2) Bone loss is much larger in patients starting glucocorticoid treatment than in those on chronic treatment.
3) Lifestyle measures like calcium, vitamin D, exercise, and fall prevention are important for preventing fractures in GIOP.
Obesity Related Glomerulopathy (ORG) - prof. Salem EldeebMNDU net
Obesity Related Glomerulopathy (ORG) is a kidney disease caused by obesity. It is characterized by glomerulomegaly, focal segmental glomerulosclerosis (FSGS), and podocyte hypertrophy and injury. The prevalence of obesity and thus ORG is increasing worldwide. ORG can lead to proteinuria, hypertension, dyslipidemia and progressive kidney damage in 10-30% of cases. Treatment involves weight loss through diet, lifestyle changes, or bariatric surgery as well as renin-angiotensin-aldosterone system blockade to reduce proteinuria and slow kidney disease progression.
- T2DM accounts for 90-95% of all diagnosed diabetes cases. It is a growing epidemic affecting 246 million people worldwide in 2007.
- The main pathophysiology of T2DM includes insulin resistance in muscle, liver and fat tissues as well as insulin deficiency due to impaired insulin secretion from pancreatic beta cells over time.
- Current treatment options for T2DM like metformin, sulfonylureas and thiazolidinediones have limitations such as side effects of weight gain, hypoglycemia, edema and heart failure which impact efficacy and safety.
This document discusses diabetic kidney disease (DKD). It begins by outlining the prevalence and scope of DKD, defining DKD, and listing the optimal management of DKD as topics. It then provides details on the diagnosis of DKD, including the earliest clinical evidence being microalbuminuria. It discusses screening guidelines and measuring urinary protein. It outlines the stages of chronic kidney disease and strategies for treating DKD, including blood glucose control, blood pressure control, and lifestyle modifications. Target HbA1c levels for preventing DKD complications are also discussed.
This document describes a case of a novel form of glycogen storage disease (GSD) found in a 62-year-old female patient. Genetic screening revealed a variant in the AGL gene encoding glycogen debranching enzyme, resulting in an amino acid substitution that is believed to impair the enzyme's glucosyltransferase activity specifically in muscle tissue. This causes symptoms like exercise-induced muscle cramps and fatigue consistent with a rare type of GSD IIIc affecting only muscle. The patient responded well to a high-protein diet and carnitine supplementation, representing a newly identified variant of GSD IIId.
This document summarizes the background and qualifications of Dr. Gwei-Bian Gao, a cardiologist and diabetes specialist. It lists his medical education, areas of specialty training, positions held at major hospitals, awards for diabetes care quality, and current practice at Muh-Kang Clinic in Kaohsiung, Taiwan. The clinic focuses on cardiology, pulmonology, endocrinology, and diabetes management. Recent clinical trials show that SGLT2 inhibitors can protect cardiac and renal function in patients with type 2 diabetes.
The document discusses diabetes mellitus and fracture risk. It notes that type 2 diabetes affects over 700,000 people in the Netherlands and is associated with higher bone mineral density but also more rapid bone loss over time. While type 2 diabetes is initially linked to higher bone density due to factors like higher body weight, studies have shown those with type 2 diabetes have a 1.7 times higher risk of hip fractures and 1.2 times higher risk of any fracture after adjusting for characteristics like age, body mass index and bone mineral density. The increased fracture risk in type 2 diabetes may be due to factors beyond bone mineral density, such as changes in bone microarchitecture, turnover and material properties from excess glucose.
Ckd-MBD & osteoporosis the management dilemma Ayman Seddik
This document discusses the management of chronic kidney disease-mineral and bone disorder (CKD-MBD) and osteoporosis in elderly patients. It outlines that CKD-MBD and osteoporosis are common in elderly populations and impact mortality and morbidity. Management is based on the stage of CKD and involves controlling serum phosphorus and calcium levels, using phosphate binders to treat hyperphosphatemia, and treating abnormal PTH levels. Guidelines recommend treating bone disease with bisphosphonates and other osteoporosis medications according to the condition and stage of CKD. The risks and benefits of different treatment options must be considered based on each patient's situation.
This clinical trial compared the efficacy and safety of two doses of ferrous bisglycinate chelate (60mg once daily and 60mg twice daily) to ferrous ascorbate (100mg once daily) in treating iron deficiency anemia in women. Over 8 weeks, all three treatments significantly increased hemoglobin levels from baseline with no significant differences between groups. Adverse events occurred in 9-13% of subjects across the groups, mostly gastrointestinal disorders, with no serious adverse events reported. The study demonstrated that ferrous bisglycinate chelate at both doses and ferrous ascorbate were effective and well-tolerated treatments for iron deficiency anemia.
The document discusses drug-induced osteoporosis, focusing on glucocorticoids, aromatase inhibitors, androgen deprivation therapy, Depo-provera, proton pump inhibitors, and selective serotonin reuptake inhibitors. It summarizes their effects on bone loss and fracture risk, mechanisms of action, and treatment approaches. Key findings include rapid bone loss associated with glucocorticoid use, increased fracture risk from aromatase inhibitors and androgen deprivation therapy for cancer patients, and conflicting data on fracture risk from proton pump inhibitor use.
intravenous iron sucrose is a ray of hope for treating iron defeciency anemia which is still a major problem in india. It circumvents the problem of compliance and its large safety encourages its routine use in antenatal care and is highly suitable for treating postpartum anemia...
Musculoskeletal Complications of Cancer and its TreatmentsInsideScientific
Cancer frequently associates with the occurrence of cachexia, a debilitating syndrome responsible for reduced tolerance to anticancer therapies, as well as increased morbidity and mortality. Dr. Bonetto's group reported that animals bearing cancers not only show reduced skeletal muscle mass and strength, but also dramatic bone loss, despite the absence of bone metastases. Their latest findings revealed that muscle and bone depletion may also occur as a direct consequence of anticancer treatments (i.e., chemotherapy). There is now substantial agreement on the fact that abnormalities of the so-called ‘muscle-bone crosstalk’ may contribute to the onset of cachexia secondary to cancer or chemotherapy. Clinical and experimental observations also suggest that pharmacological bone preservation may concurrently benefit muscle mass in animal models, burn patients and osteoporotic women.
In this webinar Dr. Bonetto will present evidence that bone preservation directly impacts muscle size and function in cachexia, thus also contributing to unraveling novel pathogenetic mechanisms and opening new avenues for treatment.
The document discusses collagen type I and II supplements for treating rheumatic diseases. Clinical trials showed that collagen type II significantly reduced symptoms of osteoarthritis, and collagen type I reduced symptoms in patients with rheumatoid arthritis and systemic sclerosis, with no serious adverse effects reported. A randomized controlled trial found that collagen type I (Colafit) significantly decreased pain and functional impairment in patients with knee osteoarthritis, compared to placebo.
Hypertrophic obesity is associated with type 2 diabetes and impaired adipogen...My Healthy Waist
By Ulf Smith, MD, PhD, Professor of Internal Medicine, The Lundberg Laboratory for Diabetes Research, Center of Excellence for Cardiovascular and Metabolic Research, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
Impact of obesity on cardiometabolic risk: Will we lose the battle?My Healthy Waist
1. Obesity and related conditions like diabetes pose a growing threat to cardiovascular health and mortality. Risk factors like obesity, physical inactivity and diabetes accounted for thousands of additional deaths in the UK from 1981-2000.
2. Studies show obesity is independently associated with coronary endothelial dysfunction and a more malignant form of coronary artery disease. Even modest excess weight increases the risk of acute conditions like unstable angina and myocardial infarction.
3. Visceral abdominal fat is metabolically active and secretes inflammatory proteins that can promote atherosclerosis. Losing weight and reducing inflammation may help lower cardiovascular risk.
treating anemia is a big challenge.oral iron therapy do not adequately treat IDA. IV ferric carboxy maltose (FCM)effectively treats IDA by circumventing the problem compliance of oral iron therapy.
The document discusses the strong link between erectile dysfunction (ED) and cardiovascular disease, as ED is correlated with reduced nitric oxide (NO) production and endothelial dysfunction. It recommends 10 steps to improve vascular health and ED, including exercise, a healthy diet low in sugar and fat, antioxidants, fish oil, and lifestyle changes like stress reduction and weight control
Abdominal obesity, intra-abdominal adiposity and related cardiometabolic risk...My Healthy Waist
By Jean-Pierre Després, PhD, FAHA, Scientific Director, International Chair on Cardiometabolic Risk, Professor, Division of Kinesiology, Université Laval, Centre de recherche de l’Institut universitaire de cardiologie et de pneumologie de Québec, Québec, QC, Canada.
The document discusses 6 case reports of patients who underwent genetic testing to identify pathogenic variants contributing to their conditions. The cases include patients with mitochondrial disease, gastrointestinal dysmotility, cardiomyopathy, abnormal movements, and Leigh disease. Next-generation sequencing identified likely pathogenic variants in genes involved in mitochondrial function, metabolism, and neurological pathways. Identifying causative genetic variants allowed for improved treatment and management of the patients' conditions.
1) Inhibition of bone formation plays a crucial role in the pathogenesis of glucocorticoid-induced osteoporosis (GIOP).
2) Bone loss is much larger in patients starting glucocorticoid treatment than in those on chronic treatment.
3) Lifestyle measures like calcium, vitamin D, exercise, and fall prevention are important for preventing fractures in GIOP.
Obesity Related Glomerulopathy (ORG) - prof. Salem EldeebMNDU net
Obesity Related Glomerulopathy (ORG) is a kidney disease caused by obesity. It is characterized by glomerulomegaly, focal segmental glomerulosclerosis (FSGS), and podocyte hypertrophy and injury. The prevalence of obesity and thus ORG is increasing worldwide. ORG can lead to proteinuria, hypertension, dyslipidemia and progressive kidney damage in 10-30% of cases. Treatment involves weight loss through diet, lifestyle changes, or bariatric surgery as well as renin-angiotensin-aldosterone system blockade to reduce proteinuria and slow kidney disease progression.
- T2DM accounts for 90-95% of all diagnosed diabetes cases. It is a growing epidemic affecting 246 million people worldwide in 2007.
- The main pathophysiology of T2DM includes insulin resistance in muscle, liver and fat tissues as well as insulin deficiency due to impaired insulin secretion from pancreatic beta cells over time.
- Current treatment options for T2DM like metformin, sulfonylureas and thiazolidinediones have limitations such as side effects of weight gain, hypoglycemia, edema and heart failure which impact efficacy and safety.
This document discusses diabetic kidney disease (DKD). It begins by outlining the prevalence and scope of DKD, defining DKD, and listing the optimal management of DKD as topics. It then provides details on the diagnosis of DKD, including the earliest clinical evidence being microalbuminuria. It discusses screening guidelines and measuring urinary protein. It outlines the stages of chronic kidney disease and strategies for treating DKD, including blood glucose control, blood pressure control, and lifestyle modifications. Target HbA1c levels for preventing DKD complications are also discussed.
1) The document discusses a Phase 3 clinical trial investigating the effects of the ASK1 inhibitor selonsertib (SEL) in patients with diabetic kidney disease (DKD).
2) The trial did not meet its primary endpoint of a 50% improvement in eGFR from baseline to week 48. However, exploratory analyses found SEL induced acute but reversible eGFR declines followed by stabilization or improvement in eGFR slope over time.
3) Adverse events including acute kidney injury and fluid overload were similar between SEL and placebo groups. The study was limited by its short duration and data issues from two sites.
Hypertension and Diabetic Kidney Disease Progression Hypertension and Diabe...MedicineAndHealthUSA
Hypertension and diabetic kidney disease progression are linked, and reducing proteinuria is key to slowing kidney disease. The document discusses how conditions like hypertension and diabetes that cause kidney damage have increased in the US population. Landmark trials found that lowering blood pressure and proteinuria reduced kidney disease progression and cardiovascular risks. Initial therapy for kidney or diabetes patients should be an ACE inhibitor or ARB to target blood pressure under 130/80 mmHg.
The document discusses the benefits of angiotensin receptor blockers (ARBs) in treating chronic kidney disease, specifically in patients with type 2 diabetes. It summarizes the results of the RENAAL clinical trial which found that losartan reduced the risk of doubling of serum creatinine, end-stage renal disease, and other kidney-related outcomes in patients with type 2 diabetes and nephropathy by 16-28% compared to placebo. The trial demonstrated that losartan provided renoprotective effects beyond blood pressure control alone in this high-risk population.
Proteinuria as Cardiovascular Risk FactorJAFAR ALSAID
This document discusses proteinuria as a cardiovascular risk factor. It begins with the pathophysiology of proteinuria and the glomerular filtration barrier. It then discusses the relationship between proteinuria and cardiovascular disease, kidney disease, and inflammation. Studies show proteinuria is associated with increased risk of cardiovascular events and mortality. The degree of proteinuria also correlates with hypertension and left ventricular dysfunction. Managing proteinuria through angiotensin receptor blockers and ACE inhibitors can reduce cardiovascular risk. The document concludes proteinuria is a significant risk factor for cardiovascular disease in patients with chronic kidney disease or diabetes.
Are you Struggling to Control of your Diabetes and Weight?
People who are overweight or obese are more prone to developing Type 2 diabetes. Those who have Type 1 and Type 2 diabetes with weight problems struggle to control their blood sugar levels. Research shows that people with diabetes find it more difficult to lose weight than those without diabetes.
Weight loss significantly improves blood sugar control and also reduces the risk of getting complications from diabetes. However, whilst attempting to lose weight, people with diabetes find it hard to restrict their intake of food since eating less may trigger hypoglycaemia (low blood sugar). All these facts explain the need for specialist input in management of weight in people with diabetes.
This Slideshow gives you insight to Diabesity
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This document discusses the physiology and clinical management of PTH and mineral metabolism disorders in patients with chronic kidney disease (CKD). It provides an overview of calcium, phosphorus, vitamin D, and PTH regulation and how their homeostasis is disrupted in CKD. Secondary hyperparathyroidism leads to elevated PTH levels and disturbances in calcium and phosphorus. If not properly managed, this can result in renal osteodystrophy, vascular calcification, and increased risk of cardiovascular events and mortality. The document reviews therapeutic options like phosphate binders and vitamin D analogs to control mineral levels and treat secondary hyperparathyroidism in CKD patients.
GENETIC DIET- Maria vranceanu dubai nutrition conferenceMARIA VRANCEANU
This 2-year study compared the effects of a ketogenic diet versus a nutrigenetic diet on weight loss and clinical parameters in 114 obese subjects. The nutrigenetic diet was personalized based on each subject's genetic test results. After 2 years, the nutrigenetic group had greater BMI loss (25.03% vs 17.62%), larger decreases in total cholesterol and blood glucose, and higher HDL levels compared to the ketogenic group. The study concludes that a nutrigenetically matched diet may be more effective than a standard ketogenic diet for long-term weight management and improvement of metabolic health markers.
This document provides an overview of hypertension including:
- Prevalence rates in various countries including the US, China, Egypt, and Saudi Arabia
- Guidelines for classifying blood pressure levels from organizations like JNC 7 and ESC/ESH
- Consequences of uncontrolled hypertension like increased risks of stroke, myocardial infarction, heart failure, and kidney disease
- Results from clinical trials demonstrating reduced risks with tighter blood pressure control
- Recommendations for achieving blood pressure targets and choosing antihypertensive medications
The document discusses beta cell dysfunction and failure in type 2 diabetes. It begins by presenting hypothetical relationships that determine glucose tolerance categories. It then discusses how beta cell adaptation and failure leads to the progression from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes. The document also examines the progressive loss of beta cell function over time as type 2 diabetes develops and worsens.
Abnormal Regulation of Placenta Growth Factor in Skeletal Muscle of Western-...Asitha Silva
This study investigated how metabolic dysfunction induced by a Western diet affects levels of placenta growth factor (PLGF) in mouse skeletal muscle. Mice were fed either a control or Western diet for 6 months to induce varying degrees of metabolic dysfunction. Skeletal muscle PLGF levels were assessed at baseline and after femoral artery occlusion. The results showed that the Western diet reduced baseline PLGF levels in skeletal muscle across all mouse models. After occlusion, PLGF upregulation was inhibited in Western diet-fed mice compared to controls. This suggests that Western diet-induced metabolic dysfunction impairs the normal upregulation of PLGF in response to arterial occlusion. As PLGF is important for arteriogenesis, this phenomenon may contribute to the reduced ability
This document discusses managing microvascular and macrovascular risk in patients with type 2 diabetes mellitus (T2DM). It provides a brief history of insulin discovery and treatment of diabetes. It then summarizes research on the impact of intensive glucose control on microvascular and macrovascular outcomes in patients with T1DM and T2DM. The document finds that intensive glucose control reduces microvascular complications but has uncertain effects on macrovascular disease. It also reviews the safety and cardiovascular effects of various glucose-lowering drugs used to treat T2DM.
- The document discusses the diagnosis and management of type 2 diabetes mellitus. It describes the pathophysiology, risk factors, diagnostic criteria and complications seen at diagnosis. Early and intensive management is needed given the loss of beta cell function at diagnosis. Goals of management include achieving blood glucose, blood pressure and lipid targets to prevent complications. The ADA/EASD consensus statement recommends initial treatment with lifestyle modification and metformin, adding basal insulin or intensive insulin if targets are not met.
La insulinoterapia es un arte y actualmente contamos con nuevas formulaciones y otras en proceso de investigación y aprobación. Ponencia presentada en las jornadas del benemérito H2M.
This document summarizes a teleconference on diabetes and metabolic syndrome in patients hospitalized with cardiovascular disease. It discusses screening for diabetes and metabolic syndrome in hospitalized CVD patients, defines metabolic syndrome, reviews the prevalence and risk factors associated with it, and how metabolic syndrome predicts diabetes and increased cardiovascular risk. It also reviews inpatient management of hyperglycemia and metabolic syndrome.
П. Сутерс "Проявления инсулинорезистентности и гликемический контроль в интен...rnw-aspen
Доклад с 15 Межрегиональной научно-практической конференции "Искусственное питание и инфузионная терапия больных в медицине критических состояний" 21-22 мая 2015 г
This document provides an overview of canagliflozin, an SGLT2 inhibitor used to treat type 2 diabetes. It discusses the pathogenesis of type 2 diabetes, progressive beta cell dysfunction, and the kidney's role in glucose regulation. It then reviews canagliflozin's mechanism of action as an SGLT2 inhibitor, increasing urinary glucose excretion and reducing blood glucose levels. The document summarizes canagliflozin's clinical trials, pharmacokinetics, efficacy, safety profile, and effects on renal function and lipids.
Similar to A Model of Type 2 Diabetes: BBZDR/Wor rat (20)
BRM has developed proprietary rat strains which are translatable models for the characterization of type 1 and type 2 diabetes as well as immune-related diseases. Its technical competencies include design and conducting studies in autoimmunity (type 1 diabetes, lupus, Rheumatoid Arthritis and Multiple Sclerosis), metabolic disease (type 2 diabetes, metabolic syndrome, obesity, dyslipidemia, liver and kidney function), virology, neurodegenerative diseases, diabetic complications (retinopathy, neuropathy, nephropathy, and encephalopathy including Alzheimer’s disease) specialized animal model development and the production and care of multiple species.
BRM is a successful biopharmaceutical company formed in 1996 by Dennis Guberski and Dr. Arthur Like of the University of Massachusetts Medical School (UMass). Over the course of 20 years the founders developed proprietary diabetes research models under the sponsorship of the National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK). BRM licensed this intellectual property portfolio from UMass in 1998 and since that time has used these proprietary tools to become one of the leading sources of customized preclinical contract research specializing in type 1 and type 2 diabetes.
- The MAD rat strain was developed to be susceptible to multiple autoimmune diseases. This study characterized the susceptibility of MAD rats to adjuvant-induced arthritis (AIA), a model of rheumatoid arthritis.
- MAD rats were found to be highly sensitive to developing inflammatory arthritis after AIA induction. Symptoms progressed from small to large joints similarly to human rheumatoid arthritis.
- A novel finding was the appearance of skin nodules coinciding with arthritis, resembling early rheumatoid nodules in humans. Treatment with dexamethasone inhibited arthritis while methotrexate partially inhibited it.
1. Biomedical Research Models, Inc. developed an inbred rat strain called the Multiple Autoimmune Disease (MAD) rat that is susceptible to developing multiple autoimmune diseases. This study characterized the MAD rat model of type 1 diabetes (T1D).
2. The study found that Toll-like receptor (TLR) ligands like polyinosinic-polycytidylic acid (poly I:C) could reliably induce T1D in MAD rats, while the TLR ligand CpG did not induce diabetes. Poly I:C induced T1D in a dose-dependent manner.
3. T1D could be induced in MAD rats up to 34 days of age but the penetrance diminished at
BRM's Capabilities in Virology, Viral Immunology and Pathology: HSV-1, HSV-2, Influenza, RSV, LCMV, and CMV. For more information, please visit our website at www.BRMCRO.com.
"The LEW.1WR1 rat is the only model so far that exhibits a low incidence of spontaneous diabetes that can be increased by perturbation. By far the most extensively studied of the models are the two BB rat strains, but all of them have provided interesting information. There are to date no rat models based on the insertion of transgenes, though genetic complementation has been used elegantly to identify the genetic defect in Komeda rats."
BRM has experience developing preclinical models for systemic lupus erythematosus (SLE) including the NZB/W F1 and MRL/lpr mouse models. These mice develop anti-dsDNA antibodies and progressive glomerulonephritis similar to human SLE. BRM has validated methods for measuring disease outcomes like proteinuria, antibody levels, immune cell profiles, and histopathology in these mice. They have also demonstrated prevention and remission of lupus symptoms in NZB/W F1 mice using treatments like anti-CD40L monoclonal antibody.
ESA/ACT Science Coffee: Diego Blas - Gravitational wave detection with orbita...Advanced-Concepts-Team
Presentation in the Science Coffee of the Advanced Concepts Team of the European Space Agency on the 07.06.2024.
Speaker: Diego Blas (IFAE/ICREA)
Title: Gravitational wave detection with orbital motion of Moon and artificial
Abstract:
In this talk I will describe some recent ideas to find gravitational waves from supermassive black holes or of primordial origin by studying their secular effect on the orbital motion of the Moon or satellites that are laser ranged.
Travis Hills of MN is Making Clean Water Accessible to All Through High Flux ...Travis Hills MN
By harnessing the power of High Flux Vacuum Membrane Distillation, Travis Hills from MN envisions a future where clean and safe drinking water is accessible to all, regardless of geographical location or economic status.
Immersive Learning That Works: Research Grounding and Paths ForwardLeonel Morgado
We will metaverse into the essence of immersive learning, into its three dimensions and conceptual models. This approach encompasses elements from teaching methodologies to social involvement, through organizational concerns and technologies. Challenging the perception of learning as knowledge transfer, we introduce a 'Uses, Practices & Strategies' model operationalized by the 'Immersive Learning Brain' and ‘Immersion Cube’ frameworks. This approach offers a comprehensive guide through the intricacies of immersive educational experiences and spotlighting research frontiers, along the immersion dimensions of system, narrative, and agency. Our discourse extends to stakeholders beyond the academic sphere, addressing the interests of technologists, instructional designers, and policymakers. We span various contexts, from formal education to organizational transformation to the new horizon of an AI-pervasive society. This keynote aims to unite the iLRN community in a collaborative journey towards a future where immersive learning research and practice coalesce, paving the way for innovative educational research and practice landscapes.
Mending Clothing to Support Sustainable Fashion_CIMaR 2024.pdfSelcen Ozturkcan
Ozturkcan, S., Berndt, A., & Angelakis, A. (2024). Mending clothing to support sustainable fashion. Presented at the 31st Annual Conference by the Consortium for International Marketing Research (CIMaR), 10-13 Jun 2024, University of Gävle, Sweden.
Candidate young stellar objects in the S-cluster: Kinematic analysis of a sub...Sérgio Sacani
Context. The observation of several L-band emission sources in the S cluster has led to a rich discussion of their nature. However, a definitive answer to the classification of the dusty objects requires an explanation for the detection of compact Doppler-shifted Brγ emission. The ionized hydrogen in combination with the observation of mid-infrared L-band continuum emission suggests that most of these sources are embedded in a dusty envelope. These embedded sources are part of the S-cluster, and their relationship to the S-stars is still under debate. To date, the question of the origin of these two populations has been vague, although all explanations favor migration processes for the individual cluster members. Aims. This work revisits the S-cluster and its dusty members orbiting the supermassive black hole SgrA* on bound Keplerian orbits from a kinematic perspective. The aim is to explore the Keplerian parameters for patterns that might imply a nonrandom distribution of the sample. Additionally, various analytical aspects are considered to address the nature of the dusty sources. Methods. Based on the photometric analysis, we estimated the individual H−K and K−L colors for the source sample and compared the results to known cluster members. The classification revealed a noticeable contrast between the S-stars and the dusty sources. To fit the flux-density distribution, we utilized the radiative transfer code HYPERION and implemented a young stellar object Class I model. We obtained the position angle from the Keplerian fit results; additionally, we analyzed the distribution of the inclinations and the longitudes of the ascending node. Results. The colors of the dusty sources suggest a stellar nature consistent with the spectral energy distribution in the near and midinfrared domains. Furthermore, the evaporation timescales of dusty and gaseous clumps in the vicinity of SgrA* are much shorter ( 2yr) than the epochs covered by the observations (≈15yr). In addition to the strong evidence for the stellar classification of the D-sources, we also find a clear disk-like pattern following the arrangements of S-stars proposed in the literature. Furthermore, we find a global intrinsic inclination for all dusty sources of 60 ± 20◦, implying a common formation process. Conclusions. The pattern of the dusty sources manifested in the distribution of the position angles, inclinations, and longitudes of the ascending node strongly suggests two different scenarios: the main-sequence stars and the dusty stellar S-cluster sources share a common formation history or migrated with a similar formation channel in the vicinity of SgrA*. Alternatively, the gravitational influence of SgrA* in combination with a massive perturber, such as a putative intermediate mass black hole in the IRS 13 cluster, forces the dusty objects and S-stars to follow a particular orbital arrangement. Key words. stars: black holes– stars: formation– Galaxy: center– galaxies: star formation
The cost of acquiring information by natural selectionCarl Bergstrom
This is a short talk that I gave at the Banff International Research Station workshop on Modeling and Theory in Population Biology. The idea is to try to understand how the burden of natural selection relates to the amount of information that selection puts into the genome.
It's based on the first part of this research paper:
The cost of information acquisition by natural selection
Ryan Seamus McGee, Olivia Kosterlitz, Artem Kaznatcheev, Benjamin Kerr, Carl T. Bergstrom
bioRxiv 2022.07.02.498577; doi: https://doi.org/10.1101/2022.07.02.498577
Discovery of An Apparent Red, High-Velocity Type Ia Supernova at 𝐳 = 2.9 wi...Sérgio Sacani
We present the JWST discovery of SN 2023adsy, a transient object located in a host galaxy JADES-GS
+
53.13485
−
27.82088
with a host spectroscopic redshift of
2.903
±
0.007
. The transient was identified in deep James Webb Space Telescope (JWST)/NIRCam imaging from the JWST Advanced Deep Extragalactic Survey (JADES) program. Photometric and spectroscopic followup with NIRCam and NIRSpec, respectively, confirm the redshift and yield UV-NIR light-curve, NIR color, and spectroscopic information all consistent with a Type Ia classification. Despite its classification as a likely SN Ia, SN 2023adsy is both fairly red (
�
(
�
−
�
)
∼
0.9
) despite a host galaxy with low-extinction and has a high Ca II velocity (
19
,
000
±
2
,
000
km/s) compared to the general population of SNe Ia. While these characteristics are consistent with some Ca-rich SNe Ia, particularly SN 2016hnk, SN 2023adsy is intrinsically brighter than the low-
�
Ca-rich population. Although such an object is too red for any low-
�
cosmological sample, we apply a fiducial standardization approach to SN 2023adsy and find that the SN 2023adsy luminosity distance measurement is in excellent agreement (
≲
1
�
) with
Λ
CDM. Therefore unlike low-
�
Ca-rich SNe Ia, SN 2023adsy is standardizable and gives no indication that SN Ia standardized luminosities change significantly with redshift. A larger sample of distant SNe Ia is required to determine if SN Ia population characteristics at high-
�
truly diverge from their low-
�
counterparts, and to confirm that standardized luminosities nevertheless remain constant with redshift.
The binding of cosmological structures by massless topological defectsSérgio Sacani
Assuming spherical symmetry and weak field, it is shown that if one solves the Poisson equation or the Einstein field
equations sourced by a topological defect, i.e. a singularity of a very specific form, the result is a localized gravitational
field capable of driving flat rotation (i.e. Keplerian circular orbits at a constant speed for all radii) of test masses on a thin
spherical shell without any underlying mass. Moreover, a large-scale structure which exploits this solution by assembling
concentrically a number of such topological defects can establish a flat stellar or galactic rotation curve, and can also deflect
light in the same manner as an equipotential (isothermal) sphere. Thus, the need for dark matter or modified gravity theory is
mitigated, at least in part.
JAMES WEBB STUDY THE MASSIVE BLACK HOLE SEEDSSérgio Sacani
The pathway(s) to seeding the massive black holes (MBHs) that exist at the heart of galaxies in the present and distant Universe remains an unsolved problem. Here we categorise, describe and quantitatively discuss the formation pathways of both light and heavy seeds. We emphasise that the most recent computational models suggest that rather than a bimodal-like mass spectrum between light and heavy seeds with light at one end and heavy at the other that instead a continuum exists. Light seeds being more ubiquitous and the heavier seeds becoming less and less abundant due the rarer environmental conditions required for their formation. We therefore examine the different mechanisms that give rise to different seed mass spectrums. We show how and why the mechanisms that produce the heaviest seeds are also among the rarest events in the Universe and are hence extremely unlikely to be the seeds for the vast majority of the MBH population. We quantify, within the limits of the current large uncertainties in the seeding processes, the expected number densities of the seed mass spectrum. We argue that light seeds must be at least 103 to 105 times more numerous than heavy seeds to explain the MBH population as a whole. Based on our current understanding of the seed population this makes heavy seeds (Mseed > 103 M⊙) a significantly more likely pathway given that heavy seeds have an abundance pattern than is close to and likely in excess of 10−4 compared to light seeds. Finally, we examine the current state-of-the-art in numerical calculations and recent observations and plot a path forward for near-future advances in both domains.
16. Severe atherosclerosis:
10 months ~8 months duration of diabetes
Complete occlusion of renal artery, x100 (Left);
Arrows identify plaque, x400 (Both panels).
17. Measurement and Calculation of
Neointima Thickness
The % stenosis was calculated as the Internal Elastic Area (IEA)
minus the Residual Area (RA) divided by the IEA ( x 100)
18. Neointima Thickness in Lean and Obese Male
BBZDR Rats One Week Post Balloon Injury
BBZDR Lean Rats Type 2 Diabetic Rats
19. Neointima Thickness in Lean and Obese Male
BBZDR Rats 4 Weeks Post Balloon Injury
BBZDR Lean Rats Type 2 Diabetes Rats
30. RAGE in BBZDR Rat Kidneys
Obese T2 Diabetic Lean Control
31. Summary
• The diabetic BBZDR male rat is a good model of
diabetic nephropathy.
• Supported by Clinical blood chemistry and
Histopathology
– Evidence of hyperfiltration and glomeruli
hypertrophy at 3months age
– Microalbumuria progressing to proteinuria from
3month through 12month
– Mesangial expansion, basement membrane thicking
and interstitial fibrosis
– Tubule expansion, aschemia and diffuse necrosis after
12months of age (10 months duration)
33. Neuropathy in BBZDR
• Experimental rat models of types 1 and 2 diabetes differ in
sympathetic neuroaxonal dystrophy. J Neuropathol Exp
Neurol. 2004 May;63(5):450-60
Schmidt RE, Dorsey DA, Beaudet LN, Parvin CA, Zhang W, Sima AA.
• C-peptide corrects endoneurial blood flow but not
oxidative stress in type 1 BB/Wor rats. Am J Physiol
Endocrinol Metab. 2004 Sep;287(3):E497-505.
Stevens MJ, Zhang W, Li F, Sima AA.
• A comparison of diabetic polyneuropathy in type II
diabetic BBZDR/Wor rats and in type I diabetic BB/Wor
rats. Diabetologia, 2000 Jun;43(6):786-93
Sima AA, Zhang W, Xu G, Sugimoto K, Guberski D, Yorek MA.
35. Diabetic Polyneuropathy (DPN)
Type 2 vs Type 1
Type 2 Type 1
• 35% /25 years
• Slow progression
• Mild axonal
degeneration
• No nodal changes
• Close to 100% /25years
• More rapid progression
• Severe axonal degeneration
and loss
• Progressive nodal/paranodal
• degeneration
36. Progression of Axo-glial Dysjunction
Axo-glialdysjunction(%)
A. BB/Wor – BBZDR/Wor- rats
Duration Of Diabetes
Baseline 4mo 6mo 8mo 12mo 14mo
0
10
20
30
40
50 Control
BB/Wor
BBZDR/ Wor
Axo-glialdysjunction(%)
20
40
60
20 30 40 50 60 70
Age (years)
Common slope: df =39, f=13.91, p< 0.001
Control: a= 0.24
b= 0.26
NIDM: a= 3.44
b= 0.26
IDDM: a= 25.43
b= 0.26
B. Human
Sima et al., J Clin Invest 1984 Sima et al., N Engl J Med, 1986
43. Retinopathy in BBZDR
• N-3 polyunstaurated Fatty acids prevent diabetic
retinopathy by inhibition of retinal vascular damage and
enhanced endothelial progenitor cell reparative function.
Plos One. 2013;8(1):e55177. Epub 2013 Jan29.
Tikhonenko M, Lydic TA, Opreanu M, Li Calzi S, Bozack S, McSorley KM, Sochacki AL, Faber MS,
Hazra S, Duclos S, Guberski D, Reid GE, Grant MB, Busik JV
• Diabetic retinopathy is associated with bone marrow
neuropathy and a depressed peripheral clock. Journal of
Experimental Medicine. 2009 Dec21;206(13):2897-906
Busik JV, Tikhonenko M, Bhatwadekar A, Opreanu M, Yakubova N, Caballero S, Player D, Nakagawa T,
Afzal A, Kielczewski J, Sochacki A, Hasty S, Li Calzi S, Kim S, Duclos S, Segal MS, Guberski DL,
Esselman WJ, Boulton ME, Grant MB.
• Time course of NADH oxidase,inducible nitric oxide
synthase and peroxynitrite in diabetic retinopathy in the
BBZ/Wor rat. Nitric Oxide. 2002 May;6(3): 295-304.
Ellis,E.A., Guberski, D.L., Huston, B. and Grant, M.B.
44. Small Pressurized Artery Myography:
As close as it gets to true organ
perfusion or function
0 50 100 150 200 250
50
75
100
125
150
175
Diameter with tone
Passive diameter
WKY
Pressure (mmHg)
Diameter(µM)
45. Endothelial Dysfunction in BBZDR Rats
Obese-Diabetic; O Lean control (age-matched)
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
Pre-diabetic age 3-4 Weeks of Diabetes
5 Months of Diabetes 10 Months of Diabetes
55. iNOS and Nitrotyrosine
Immunoreactivity
ANIMAL GROUP iNOS NITROTYROSINE
PRE-DIABETIC
(BBZ/Wor)
3.7 ± 0.81 %
C
8.2 ± 1.70 part/50 µm
2 C
NEW ONSET DIABETES
(BBZ/Wor)
69.6 ± 5.88 %
A
60.8 ± 16.91 part./50 µm
2 A
CHRONIC DIABETES
(BBZ/Wor)
49.9 ± 9.75 %
B
29.5 ± 4.31 part./50 µm
2 B
NON-DIABETIC
CONTROLS (BB DR
/Wor)
8.7 ± 4.66 %
C
9.0 ± 1.87 part./50 µm
2 C
A: p = 0.0001
B: p = 0.0001
Means with the same letter (A, B, C) are not significantly different.
56. Time Course of Vascular Changes in BBZDR/Wor
Rat With Duration of Hyperglycemia
Length of hyperglycemia 1 week 4-6 months 18-24 months
NADH oxidase
Free Radicals
iNOS
Nitrotyrosine
eNOS ¯ ¯ ¯
NOS cofactors - ¯ ¯
Vessel Diameter ¯ ¯
57. Small Pressurized Artery Myography:
As close as it gets to true organ
perfusion or function
0 50 100 150 200 250
50
75
100
125
150
175
Diameter with tone
Passive diameter
WKY
Pressure (mmHg)
Diameter(µM)
66. Endothelial Dysfunction
Obese-Diabetic; O Lean control (age-matched)
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
-10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
log[Histamine] M
%Myogenictone
Pre-diabetic age 3-4 Weeks of Diabetes
5 Months of Diabetes 10 Months of Diabetes
67. Arterial smooth muscle hyper-reactivity
Pre-diabetic age 3-4 Weeks of Diabetes
5 Months of Diabetes 10 Months of Diabetes
Obese-Diabetic; O Lean control (age-matched)
-12 -11 -10 -9 -8 -7 -6 -5
0
25
50
75
100
log[5-Hydroxy tryptamine] M
%KClConstriction
-12 -11 -10 -9 -8 -7 -6 -5
0
25
50
75
100
log[5-Hydroxy tryptamine] M
%KClConstriction
-12 -11 -10 -9 -8 -7 -6 -5
0
25
50
75
100
log[5-Hydroxy tryptamine] M
%KClConstriction
-12 -11 -10 -9 -8 -7 -6 -5
0
25
50
75
100
log[5-Hydroxy tryptamine] M
%KClConstriction
68. Pre-diabetic age 3-4 Weeks of Diabetes
5 Months of Diabetes 10 Months of Diabetes
Obese-Diabetic; O Lean control (age-matched)
-9 -8 -7 -6 -5 -4
0
25
50
75
100
125
log[U-73122] M
%Myogenictone
-9 -8 -7 -6 -5 -4
0
25
50
75
100
125
log[U-73122] M
%Myogenictone
-9 -8 -7 -6 -5 -4
0
25
50
75
100
125
log[U-73122] M
%Myogenictone
-9 -8 -7 -6 -5 -4
0
25
50
75
100
125
log[U-73122] M
%Myogenictone
Arterial smooth muscle hyper-reactivity PLC activation
69. Autoregulation in rat (Sprague Dawley)
ophthalmic artery
0 30 60 90 120 150 180 210
100
150
200
250
300
Diameter with tone
Passive diameter
Myogenic tone
0
25
50
Intraluminal Pressure (mm Hg)
Lumendiameter(microns)
Myogenictone(%)
70. -15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
Serotonin
Phenylephrine
Vasopressin
UK-14304
U-46619
log M [Vasoconstrictor]
%KCl(60mM)response
-15 -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3
0
50
100
150
log M [Endothelin-1]
%KCl(60mM)response
Effect of different vasoconstrictors
in ophthalmic artery
Order of efficacy:
Endothelin-1 > Vasopressin = Serotonin = Phenylephrine > U-46619 > UK 14304
Order of potency:
Endothelin-1 > Vasopressin = Serotonin > U-46619 > UK 14304 > Phenylephrine
71. -14 -13 -12 -11 -10 -9 -8 -7 -6 -5 -4 -3
0
25
50
75
100
125
Histamine
Carbachol
Adenosine
CGRP
Isoprenaline
VIP
log M [Vasodilator]
Myogenictone(%)
Order of efficacy:
Carbachol > Isoprenaline > Histamine = CGRP = VIP = Adenosine
Order of potency:
CGRP > VIP > Carbachol = Isoprenaline > Adenosine = Histamine
Bradykinin, substance P and octreotide did not produce sustained dilatory responses
Effect of different vasodilators
in ophthalmic artery
72. -9 -8 -7 -6 -5 -4 -3
20
60
100
140
180
L-NAME
Indomethacin
log M [Inhibitor]
Myogenictone(%)
Effect of the inhibition of NOS
and prostaglandin synthesis on myogenic tone
in rat ophthalmic artery
73. CNS Controls Release of EPC’s
• Bone marrow derived epithelial
progenitor cells (EPCs) home to sites of
vascular injury and help to maintain
capillary integrity or re-perfuse acellular
capillaries
• The release of EPCs from bone marrow
follows a circadian rhythmicity in
response to local adrenergic signals
(Mendez-Ferrer et al. 2008). Circadian
rhythms are driven by a central clock
(suprachiasmaticnucleus, SCN) and
peripheral clocks (tissues)
• Clock genes induce circadian rhythm for EPC release by synchronous interplay of
positive (Clock, Bmal1) and negative (Per1, Per2, Cry1, Cry2) loops of the peripheral
circadian clock
J Busik et. al,. (2009) J. Exp. Med
78. Conclusions
• BBZ has most of the features of diabetic
retinopathy as observed in humans
• Evaluation of drug therapies can be
performed using
– Histological studies
– Immunological studies
– Functional studies using small vessels