This document discusses a mitochondrial etiology of complex diseases. It proposes that mitochondrial dysfunction underlies the genetic and environmental causes of common complex diseases. Variation in the mitochondrial genome, including ancient adaptive polymorphisms and recent deleterious mutations, can predispose individuals to diseases. Specific mitochondrial DNA mutations can cause different diseases or phenotypes depending on factors like heteroplasmy level, haplogroup background, and environment. Mouse models support the role of mitochondrial DNA mutations in various tissues and diseases.
Combined Esophagogastrectomies: Survival Outcomes in Patients with Local Adva...Oleg Kshivets
CONCLUSIONS: 5YS of local advanced ECP after combined radical procedures significantly depended on: tumor characteristics, blood cell circuit, cell ratio factors, biochemical factors, hemostasis system, anthropometric data and adjuvant treatment. Optimal strategies for local advanced ECP are: 1) availability of very experienced thoracoabdominal surgeons because of complexity radical procedures; 2) aggressive en block surgery and adequate lymph node dissection for completeness; 3) precise prediction; 4) AT for ECP with unfavorable prognos
Neurosarcoidosis is a multisystem granulomatous disease of unknown etiology where noncaseating granulomas can affect multiple organs including the lungs, heart, skin and nervous system. It most commonly involves the lungs in 90% of cases. The central nervous system is involved in 5-16% of cases, with cranial neuropathies being the most frequent neurological manifestation. Diagnosis involves evidence of systemic sarcoidosis along with neurological symptoms, and can be supported by MRI, lumbar puncture and biopsy when possible. Corticosteroids are the main treatment to suppress inflammation and immune activity, and some severe or refractory cases may require additional immunosuppressants. Prognosis depends on location
Neurosarcoidosis is a multisystem granulomatous disease of unknown etiology where noncaseating granulomas can affect multiple organs including the lungs, heart, skin and nervous system. It most commonly involves the lungs in 90% of cases. The central nervous system is involved in 5-16% of cases, with cranial neuropathies, encephalitis, meningitis and mass lesions being common neurological manifestations. Treatment involves corticosteroids as the mainstay, with immunosuppressants also used in refractory cases. Prognosis depends on location and type of involvement, with 72% of neurological cases deteriorating within 18 months if not treated.
The document discusses the aims of a thesis investigating quantitative proton magnetic resonance spectroscopy in multiple sclerosis and traumatic brain injury. The three aims are: 1) To improve quantification precision of metabolic concentrations by measuring how T2 changes influence apparent concentrations in controls and MS patients. 2) To study diffuse metabolic changes in early relapsing-remitting MS. 3) To assess localized thalamic damage in mild traumatic brain injury and help define metabolic change limits for differentiating mild from more severe TBI.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Local Advanced Esophageal Cancer (T3-4N0-2M0): Artificial Intelligence, Syner...Oleg Kshivets
5YS of local advanced ECP after combined radical procedures significantly depended on: tumor characteristics, blood cell circuit, cell ratio factors, biochemical factors, hemostasis system, anthropometric data and adjuvant treatment. Optimal strategies for local advanced ECP are: 1) availability of very experienced thoracoabdominal surgeons because of complexity radical procedures; 2) aggressive en block surgery and adequate lymph node dissection for completeness; 3) precise prediction; 4) AT for ECP with unfavorable prognosis.
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...KineMed, Inc.
The document discusses using measurements of causal pathways to improve predictability in disease outcomes and drug development. It outlines some key challenges, including the fundamental unpredictability of complex biological systems and high attrition rates in pharmaceutical development. The author proposes that measuring the activity of disease-driving processes, or "causal pathways", could help navigate this complexity and transform medicine development by providing a link between molecular targets and whole system outcomes. Examples of causal pathways for various diseases are given, and new kinetic technologies for measuring dynamic proteomes and metabolic water fluxes are described.
Combined Esophagogastrectomies: Survival Outcomes in Patients with Local Adva...Oleg Kshivets
CONCLUSIONS: 5YS of local advanced ECP after combined radical procedures significantly depended on: tumor characteristics, blood cell circuit, cell ratio factors, biochemical factors, hemostasis system, anthropometric data and adjuvant treatment. Optimal strategies for local advanced ECP are: 1) availability of very experienced thoracoabdominal surgeons because of complexity radical procedures; 2) aggressive en block surgery and adequate lymph node dissection for completeness; 3) precise prediction; 4) AT for ECP with unfavorable prognos
Neurosarcoidosis is a multisystem granulomatous disease of unknown etiology where noncaseating granulomas can affect multiple organs including the lungs, heart, skin and nervous system. It most commonly involves the lungs in 90% of cases. The central nervous system is involved in 5-16% of cases, with cranial neuropathies being the most frequent neurological manifestation. Diagnosis involves evidence of systemic sarcoidosis along with neurological symptoms, and can be supported by MRI, lumbar puncture and biopsy when possible. Corticosteroids are the main treatment to suppress inflammation and immune activity, and some severe or refractory cases may require additional immunosuppressants. Prognosis depends on location
Neurosarcoidosis is a multisystem granulomatous disease of unknown etiology where noncaseating granulomas can affect multiple organs including the lungs, heart, skin and nervous system. It most commonly involves the lungs in 90% of cases. The central nervous system is involved in 5-16% of cases, with cranial neuropathies, encephalitis, meningitis and mass lesions being common neurological manifestations. Treatment involves corticosteroids as the mainstay, with immunosuppressants also used in refractory cases. Prognosis depends on location and type of involvement, with 72% of neurological cases deteriorating within 18 months if not treated.
The document discusses the aims of a thesis investigating quantitative proton magnetic resonance spectroscopy in multiple sclerosis and traumatic brain injury. The three aims are: 1) To improve quantification precision of metabolic concentrations by measuring how T2 changes influence apparent concentrations in controls and MS patients. 2) To study diffuse metabolic changes in early relapsing-remitting MS. 3) To assess localized thalamic damage in mild traumatic brain injury and help define metabolic change limits for differentiating mild from more severe TBI.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Local Advanced Esophageal Cancer (T3-4N0-2M0): Artificial Intelligence, Syner...Oleg Kshivets
5YS of local advanced ECP after combined radical procedures significantly depended on: tumor characteristics, blood cell circuit, cell ratio factors, biochemical factors, hemostasis system, anthropometric data and adjuvant treatment. Optimal strategies for local advanced ECP are: 1) availability of very experienced thoracoabdominal surgeons because of complexity radical procedures; 2) aggressive en block surgery and adequate lymph node dissection for completeness; 3) precise prediction; 4) AT for ECP with unfavorable prognosis.
Personalized & Translational Medicine - KineMed, Inc. - Marc Hellerstein, MD,...KineMed, Inc.
The document discusses using measurements of causal pathways to improve predictability in disease outcomes and drug development. It outlines some key challenges, including the fundamental unpredictability of complex biological systems and high attrition rates in pharmaceutical development. The author proposes that measuring the activity of disease-driving processes, or "causal pathways", could help navigate this complexity and transform medicine development by providing a link between molecular targets and whole system outcomes. Examples of causal pathways for various diseases are given, and new kinetic technologies for measuring dynamic proteomes and metabolic water fluxes are described.
Kshivets Oleg Optimization of Management for Esophageal Cancer Patients (T1-...Oleg Kshivets
Optimization of Management for Esophageal Cancer Patients (T1-4N0-2M0).
Kshivets Oleg Surgery Department, Bagrationovsk Hospital, Bagrationovsk, Kaliningrad, Russia
ABSTRACT
OBJECTIVE: 5-survival (5YS) and life span after radical surgery for esophageal cancer (EC) pa¬tients (ECP)(T1-4N0-2M0) - alive supersysems was analyzed. The importance must be stressed of using complex system analysis, artificial intelligence (neural networks computing), simulation modeling and statistical methods in combination, because the different approaches yield complementary pieces of prognostic information.
METHODS: We analyzed data of 563 consecutive ECP (age=56.6±8.9 years; tumor size=6±3.5 cm) radically operated (R0) and monitored in 1975-2024 (m=419, f=144; esophagogastrectomies (EG) Garlock=289, EG Lewis=274, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium, splenectomy=170; adenocarcinoma=323, squamous=230, mix=10; T1=131, T2=119, T3=185, T4=128; N0=285, N1=71, N2=207; G1=161, G2=143, G3=259; early EC=112, invasive=451; only surgery=428, adjuvant chemoimmunoradiotherapy-AT=135: 5-FU+thymalin/taktivin+radiotherapy 45-50Gy). Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence.
RESULTS: Overall life span (LS) was 1915.4±2284.8 days and cumulative 5-year survival (5YS) reached 52.6%, 10 years – 46.3%, 20 years – 33.3%, 30 years – 27.5%. 193 ECP lived more than 5 years (LS=4309.1±2507.4 days), 105 ECP – more than 10 years (LS=5860.8±2469.2 days). 228 ECP died because of EC (LS=629.8±324.1 days). AT significantly improved 5YS (69% vs. 49.1%) (P=0.0007 by log-rank test). 5YS of ECP of upper/3 was significantly better than others (65.3% vs.50.3%) (P=0.003). Cox modeling displayed that 5YS of ECP significantly depended on: phase transition (PT) N0—N12 in terms of synergetics, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), T, G, histology, age, AT, localization, prothrombin index, hemorrhage time, residual nitrogen, protein (P=0.000-0.019). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and healthy cells/CC (rank=1), PT N0—N12 (2), PT early-invasive EC (3), erythrocytes/CC (4), thrombocytes/CC (5); segmented neutrophils/CC (6), stick neutrophils/CC (7), lymphocytes/CC (8), eosinophils/CC (9), monocytes/CC (10), leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5-year survival of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC cell dynamics; 9) EC characteristics; 10) tumor localization; 11) anthropometric data; 12) surgery type. Optimal diagnosis and trea
This document summarizes a presentation about a novel "knock-in" mouse model that expresses a catalytically inactive form of tissue transglutaminase (TG2). The TG2-C277S mouse model was developed using CRISPR/Cas9 gene editing to mutate the active site cysteine residue of TG2. Biochemical analysis showed the mutant TG2 lacked crosslinking activity but retained GTP binding ability. Preliminary analysis found the TG2-C277S mice expressed normal levels of TG2 protein and its interaction with integrins and fibronectin were preserved. This novel mouse model will provide insights into TG2 functions in vascular aging independent of its enzymatic crosslinking activity.
5-Year Survival of Non-Small Cell Lung Cancer Patients after Radical Surgery Significantly Depended on Phase Transition “Early-Invasive Cancer”, Lymph Node Metastases and Cell Ratio Factors
This document summarizes key findings regarding dose-limiting toxicities from radiation therapy for various brain structures and tumors. It notes that necrosis rates for brain tumors start around 5% at 60 Gy, with various structures like the optic nerves and endocrine system showing toxicity starting at doses of 50-45 Gy. Late toxicities from a phase III trial escalating glioblastoma radiation from 60 to 72 Gy showed slightly higher rates of neurological and other toxicities in the higher dose arm. Further evidence is discussed relating radiation dose and fractionation to risks of dementia, cochlear dysfunction, and other issues. Intensity modulated radiation therapy may help reduce doses to critical structures like the optic chiasm compared to 3D conformal radiation therapy based
Mitochondrial diseases are caused by defects in the mitochondria or mitochondrial genome. The mitochondria produce energy in cells through oxidative phosphorylation and have important roles in calcium regulation, apoptosis, and reactive oxygen species generation. Mitochondrial DNA mutations can cause a variety of clinical syndromes affecting high-energy tissues like brain, muscle, heart. Common syndromes include MELAS, MERRF, and Leigh syndrome. Diagnosis involves assessing clinical features, blood/CSF lactate levels, muscle biopsy showing ragged red fibers, and genetic testing. Treatment focuses on managing symptoms while avoiding metabolic stress.
The document discusses various topics related to neurology including:
1. Common neurological disorders such as headache, low back pain, and stroke.
2. Components of a neurological examination including signs, reflexes, and tests of sensory and motor function.
3. Diagnostic tools used in neurology such as CT, MRI, angiography, EEG, lumbar puncture, and PET.
4. Types of disturbances of consciousness including those caused by brainstem or cortical damage.
5. Criteria for determining brain death.
This document provides an overview of mitochondrial diagnosis and disease. It discusses the basics of mitochondria, how mitochondrial diseases present clinically, and the various diagnostic approaches and tests used. Diagnosis often requires a combination of clinical evaluation, biochemical and metabolic testing, imaging, tissue biopsy, and molecular genetic analysis. Muscle biopsy remains the gold standard for testing but blood and other tissues can also provide useful information, though heteroplasmy can complicate interpretation. The field of mitochondrial medicine is continually expanding to identify new disease subtypes and improve diagnosis and care.
This study examines the relationship between metabolic syndrome and neuroendocrine and autonomic function. It finds that men with metabolic syndrome have higher levels of cortisol metabolites and catecholamines in their urine, as well as higher heart rate and lower heart rate variability, compared to healthy controls. These differences suggest increased activity of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system in metabolic syndrome. Psychosocial factors explained part of these neuroendocrine differences. Many of the changes appeared reversible in those who no longer had metabolic syndrome. The study provides initial evidence that chronic stress may contribute to the development of metabolic syndrome.
Mitochondrial DNA (mtDNA) encodes proteins that are essential components of the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Defects in mtDNA or nuclear genes involved in mitochondrial functions can cause a wide range of mitochondrial diseases. MtDNA is maternally inherited and mutations can be transmitted from mother to offspring. Common mitochondrial diseases include Chronic Progressive External Ophthalmoplegia (CPEO), Kearns-Sayre Syndrome (KSS), MELAS, MERRF, and Leber Hereditary Optic Neuropathy (LHON). These diseases have varying clinical features depending on the mutation and often affect the brain, muscles, and eyes.
This case report describes a 76-year-old male patient diagnosed with Marine-Lenhart syndrome. The patient had a history of Graves' disease treated with antithyroid drugs. Tests showed suppressed TSH levels and the patient was referred to an endocrinology department. Exams including ultrasound and scintigraphy revealed the patient had Graves' disease along with a hyperactive nodule in the thyroid, consistent with Marine-Lenhart syndrome. The patient was treated with antithyroid drugs followed by radioactive iodine therapy. Follow up showed improvement of hyperthyroidism symptoms. Marine-Lenhart syndrome is a rare cause of hyperthyroidism where a patient has Graves' disease concurrently with a hyperfunctional thyroid nodule.
This study investigated apoptosis in a transgenic mouse model of ALS. The researchers found:
1) DNA fragmentation, a marker of apoptosis, was significantly higher in the brain regions of mice expressing a mutant SOD1 gene compared to control mice, as shown by TUNEL staining and ELISA assays.
2) Double staining showed many TUNEL-positive motoneurons and glial cells in the spinal cord and brainstem of mutant SOD1 mice, but not controls.
3) Electron microscopy confirmed neuronal and glial apoptosis in these regions through characteristic morphological features in mutant SOD1 mice.
4) TUNEL-positive neurons were also observed in the motor and sensory cortices of mutant
Learning Objectives:
Describe the consequences of hyper- and hypovolemia for surgical and critically ill patients.
Develop a fluid management strategy for individual patients
Esophageal Cancer: Artificial Intelligence, Synergetics, Complex System Analy...Oleg Kshivets
5-year survival of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC cell dynamics; 9) EC characteristics; 10) tumor localization; 11) anthropometric data; 12) surgery type. Optimal diagnosis and treatment strategies for EC are: 1) screening and early detection of EC; 2) availability of experienced thoracoabdominal surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for ECP with unfavorable prognosis.
differentiating different brain lesion using MR Spectroscopy which is a newer MR technique to quantify different metabolites present within the lesion and adjacent parenchyma
The document provides an overview of bipolar disorder including:
1. The lifetime and 12-month prevalence of bipolar spectrum disorders based on a large US population study.
2. Bipolar disorder has a complex symptomatic presentation and patients experience a constant risk of relapse over decades.
3. Genetics plays a large role in bipolar disorder liability and genome-wide association studies have identified several susceptibility genes.
4. Structural and functional brain imaging research has found differences in bipolar patients in areas involved in emotion regulation, cognitive control, and reward processing.
The document discusses oligodendroglioma, a rare type of brain tumor. Key points include:
- Oligodendrogliomas most commonly occur in the cerebral hemispheres in adults aged 30-50. Surgery is the primary treatment when possible, along with radiation and chemotherapy.
- MRI is used for diagnosis. Tumors are graded on a scale of II-III according to the WHO system. Lower grade (II) tumors can later transform to higher grade (III).
- While surgery aims for gross total resection, this is often not possible. Adjuvant treatment depends on factors like tumor location and extent of resection. Radiation is usually given after symptoms appear rather than
Medullary carcinoma of thyroid genene m. bekele, md, faceGofasefer
1) This document describes the case of a patient with metastatic medullary thyroid carcinoma (MTC) who underwent multiple surgeries and treatments over several years as their disease progressed and calcitonin levels increased.
2) Vandetanib, a drug that targets the RET gene mutation often present in MTC, was approved by the FDA in 2011 based on results of the ZETA clinical trial showing it significantly increased progression-free survival compared to placebo.
3) The ZETA trial involved 331 patients randomized to receive either vandetanib 300mg daily or placebo, with the primary endpoint being progression-free survival assessed by independent review. Vandetanib was found to nearly halve the risk of progression or death
This study evaluated an adjuvant WT1 vaccine (SLS-001) for patients with malignant pleural mesothelioma after multimodality therapy. Seventy-eight patients received either the WT1 vaccine or a control immunotherapy every two weeks for six doses. The primary endpoint was one-year progression-free survival. The study was closed early due to futility in both arms. While injection site reactions were common, clinically significant severe events did not occur. Median overall survival was 24.8 months for the vaccine group and 16.6 months for the control, though the difference was not statistically significant. The WT1 vaccine induced CD4+ and CD8+ T cell responses and had a manageable safety profile. A
This study analyzed data from 708 lung cancer patients who underwent surgery to determine optimal diagnosis and treatment strategies. Overall survival was 71.1% at 5 years and decreased to 63% at 10 years and 43.4% at 20 years. Adjuvant chemoimmunoradiotherapy significantly improved 5-year survival for patients with lymph node involvement. Neural network modeling revealed that 5-year survival was most dependent on the phase transition between early and invasive cancer, lymph node status, and various cell ratio factors. The optimal diagnosis and treatment strategies identified were early screening and detection, experienced surgeons, aggressive surgery with lymph node dissection, precise prediction modeling, and adjuvant therapy for high-risk patients.
A mitochondrion (singular of mitochondria) is part of every cell in the body that contains genetic material.
Mitochondria are responsible for processing oxygen and converting substances from the foods we eat into energy for essential cell functions.
The mitochondria of the zygote come from the oocyte, that is, from the mother and almost never from the sperm, form of transmission is called maternal inheritance
Which mitochondrial gene is mutated.
The extent of replicative segregation of the mutant mitochondrial genome during the early stages of embryonic development.
The abundance of the mutant mitochondrial gene in a particular tissue.
The threshold level of mutant mitochondrial DNA required in a tissue before an abnormality is evident clinically
Mitochondrial disease affects tissues most highly dependent on ATP production
*Nerves
*Muscles
Endocrine
Kidney
Low energy-requiring tissues are rarely directly affected, but may be secondarily
Lung
Connective tissue
Symptoms can be intermittent
Increased energy demand (illness, exercise)
Decreased energy supply (fasting)
Common feature
myoclonus epilepsy, deafness, blindness, anemia, diabetes, seizures and loss of cerebral blood supply (stroke).
Myoclonic epilepsy and ragged-red fiber disease (MERRF)
MERRF is a member of a group of disorders called mitochondrial encephalomyopathies that feature mitochondrial defects with altered brain and muscle functions.
The term “ragged red fibers” refers to large clumps of abnormal mitochondria that accumulate mostly in muscle cells and are stained red by a dye that is specific for complex II of the electron transport chain.
rare, maternally inherited, heteroplasmic, (point mutation in tRNA lysine gene)
Mutation is MTTK*MERRF8344G.
MT means mitochondrial gene is mutated
T means transfer RNA gene
K means the single-letter amino acid designation for lysine
MERRF means the clinical features
8344G means the mutant nucleotide is guanine (G) at nucleotide position 8344
If 90% of the mitochondria in nerve and muscle cells carry the MTTK*MERRF8344G mutation, then the defining symptoms of MERRF are present.
Maternally inherited mitochondrial disease
The MTTL1*MELAS3243G mutation accounts for more than 80% of the cases of MELAS.
This base substitution is in one of the two mitochondrial transfer RNALeu genes.
the A3243G mutation occurs in thetRNALeu(UUR) gene
When this mutation is present in ≥90% of the mitochondrial DNA of muscle tissue, there is an increased likelihood of recurrent strokes, dementia, epilepsy, and ataxia.
When heteroplasmy for the A3243G mutation
is ~40% to 50%, chronic progressive external ophthalmoplegia (CPEO), myopathy, and deafness are likely to occur.
Other MELAS mutations occur at sites 3252, 3271, and 3291 within the tRNALeu(UUR) gene and in the mitochondrial tRNAVal (MTTV) and COX III (MTCO3) genes.
Reduced activities in Complexes I and IV are established
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
A proprietary approach developed by bringing together the best of learning theories from Psychology, design principles from the world of visualization, and pedagogical methods from over a decade of training experience, that enables you to: Learn better, faster!
8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
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Kshivets Oleg Optimization of Management for Esophageal Cancer Patients (T1-...Oleg Kshivets
Optimization of Management for Esophageal Cancer Patients (T1-4N0-2M0).
Kshivets Oleg Surgery Department, Bagrationovsk Hospital, Bagrationovsk, Kaliningrad, Russia
ABSTRACT
OBJECTIVE: 5-survival (5YS) and life span after radical surgery for esophageal cancer (EC) pa¬tients (ECP)(T1-4N0-2M0) - alive supersysems was analyzed. The importance must be stressed of using complex system analysis, artificial intelligence (neural networks computing), simulation modeling and statistical methods in combination, because the different approaches yield complementary pieces of prognostic information.
METHODS: We analyzed data of 563 consecutive ECP (age=56.6±8.9 years; tumor size=6±3.5 cm) radically operated (R0) and monitored in 1975-2024 (m=419, f=144; esophagogastrectomies (EG) Garlock=289, EG Lewis=274, combined EG with resection of pancreas, liver, diaphragm, aorta, VCS, colon transversum, lung, trachea, pericardium, splenectomy=170; adenocarcinoma=323, squamous=230, mix=10; T1=131, T2=119, T3=185, T4=128; N0=285, N1=71, N2=207; G1=161, G2=143, G3=259; early EC=112, invasive=451; only surgery=428, adjuvant chemoimmunoradiotherapy-AT=135: 5-FU+thymalin/taktivin+radiotherapy 45-50Gy). Multivariate Cox modeling, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence.
RESULTS: Overall life span (LS) was 1915.4±2284.8 days and cumulative 5-year survival (5YS) reached 52.6%, 10 years – 46.3%, 20 years – 33.3%, 30 years – 27.5%. 193 ECP lived more than 5 years (LS=4309.1±2507.4 days), 105 ECP – more than 10 years (LS=5860.8±2469.2 days). 228 ECP died because of EC (LS=629.8±324.1 days). AT significantly improved 5YS (69% vs. 49.1%) (P=0.0007 by log-rank test). 5YS of ECP of upper/3 was significantly better than others (65.3% vs.50.3%) (P=0.003). Cox modeling displayed that 5YS of ECP significantly depended on: phase transition (PT) N0—N12 in terms of synergetics, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), T, G, histology, age, AT, localization, prothrombin index, hemorrhage time, residual nitrogen, protein (P=0.000-0.019). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and healthy cells/CC (rank=1), PT N0—N12 (2), PT early-invasive EC (3), erythrocytes/CC (4), thrombocytes/CC (5); segmented neutrophils/CC (6), stick neutrophils/CC (7), lymphocytes/CC (8), eosinophils/CC (9), monocytes/CC (10), leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5-year survival of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC cell dynamics; 9) EC characteristics; 10) tumor localization; 11) anthropometric data; 12) surgery type. Optimal diagnosis and trea
This document summarizes a presentation about a novel "knock-in" mouse model that expresses a catalytically inactive form of tissue transglutaminase (TG2). The TG2-C277S mouse model was developed using CRISPR/Cas9 gene editing to mutate the active site cysteine residue of TG2. Biochemical analysis showed the mutant TG2 lacked crosslinking activity but retained GTP binding ability. Preliminary analysis found the TG2-C277S mice expressed normal levels of TG2 protein and its interaction with integrins and fibronectin were preserved. This novel mouse model will provide insights into TG2 functions in vascular aging independent of its enzymatic crosslinking activity.
5-Year Survival of Non-Small Cell Lung Cancer Patients after Radical Surgery Significantly Depended on Phase Transition “Early-Invasive Cancer”, Lymph Node Metastases and Cell Ratio Factors
This document summarizes key findings regarding dose-limiting toxicities from radiation therapy for various brain structures and tumors. It notes that necrosis rates for brain tumors start around 5% at 60 Gy, with various structures like the optic nerves and endocrine system showing toxicity starting at doses of 50-45 Gy. Late toxicities from a phase III trial escalating glioblastoma radiation from 60 to 72 Gy showed slightly higher rates of neurological and other toxicities in the higher dose arm. Further evidence is discussed relating radiation dose and fractionation to risks of dementia, cochlear dysfunction, and other issues. Intensity modulated radiation therapy may help reduce doses to critical structures like the optic chiasm compared to 3D conformal radiation therapy based
Mitochondrial diseases are caused by defects in the mitochondria or mitochondrial genome. The mitochondria produce energy in cells through oxidative phosphorylation and have important roles in calcium regulation, apoptosis, and reactive oxygen species generation. Mitochondrial DNA mutations can cause a variety of clinical syndromes affecting high-energy tissues like brain, muscle, heart. Common syndromes include MELAS, MERRF, and Leigh syndrome. Diagnosis involves assessing clinical features, blood/CSF lactate levels, muscle biopsy showing ragged red fibers, and genetic testing. Treatment focuses on managing symptoms while avoiding metabolic stress.
The document discusses various topics related to neurology including:
1. Common neurological disorders such as headache, low back pain, and stroke.
2. Components of a neurological examination including signs, reflexes, and tests of sensory and motor function.
3. Diagnostic tools used in neurology such as CT, MRI, angiography, EEG, lumbar puncture, and PET.
4. Types of disturbances of consciousness including those caused by brainstem or cortical damage.
5. Criteria for determining brain death.
This document provides an overview of mitochondrial diagnosis and disease. It discusses the basics of mitochondria, how mitochondrial diseases present clinically, and the various diagnostic approaches and tests used. Diagnosis often requires a combination of clinical evaluation, biochemical and metabolic testing, imaging, tissue biopsy, and molecular genetic analysis. Muscle biopsy remains the gold standard for testing but blood and other tissues can also provide useful information, though heteroplasmy can complicate interpretation. The field of mitochondrial medicine is continually expanding to identify new disease subtypes and improve diagnosis and care.
This study examines the relationship between metabolic syndrome and neuroendocrine and autonomic function. It finds that men with metabolic syndrome have higher levels of cortisol metabolites and catecholamines in their urine, as well as higher heart rate and lower heart rate variability, compared to healthy controls. These differences suggest increased activity of the hypothalamic-pituitary-adrenal axis and sympathetic nervous system in metabolic syndrome. Psychosocial factors explained part of these neuroendocrine differences. Many of the changes appeared reversible in those who no longer had metabolic syndrome. The study provides initial evidence that chronic stress may contribute to the development of metabolic syndrome.
Mitochondrial DNA (mtDNA) encodes proteins that are essential components of the oxidative phosphorylation (OXPHOS) system located in the inner mitochondrial membrane. Defects in mtDNA or nuclear genes involved in mitochondrial functions can cause a wide range of mitochondrial diseases. MtDNA is maternally inherited and mutations can be transmitted from mother to offspring. Common mitochondrial diseases include Chronic Progressive External Ophthalmoplegia (CPEO), Kearns-Sayre Syndrome (KSS), MELAS, MERRF, and Leber Hereditary Optic Neuropathy (LHON). These diseases have varying clinical features depending on the mutation and often affect the brain, muscles, and eyes.
This case report describes a 76-year-old male patient diagnosed with Marine-Lenhart syndrome. The patient had a history of Graves' disease treated with antithyroid drugs. Tests showed suppressed TSH levels and the patient was referred to an endocrinology department. Exams including ultrasound and scintigraphy revealed the patient had Graves' disease along with a hyperactive nodule in the thyroid, consistent with Marine-Lenhart syndrome. The patient was treated with antithyroid drugs followed by radioactive iodine therapy. Follow up showed improvement of hyperthyroidism symptoms. Marine-Lenhart syndrome is a rare cause of hyperthyroidism where a patient has Graves' disease concurrently with a hyperfunctional thyroid nodule.
This study investigated apoptosis in a transgenic mouse model of ALS. The researchers found:
1) DNA fragmentation, a marker of apoptosis, was significantly higher in the brain regions of mice expressing a mutant SOD1 gene compared to control mice, as shown by TUNEL staining and ELISA assays.
2) Double staining showed many TUNEL-positive motoneurons and glial cells in the spinal cord and brainstem of mutant SOD1 mice, but not controls.
3) Electron microscopy confirmed neuronal and glial apoptosis in these regions through characteristic morphological features in mutant SOD1 mice.
4) TUNEL-positive neurons were also observed in the motor and sensory cortices of mutant
Learning Objectives:
Describe the consequences of hyper- and hypovolemia for surgical and critically ill patients.
Develop a fluid management strategy for individual patients
Esophageal Cancer: Artificial Intelligence, Synergetics, Complex System Analy...Oleg Kshivets
5-year survival of ECP after radical procedures significantly depended on: 1) PT “early-invasive cancer”; 2) PT N0--N12; 3) Cell Ratio Factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) EC cell dynamics; 9) EC characteristics; 10) tumor localization; 11) anthropometric data; 12) surgery type. Optimal diagnosis and treatment strategies for EC are: 1) screening and early detection of EC; 2) availability of experienced thoracoabdominal surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for ECP with unfavorable prognosis.
differentiating different brain lesion using MR Spectroscopy which is a newer MR technique to quantify different metabolites present within the lesion and adjacent parenchyma
The document provides an overview of bipolar disorder including:
1. The lifetime and 12-month prevalence of bipolar spectrum disorders based on a large US population study.
2. Bipolar disorder has a complex symptomatic presentation and patients experience a constant risk of relapse over decades.
3. Genetics plays a large role in bipolar disorder liability and genome-wide association studies have identified several susceptibility genes.
4. Structural and functional brain imaging research has found differences in bipolar patients in areas involved in emotion regulation, cognitive control, and reward processing.
The document discusses oligodendroglioma, a rare type of brain tumor. Key points include:
- Oligodendrogliomas most commonly occur in the cerebral hemispheres in adults aged 30-50. Surgery is the primary treatment when possible, along with radiation and chemotherapy.
- MRI is used for diagnosis. Tumors are graded on a scale of II-III according to the WHO system. Lower grade (II) tumors can later transform to higher grade (III).
- While surgery aims for gross total resection, this is often not possible. Adjuvant treatment depends on factors like tumor location and extent of resection. Radiation is usually given after symptoms appear rather than
Medullary carcinoma of thyroid genene m. bekele, md, faceGofasefer
1) This document describes the case of a patient with metastatic medullary thyroid carcinoma (MTC) who underwent multiple surgeries and treatments over several years as their disease progressed and calcitonin levels increased.
2) Vandetanib, a drug that targets the RET gene mutation often present in MTC, was approved by the FDA in 2011 based on results of the ZETA clinical trial showing it significantly increased progression-free survival compared to placebo.
3) The ZETA trial involved 331 patients randomized to receive either vandetanib 300mg daily or placebo, with the primary endpoint being progression-free survival assessed by independent review. Vandetanib was found to nearly halve the risk of progression or death
This study evaluated an adjuvant WT1 vaccine (SLS-001) for patients with malignant pleural mesothelioma after multimodality therapy. Seventy-eight patients received either the WT1 vaccine or a control immunotherapy every two weeks for six doses. The primary endpoint was one-year progression-free survival. The study was closed early due to futility in both arms. While injection site reactions were common, clinically significant severe events did not occur. Median overall survival was 24.8 months for the vaccine group and 16.6 months for the control, though the difference was not statistically significant. The WT1 vaccine induced CD4+ and CD8+ T cell responses and had a manageable safety profile. A
This study analyzed data from 708 lung cancer patients who underwent surgery to determine optimal diagnosis and treatment strategies. Overall survival was 71.1% at 5 years and decreased to 63% at 10 years and 43.4% at 20 years. Adjuvant chemoimmunoradiotherapy significantly improved 5-year survival for patients with lymph node involvement. Neural network modeling revealed that 5-year survival was most dependent on the phase transition between early and invasive cancer, lymph node status, and various cell ratio factors. The optimal diagnosis and treatment strategies identified were early screening and detection, experienced surgeons, aggressive surgery with lymph node dissection, precise prediction modeling, and adjuvant therapy for high-risk patients.
A mitochondrion (singular of mitochondria) is part of every cell in the body that contains genetic material.
Mitochondria are responsible for processing oxygen and converting substances from the foods we eat into energy for essential cell functions.
The mitochondria of the zygote come from the oocyte, that is, from the mother and almost never from the sperm, form of transmission is called maternal inheritance
Which mitochondrial gene is mutated.
The extent of replicative segregation of the mutant mitochondrial genome during the early stages of embryonic development.
The abundance of the mutant mitochondrial gene in a particular tissue.
The threshold level of mutant mitochondrial DNA required in a tissue before an abnormality is evident clinically
Mitochondrial disease affects tissues most highly dependent on ATP production
*Nerves
*Muscles
Endocrine
Kidney
Low energy-requiring tissues are rarely directly affected, but may be secondarily
Lung
Connective tissue
Symptoms can be intermittent
Increased energy demand (illness, exercise)
Decreased energy supply (fasting)
Common feature
myoclonus epilepsy, deafness, blindness, anemia, diabetes, seizures and loss of cerebral blood supply (stroke).
Myoclonic epilepsy and ragged-red fiber disease (MERRF)
MERRF is a member of a group of disorders called mitochondrial encephalomyopathies that feature mitochondrial defects with altered brain and muscle functions.
The term “ragged red fibers” refers to large clumps of abnormal mitochondria that accumulate mostly in muscle cells and are stained red by a dye that is specific for complex II of the electron transport chain.
rare, maternally inherited, heteroplasmic, (point mutation in tRNA lysine gene)
Mutation is MTTK*MERRF8344G.
MT means mitochondrial gene is mutated
T means transfer RNA gene
K means the single-letter amino acid designation for lysine
MERRF means the clinical features
8344G means the mutant nucleotide is guanine (G) at nucleotide position 8344
If 90% of the mitochondria in nerve and muscle cells carry the MTTK*MERRF8344G mutation, then the defining symptoms of MERRF are present.
Maternally inherited mitochondrial disease
The MTTL1*MELAS3243G mutation accounts for more than 80% of the cases of MELAS.
This base substitution is in one of the two mitochondrial transfer RNALeu genes.
the A3243G mutation occurs in thetRNALeu(UUR) gene
When this mutation is present in ≥90% of the mitochondrial DNA of muscle tissue, there is an increased likelihood of recurrent strokes, dementia, epilepsy, and ataxia.
When heteroplasmy for the A3243G mutation
is ~40% to 50%, chronic progressive external ophthalmoplegia (CPEO), myopathy, and deafness are likely to occur.
Other MELAS mutations occur at sites 3252, 3271, and 3291 within the tRNALeu(UUR) gene and in the mitochondrial tRNAVal (MTTV) and COX III (MTCO3) genes.
Reduced activities in Complexes I and IV are established
Similar to Dr. Wallace - Mitochondrial Genetics and Disease (20)
Promoting Wellbeing - Applied Social Psychology - Psychology SuperNotesPsychoTech Services
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8 Surprising Reasons To Meditate 40 Minutes A Day That Can Change Your Life.pptxHolistified Wellness
We’re talking about Vedic Meditation, a form of meditation that has been around for at least 5,000 years. Back then, the people who lived in the Indus Valley, now known as India and Pakistan, practised meditation as a fundamental part of daily life. This knowledge that has given us yoga and Ayurveda, was known as Veda, hence the name Vedic. And though there are some written records, the practice has been passed down verbally from generation to generation.
Rasamanikya is a excellent preparation in the field of Rasashastra, it is used in various Kushtha Roga, Shwasa, Vicharchika, Bhagandara, Vatarakta, and Phiranga Roga. In this article Preparation& Comparative analytical profile for both Formulationon i.e Rasamanikya prepared by Kushmanda swarasa & Churnodhaka Shodita Haratala. The study aims to provide insights into the comparative efficacy and analytical aspects of these formulations for enhanced therapeutic outcomes.
share - Lions, tigers, AI and health misinformation, oh my!.pptxTina Purnat
• Pitfalls and pivots needed to use AI effectively in public health
• Evidence-based strategies to address health misinformation effectively
• Building trust with communities online and offline
• Equipping health professionals to address questions, concerns and health misinformation
• Assessing risk and mitigating harm from adverse health narratives in communities, health workforce and health system
- Video recording of this lecture in English language: https://youtu.be/kqbnxVAZs-0
- Video recording of this lecture in Arabic language: https://youtu.be/SINlygW1Mpc
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These lecture slides, by Dr Sidra Arshad, offer a quick overview of the physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar lead (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
6. Describe the flow of current around the heart during the cardiac cycle
7. Discuss the placement and polarity of the leads of electrocardiograph
8. Describe the normal electrocardiograms recorded from the limb leads and explain the physiological basis of the different records that are obtained
9. Define mean electrical vector (axis) of the heart and give the normal range
10. Define the mean QRS vector
11. Describe the axes of leads (hexagonal reference system)
12. Comprehend the vectorial analysis of the normal ECG
13. Determine the mean electrical axis of the ventricular QRS and appreciate the mean axis deviation
14. Explain the concepts of current of injury, J point, and their significance
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. Chapter 3, Cardiology Explained, https://www.ncbi.nlm.nih.gov/books/NBK2214/
7. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
Adhd Medication Shortage Uk - trinexpharmacy.comreignlana06
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Osteoporosis - Definition , Evaluation and Management .pdfJim Jacob Roy
Osteoporosis is an increasing cause of morbidity among the elderly.
In this document , a brief outline of osteoporosis is given , including the risk factors of osteoporosis fractures , the indications for testing bone mineral density and the management of osteoporosis
Local Advanced Lung Cancer: Artificial Intelligence, Synergetics, Complex Sys...Oleg Kshivets
Overall life span (LS) was 1671.7±1721.6 days and cumulative 5YS reached 62.4%, 10 years – 50.4%, 20 years – 44.6%. 94 LCP lived more than 5 years without cancer (LS=2958.6±1723.6 days), 22 – more than 10 years (LS=5571±1841.8 days). 67 LCP died because of LC (LS=471.9±344 days). AT significantly improved 5YS (68% vs. 53.7%) (P=0.028 by log-rank test). Cox modeling displayed that 5YS of LCP significantly depended on: N0-N12, T3-4, blood cell circuit, cell ratio factors (ratio between cancer cells-CC and blood cells subpopulations), LC cell dynamics, recalcification time, heparin tolerance, prothrombin index, protein, AT, procedure type (P=0.000-0.031). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and N0-12 (rank=1), thrombocytes/CC (rank=2), segmented neutrophils/CC (3), eosinophils/CC (4), erythrocytes/CC (5), healthy cells/CC (6), lymphocytes/CC (7), stick neutrophils/CC (8), leucocytes/CC (9), monocytes/CC (10). Correct prediction of 5YS was 100% by neural networks computing (error=0.000; area under ROC curve=1.0).
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1. A MITOCHONDRIAL ETIOLOGY OF COMPLEX DISEASES
Why can’t we understand and cure the common diseases?
Neuropsychiatric Disorders: Autism, ADHD, Schizophrenia, Bipolar Disease,
Stress Response, Alzheimer Disease, Parkinson Disease, ALS, Multiple Sclerosis,
Blindness, Deafness…
Heart-Muscle: Cardiomyopathy, Myopathy, Chronic Fatigue…
Visceral: Renal, Hepatic, Immunological…
Metabolic: Diabetes, Obesity, Cardiovascular Disease…
Cancer & Aging
Western medicine has approached the common diseases primarily from an
anatomical and Mendelian perspective, but
Life = Anatomy + Energetics + Information
Consequently, the role of bioenergetics and non-Mendelian
bioenergetic inheritance has been largely ignored.
Our hypothesis is that bioenergetic dysfunction lies at the nexus of the genetic
and environmental “causes” of the “common-complex” diseases.
2.
3. Information Flow in The Cell
DNA
Stored Genetic Information
PROTEINS
Yield Structure (skin, hair)
Replication
Transcription
Translation
Nucleus
Cytoplasm
mRNA + Ribosomes (interpreting structures)
RNA
Working Copy of Gene (message)
4.
5. THE EUKARYOTIC CELL IS COMPOSED OF TWO ORGANISMS
THE MITOCHONDRIA SPECIALZED
IN ENERGY
1000s of mtDNAs + ~1500 nDNA genes
6. ENERGY: Fats + Sugars + Oxygen = Energy (heat + work) + CO2 + H2O
REDOX BALANCE: Thiol-Disulfide Regulation of Pathways and Transcription Factors.
REACTIVE OXYGEN SPECIES (ROS): Oxygen Radicals + Signal Transduction.
Ca++ REGULATION: Regulates Cytosol Ca++, Metabolism, & mtPTP.
APOPTOSIS: Energy ↓ + ROS ↑ = mtPTP Activated → Cell Death (Apoptosis).
EPIGENOMIC REGULATION: Mito. (ATP, acetyl CoA, SAM, α-ketoglutarate) modify epigenome.
MITOCHONDRIAL FUNCTION IS CENTRAL TO HEALTH
ANT1 =
heart,
muscle,
brain.
ANT2 =
systemic
.
NNT
7. THE MITOCHONDRIAL GENOME IS DISTRIBUTED ACROSS THE nDNA & mtDNA
THE MITOCHONDRIAL GENOME:
~ 1500 nDNA Genes
Dispersed Across the Chromosomes
+ 37 mtDNA Genes
High Mutation Rate: ROS
8. THE BODY’S ANALTOMY IS DEFINED BY ENERGY
Origin of Tissue-Specific Disease
• Energy Utilizing Tissues:
– Brain: High demand-Low reserve.
~2% body weight but uses ~20% of the O2.
– Heart, Muscle, Renal, etc.: Constant demand-High reserve.
• Energy Storage Tissues:
– WAT: Energy storage for activities.
– BAT: Energy storage for thermal regulation.
• Energy Homeostasis Tissues:
– Liver: Glucose homeostasis.
• Energy Sensing Tissues:
– Purpose: Monitor & adapt to seasonal plant carbohydrates
– Pancreatic β Cells: Glucose abundant-Insulin signaling.
– Pancreatic α Cells: Glucose limitation-Glucagon signaling.
12. LEBER HEREDITARY OPTIC NEUROPATHY MATERNAL INHERITANCE, MALE
BIAS, & BACKGROUND REGULATION OF EXPRESSIVITY
Mutation
3460A
11778A
14484C
Gene
ND1
ND4
ND6
~ % Patients Complex I Defect AA Cons % Hplgr J ND1 3394C
15 Severe Moderate ~10 -
50 Moderate Moderate 29 +
15 Mild Low 79 +
Penetrance of Milder Mutations exacerbated
by Haplogroup J or ND1 T3394C (Y30H)
MATERNALLY INHERITED
OPTIC NEUROPATHY,
VARIABLE PENETRANCE,
& 4:1 MALE BIAS
mtDNA ND4 np 11778 G>A
arginine 340 to histidine
13. ANCIENT mtDNA VARIANTS PREDISPOSE TO COMMON DISEASES
mtDNA VARIATION CORRELATES WITH THE GEOGRAPHIC LOCATIONS OF
INDIGENOUS PEOPLES.
Groups of Related mtDNA Haplotypes (Haplogroups) were Founded by Adaptive
Variants that Permitted Migration into New Environments.
M
Mutation rate = 2.2 – 2.9% / MYR
Time estimates are YBP.
15. NODAL SUBSTITUTIONS ALTERING CONSERVED AMINO
ACIDS INITIATE EACH mtDNA HAPLOGROUP
EUROPEAN HAPLOGROUPS T & J
Hplgr Gene npΔ CI % Funct
T ND2 4917A 90 ?
J1 Cytb 14798C 79 Qi
J2 Cytb 15257A 95 Qo
16. AD = 3.3%,
PD = 5.3%,
AD+PD = 6.8%,
CNTL = 0.4%
Haplogroup H5a
One event = ancient
polymorphism
AD + PD
ND1 A3397G Met 31Val
Two independent events = recent
deleterious mutation
EUROPEAN ASSOCIATION OF tRNAGln
A4336G & ND1 (M31V) WITH ALZHEIMER &
PARKINSON DISEASE
17. ADAPTATIVE SELECTION
0
5
10
15
20
25
30
35
40
1000 2000 3000 4000 5000
M9relativefrequency
0
5
10
15
20
25
30
35
40
1000 2000 3000 4000 5000
T3394Crelativefrequency
Lianhshan
Gannan
Qinghai
Diqing
Shigatse
LhasaChamdo
Nyingchi
Shannan
Nagchu
Lianhshan
Gannan
Qinghai
Diqing
Shigatse
Nagchu
Lhasa
Chamdo
Nyingchi
Shannan
0
5
10
15
20
25
30
35
40
1000 2000 3000 4000 5000
M9relativefrequency
0
5
10
15
20
25
30
35
40
1000 2000 3000 4000 5000
T3394Crelativefrequency
Lianhshan
Gannan
Qinghai
Diqing
Shigatse
LhasaChamdo
Nyingchi
Shannan
Nagchu
Lianhshan
Gannan
Qinghai
Diqing
Shigatse
Nagchu
Lhasa
Chamdo
Nyingchi
Shannan
M9 3394C
L3
M8
M14
M11
D
D5
M15
T3394C
D4
M9
G
M2
G2
T3394C
T3394C
G3b
M13
A B
F
U1
B5
B4a
C10400T
M
T10873C
N
L3
M8
M14
M11
D
D5
M15
T3394C
D4
M9
G
M2
G2
T3394C
T3394C
G3b
M13
A B
F
U1
B5
B4a
C10400T
M
T10873C
N
mtDNA AMINO ACID SUBSTITUTIONS CAN
BE POSITIVE OR NEGATIVE DEPENDING
ON CONTEXT
M [ND3 10398G (114A)]
IS ENRICHED IN TIBET &
[ND1 3394C (30H)]
IS PATHOGENIC ON N
BUT ADAPTIVE ON M IN TIBETANS
21. Leigh Syndrome
Lactic Acidosis
SN Deafness
Epileptic Seizures
Metabolic Failure
Muscle Myopathy
Cerebral atrophy
Death
Optic Atrophy
Cerebellar
Atrophy
HETEROPLASMIC mtDNA MUTATIONS SEGREGATE RAPIDLY
A HUMAN HETEROPLASMIC mtDNA ND6 G14600A P25L MUTATION
SEGREGATES TO GIVE VARIOUS PHENOTYPES
Malfatti –Zevani
22. MOUSE MODELS OF mtDNA DISEASE:
ND6 = NEURODEGERATION
COI = CARDIOMYOPATHY & METABOLIC SYNDROME
129 + NZB = NEUROPSYCHIATRIC DISEASE
Mouse ND6 nt G13997A (P25L) = Human ND6 G14600A (P25L),
COI nt 6589 T>C (V421A), &
129+NZB Heteroplasmy
Disaggregate
Female ES Cells:
ND6 13997G>A (P25L) or
COI nt 6589 T>C (V421A) mtDNA
129 +NZB Heteroplasmic mtDNAs
ES Cell cybrids
Pseudopregnant
mother
Female Chimera
ND6 13997G>A (P25L),
COI nt 6589 T>C (V421A),
129 + NZB Heteroplasmic mtDNA Mice
Mouse Cell Line Mutants
ND6 13997G>A (P25L) mtDNA,
COI nt 6589 T>C (V421A) mtDNA,
129 + NZB mtDNA
R6G
129 Mice
23. THE mtDNA ND6 P25L MUTATION RESULTS IN ELEVATED REACTIVE
SPECIED (ROS) PRODUCITON AND NEUROLOGICAL DISEASE
INCREASED ROS PRODUCTION, NORMAL ATP
ALTERED EEGs
NEURONAL
DEGENERATION
7
24. Mitochondrial
Myopathy
Mitochondrial
Cardiomyopathy
THE COI V421A mtDNA MOUSE EXHIBITS MYOPATHY,
CARDIOMYOPATHY & METABOLIC SYNDROME
COI (6589T>C, V421A) MISSENSE MUTATION
Glucose Level
Time (min)
BloodGlucose(mg/dL)
0 50 100 150
0
100
200
300
B6ME
ND6
COI
**
**
**
Insulin Level
Time (min)
PlasmaInsulin(ng/mL)
0 50 100 150
0.0
0.5
1.0
1.5
2.0
B6ME
ND6
COI
**
*
*
Glucose Intolerance &
Insulin Resistance
25. 91 “129” vs “NZB” mtDNAs differences: 15 aaΔ +5 tRNA +7 rRNA + 11 CR
MATERNAL TRANSMISSION OF NORMAL mtDNA HETERPLASMY
M NW
BamH A4276G
0 2000 4000 6000 8000 10000 12000 14000 16000
I I II I II I III II I II III I I I II III I I I II I I II III I I II I II IIIII I IIII II I III I II I I I I IIIIII I II I IIII II I I III
Backcrossed 20 generations onto C57BL/6L nDNA.
Permitted nZB-129 mtDNAs to segregate.
Correlated mtDNA NZB-129 genotypes with behavior.
CREATION OF NZB-129 HETEROPLASMIC MICE
31. Thank You
ENERGY IS LIFE
Masha Lvova
Grant MacGregor
Meagan McManus
Debbie Murdock
Dan Mishmar
Xilma Ortiz-Gonzalez
Marin Picard
Julia Platt
Parsanth Potluri
Eduardo Ruiz-Pesini
Mark Sharpley
Larry Singh
Jesus Tintos
Katrina Waymire
Tal Yardeni
CMEM, CHOP
MAMMAG, UCI
MEM, Emory
Alessia Angelin
Dimitra Chalkia
Olga Derbeneva
Weiwei Fan
Sage Hancock
Taosheng Huang
Kierstin Keller
Ryan Lin
NIH, Autism Speaks, Simons Foundation
UCI EE
Peter Burke
CHOP
Stewart Anderson
Jeff Golden
Wayne Hancock
Eric Marsh
Ulf H. Beier
Mount Sinai Cardiology
Jagat Narula
Taiwan Natl University
Leeming Chuang
Yi-Cheng Chang
Third Military Med Schl,
Chongqing
Fuyun Ji
Guisheng Qian
Yaoli Wang
Wake Forest University
Lorna Moore
Epigenomics, UCI
Kristin Eckel-Mahan
Satoru Masubuchi
Paolo Sassone-Corsi
DNA BioTech, S Africa
Antonlle Olckers
Novosibirsk, Russia
Rem Sukernik