Chemical Pathology of Homocysteine VIII. Effects of Tocotrienol, Geranylgeraniol, and Squalene on Thioretinaco Ozonide, Mitochondrial Permeability, and Oxidative Phosphorylation in Arteriosclerosis, Cancer, Neurodegeneration and Aging.

A century ago a fat-soluble vitamin from leafy vegetables, later named vitamin E, was discovered to enhance fertility in animals. Vitamin E consists of 8 isomers of tocopherols and tocotrienols, each containing chromanol groups that confer antioxidant properties and differ only in the 15-carbon saturated phytyl poly-isoprenoid side chain of tocopherols and the 15-carbon unsaturated farnesyl poly-isoprenoid side chain of tocotrienols. Although tocotrienol was first isolated from rubber plants in 1964, its importance in multiple disease processes was not recognized until two decades later, when the cholesterol-lowering and anti-cancer effects were first reported.

Environmental Pollution, Oxidative Stress and Thioretinaco Ozonide: Effects of Glyphosate, Fluoride and Electromagnetic Fields on Mitochondrial Dysfunction in Carcinogenesis, Atherogenesis and Aging.

Environmental pollutants, such as pesticides, herbicides, additives to food and water, and electromagnetic fields threaten public health by promotion of cancer, heart disease and chronic diseases of aging. Many of these pollutants cause adverse health outcomes by effects on mitochondrial function to produce oxidative stress through loss of the active site complex for oxidative phosphorylation, thioretinaco ozonide oxygen nicotinamide adenine dinucleotide phosphate, from opening of the mitochondrial permeability transition pore. Glyphosate, fluoride, and electromagnetic fields are examples of carcinogenic pollutants that promote loss and decomposition of the active site for oxidative phosphorylation, producing mitochondrial dysfunction and oxidative stress.

Recent advances in network medicine: From disease mechanisms to new treatment strategies.

Conventional reductionist approaches have guided most of our understanding in disease diagnostic and treatment. However, most diseases are not consequence of perturbations in a single protein or metabolite, but rather of the effect that these perturbations have in their cellular context. The emerging field of network medicine offers a set of tools to explore molecular networks and to retrieve insights about mechanisms of different diseases.

Chemical Pathology of Homocysteine VII. Cholesterol, Thioretinaco Ozonide, Mitochondrial Dysfunction, and Prevention of Mortality.

The purpose of this review is to elucidate how low blood cholesterol promotes mitochondrial dysfunction and mortality by the loss of thioretinaco ozonide from opening of the mitochondrial permeability transition pore (mPTP). Mortality from infections and cancer are both inversely associated with blood cholesterol, as determined by multiple cohort studies from 10 to 30 years earlier. Moreover, low-density lipoprotein (LDL) is inversely related to all-cause and/or cardiovascular mortality, as determined by followup study of elderly cohorts.

Chemical Pathology of Homocysteine VI. Aging, Cellular Senescence, and Mitochondrial Dysfunction.

Following the discovery that caloric restriction extends the lifespan of many species of animals, the free radical theory of aging attributes the occurrence of oxidized nucleic acids, proteins, and lipids to reactive oxygen radical species originating from the metabolism of foods and the diminished efficacy of oxidative metabolism. Because of the decline of many critical neuro-hormones in aging, the neuroendocrine theory of aging attributes these changes to reduced feedback control of hormone production by the hypothalamus. Several rare genetic diseases attribute accelerated aging to changes in deoxyribonucleic acid (DNA) repair, depletion of the coenzyme nicotinamide adenine dinucleotide (NAD), and altered methionine and homocysteine metabolism.

Loss of the Thioretinaco Ozonide Oxygen Adenosine Triphosphate Complex from Mitochondria Produces Mitochondrial Dysfunction and Carcinogenesis.

The active site of oxidative phosphorylation and adenosine triphosphate (ATP) biosynthesis is proposed to consist of thioretinaco, a complex of two molecules of thioretinamide with cobalamin, oxidized to the disulfonium derivative, thioretinaco ozonide, and complexed with oxygen, nicotinamide adenine dinucleotide, inorganic phosphate and ATP. Reduction of the active site complex by electrons from mitochondrial electron transport complexes releases ATP from binding to the active site, producing nicotinamide riboside and hydroperoxide and generating a membrane potential from proton transport to the active site. Opening of the mitochondrial permeability transition pore from decreased mitochondrial melatonin leads to loss of the active site complex from mitochondrial membranes, as observed in aging and dementia.

Hypothesis: role for ammonia neutralization in the prevention and reversal of heart failure.

Ammonia plays a central role in the life and death of all living organisms and has been studied for over 100 yr. Ammonia is necessary for growth and development, but it is toxic in excess, and, as a result, differing methods of ammonia neutralization have evolved. After physiological and pathological stress to the heart, tissue ammonia levels rise.

Melatonin, Hyperhomocysteinemia, Thioretinaco Ozonide, Adenosylmethionine and Mitochondrial Dysfunction in Aging and Dementia.

The indoleamine hormone melatonin is synthesized by the pineal gland, controls circadian rhythm, and is dependent upon adenosyl methionine for enzymatic synthesis of melatonin from N-acetyl serotonin. Pineal melatonin secretion declines dramatically with aging and dementia. Elevated plasma homocysteine is a risk factor for atherosclerosis and Alzheimer's disease, and the marked decline in adenosyl methionine with aging leads to dysregulation of methionine metabolism and hyperhomocysteinemia.

The categories, frequencies, and stability of idiosyncratic eye-movement patterns to faces.

The spatial pattern of eye-movements to faces considered typical for neurologically healthy individuals is a roughly T-shaped distribution over the internal facial features with peak fixation density tending toward the left eye (observer's perspective). However, recent studies indicate that striking deviations from this classic pattern are common within the population and are highly stable over time. The classic pattern actually reflects the average of these various idiosyncratic eye-movement patterns across individuals.

Patients with Diabetes and Significant Epicardial Coronary Artery Disease Have Increased Systolic Left Ventricular Apical Rotation and Rotation Rate at Rest.

Objective: The purpose of this study was to determine whether resting myocardial deformation and rotation may be altered in diabetic patients with significant epicardial coronary artery disease (CAD) with normal left ventricular ejection fraction.

Design: A prospective observational study.

Setting: Diagnosis of epicardial CAD in patients with diabetes.

Shared medical appointments for patients with diabetes: glycemic reduction in high-risk patients.

Purpose: To assess the impact on glycemic control (A1c, %) in a primary care urban Veterans Affairs (VA) shared medical appointments (SMAs).

Data Sources: A retrospective pretest/posttest study included all patients who had attended ≥1 SMA from 4/06 to 12/10. A1cs 810 days pre- and postinitial SMA were obtained from 90-day time periods.

Delineating melanoma using multimodal polarized light imaging.

Background And Significance: Melanoma accounts for 3% of all skin cancers but causes 83% of skin cancer deaths. The first step in treatment of melanoma is the removal of the lesions, usually by surgical excision. Currently most lesions are removed without intraoperative margin control.

Gaze-evoked nystagmus: a case report and literature review.

Background: A sustained gaze-evoked nystagmus (GEN) is an important ocular finding that may indicate serious neurologic pathology. It is also a finding that can be missed easily during routine extraocular muscle (EOM) testing. This report presents a case that should familiarize the reader with GEN and presents a novel approach to testing EOM function.

Monoclonal antibodies in the treatment of cancer, Part 2.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells.

Monoclonal antibodies in the treatment of cancer, Part 1.

Monoclonal antibodies used in the treatment of cancer are discussed. Monoclonal antibodies are a new class of agents targeted at specific receptors on cancer cells. In addition to having direct cellular effects, antibodies can carry substances, such as radioactive isotopes, toxins, and antineoplastic agents, to the targeted cells.

Tamoxifen for prevention of breast cancer.

Objective: To review data on the use of tamoxifen for primary prevention of breast cancer.

Data Sources: A literature search was performed through MEDLINE (1992-May 2002) using the key words tamoxifen, breast cancer, and prevention.

Data Synthesis: Breast cancer is the most common malignancy detected in American women.

A psychometric evaluation of the BDI-II in treatment-seeking substance abusers.

The Beck Depression Inventory-II (BDI-II) was administered to 416 consecutive male admissions to a 28-day residential chemical dependence treatment program as part of a routine intake procedure. Psychometric analyses revealed that the BDI-II scores were internally consistent in this treatment-seeking population based on coefficient alpha. The mean BDI-II score for patients in this study was higher than that noted for other clinical samples in previous studies.

Phosphatidylinositol 3-kinase-dependent stabilization of alpha1(I) collagen mRNA in human lung fibroblasts.

We investigated the role of phosphatidylinositol 3-kinase (PI3K) in the expression of alpha1(I) collagen mRNA. We report that the basal level of alpha1(I) collagen mRNA was reduced when PI3K activity was inhibited by either LY-294002 or wortmannin. These PI3K inhibitors also blocked increases of alpha1(I) collagen mRNA levels after the addition of transforming growth factor-beta.

Regulation of angiotensin II-stimulated osteopontin expression in cardiac microvascular endothelial cells: role of p42/44 mitogen-activated protein kinase and reactive oxygen species.

Using spontaneously hypertensive and aortic banded rats, we have shown that expression of myocardial osteopontin, an extracellular matrix protein, coincides with the development of heart failure and is inhibited by captopril, suggesting a role for angiotensin II (ANG II). This study tested whether ANG II induces osteopontin expression in adult rat ventricular myocytes and cardiac microvascular endothelial cells (CMEC), and if so, whether induction is mediated via activation of mitogen-activated protein kinases (p42/44 MAPK) and involves reactive oxygen species (ROS). ANG II (1 microM, 16 h) increased osteopontin expression (fold increase 3.

Exaggerated left ventricular dilation and reduced collagen deposition after myocardial infarction in mice lacking osteopontin.

Osteopontin (OPN), an extracellular matrix protein, is expressed in the myocardium with hypertrophy and failure. We tested the hypothesis that OPN plays a role in left ventricular (LV) remodeling after myocardial infarction (MI). Accordingly, OPN expression and LV structural and functional remodeling were determined in wild-type (WT) and OPN knockout (KO) mice 4 weeks after MI.

Primary retroperitoneal seminoma with utrasonically abnormal testes.

Primary retroperitoneal seminomas account for approximately 2% of all seminomas. Differentiating the primary retroperitoneal tumor from a metastatic tumor with an occult testicular primary remains difficult despite the availability of ultrasonic examination. We present a case of primary retroperitoneal seminoma with ultrasonically demonstrated abnormalities in both testes.

Chronic ischemia alters prostate structure and reactivity in rabbits.

Purpose: Autopsy studies performed in men older than 80 years old have demonstrated that 90% have histological evidence of benign prostatic hyperplasia. Despite this fact pressure flow studies in men of this age who are referred for the evaluation of lower urinary tract symptoms have shown that only 40% have evidence of bladder outlet obstruction. To our knowledge the specific features of benign prostatic hyperplasia responsible for bladder outlet obstruction are not known.

Inhibition of protein phosphatase 1 induces apoptosis in neonatal rat cardiac myocytes: role of adrenergic receptor stimulation.

The mechanisms that regulate cardiac myocyte apoptosis are not well understood. To study the role of protein phosphatase 1 (PP1) and 2A (PP2A) in apoptosis, we exposed cultured neonatal rat cardiac myocytes to the phosphatase inhibitor okadaic acid (OA). Exposure (18 h) to 100 nM OA (a concentration which inhibits both PP1 and PP2A) decreased the number of adherent cells, caused genomic DNA fragmentation, and increased the percentage of apoptotic cells.

Hypoxia inhibits amino acid uptake in human lung fibroblasts.

Hypoxia and amino acid deprivation downregulate expression of extracellular matrix genes in lung fibroblasts. We examined the effect of hypoxia on amino acid uptake and protein formation in human lung fibroblasts. Low O(2) tension (0% O(2)) suppressed incorporation of [(3)H]proline into type I collagen without affecting [(35)S]methionine labeling of other proteins.

Role of gut-enriched Krüppel-like factor in colonic cell growth and differentiation.

Cancer cells differ from normal cells in many aspects, including hyperproliferation and loss of differentiation. Recent research has focused on the role of transcription factors in regulating abnormal cell growth. Gut-enriched Krüppel-like factor (GKLF) is a newly identified eukaryotic zinc finger protein expressed extensively in the gastrointestinal tract.