Topiramate protects apoE-deficient mice from kidney damage without affecting plasma lipids.

Topiramate is an anticonvulsant drug also prescribed for migraine prophylaxis that acts through several mechanisms of action. Several studies indicate that topiramate induces weight loss and a moderate reduction of plasma lipids and glucose. Based on these favourable metabolic effects, aim of this study was to evaluate if topiramate could modulate atherosclerosis development and protect target organs of dysmetabolic conditions. Thirty apoE-deficient mice were divided into three groups and fed for 12 weeks a high fat diet (Control) or the same diet containing topiramate at 0.125% and 0.250%. Body weight, water and food intake were monitored throughout the study. Plasma lipids and glucose levels were measured and a glucose tolerance test was performed. Atherosclerosis development was evaluated in the whole aorta and at the aortic sinus. Histological analysis of liver, kidney and adipose tissue was performed. Topiramate did not affect weight gain and food intake. Glucose tolerance and plasma lipids were not changed and, in turn, atherosclerosis development was not different among groups. Topiramate did not modify liver and adipose tissue histology. Conversely, in the kidneys, the treatment reduced the occurrence of glomerular lipidosis by decreasing foam cells accumulation and reducing the expression of inflammatory markers. Blood urea nitrogen levels were also reduced by treatment. Our results indicate that topiramate does not affect atherosclerosis development, but preserves kidney structure and function. The study suggests that topiramate could be investigated in drug repurposing studies for the treatment of glomerular lipidosis.

How does the quality of phospholipidosis data influence the predictivity of structural alerts?

The ability of drugs to induce phospholipidosis (PLD) is linked directly to their molecular substructures: hydrophobic, cyclic moieties with hydrophilic, peripheral amine groups. These structural properties can be captured and coded into SMILES arbitrary target specification (SMARTS) patterns. Such structural alerts, which are capable of identifying potential PLD inducers, should ideally be developed on a relatively large but reliable data set. We had previously developed a model based on SMARTS patterns consisting of 32 structural fragments using information from 450 chemicals. In the present study, additional PLD structural alerts have been developed based on a newer and larger data set combining two data sets published recently by the United States Food and Drug Administration (US FDA). To assess the predictive performance of the updated SMARTS model, two publicly available data sets were considered. These data sets were constructed using different criteria and hence represent different standards for overall quality. In the first data set high quality was assured as all negative chemicals were confirmed by the gold standard method for the detection of PLD-transmission electron microscopy (EM). The second data set was constructed from seven previously published data sets and then curated by removing compounds where conflicting results were found for PLD activity. Evaluation of the updated SMARTS model showed a strong, positive correlation between predictive performance of the alerts and the quality of the data set used for the assessment. The results of this study confirm the importance of using high quality data for modeling and evaluation, especially in the case of PLD, where species, tissue, and dose dependence of results are additional confounding factors.

[The lipidosis in the liver of the dairy cow: Part 2 Genetic predisposition and prophylaxis]. / Die Leberverfettung der Milchkuh: Teil 2.

Hepatic lipidosis in dairy cows is the result of a disturbed balance between the uptake of non-esterified fatty acids (NEFA), their metabolism in the hepatocytes, and the limited efflux of TG as very-low-density lipoprotein (VLDL). Lipidosis and the associated risk for ketosis represents a consequence of selecting dairy cows primarily for milk production without considering the basic physiological mechanisms of this trait. The overall risk for lipidosis and ketosis possesses a genetic background and the recently released new breeding value of the German Holstein Friesian cows now sets the path for correction of this risk and in that confirms the assumed genetic threat. Ectopic fat deposition in the liver is the result of various steps including lipolysis, uptake of fat by the liver cell, its metabolism, and finally release as very-low-density lipoprotein (VLDL). These reactions may be modulated directly or indirectly and hence, serve as basis for prophylactic measures. The pertaining methods are described in order to support an improved understanding of the pathogenesis of lipidosis and ketosis. They consist of feeding a glucogenic diet, restricted feeding during the close-up time as well as supplementation with choline, niacin, carnitine, or the reduction of milking frequency. Prophylactic measures for the prevention of ketosis are also included in this discussion.

The role of manganese in etiopathogenesis and prevention of selected diseases.

Manganese (Mn) is an essential trace element, necessary for development and growth of the organism. The adequate content of this element in the body determines proper metabolism of amino acids, cholesterol and carbohydrates. This mineral influences activity of several enzymes involved in metabolic and redox processes. Mn absorption and retention disturbances may participate in etiopathogenesis of some diseases and disorders. This article is a review of knowledge about the role of Mn in etiopathogenesis and prevention of selected diseases: brain disorders, diabetes, lipid disturbances and cancers.

Protective effects of sulforaphane on type 2 diabetes-induced cardiomyopathy via AMPK-mediated activation of lipid metabolic pathways and NRF2 function.

BACKGROUND: AMP-activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. It was reported that sulforaphane (SFN) prevented type 2 diabetes (T2D)-induced cardiomyopathy accompanied by the activation of AMPK; In this study, AMPK's pivotal role in SFN-mediated prevention against T2D-induced cardiomyopathy was tested using global deletion of AMPKα2 gene (AMPKα2-KO) mice. METHODS AND RESULTS: T2D was established by feeding 3-month high-fat diet (HFD) to induce insulin resistance, followed by an intraperitoneal injection of streptozotocin (STZ) to induce mild hyperglycemia in both AMPKα2-KO and wild-type (WT) mice. Then both T2D and control mice were subsequently treated with or without SFN for 3 months while continually feeding HFD or normal diet. Upon completion of the 3-month treatment, five mice from each group were sacrificed as a 3-month time-point (3 M). The rest continued normal diet or HFD until terminating study at the sixth month (6 M) of diabetes. Cardiac function was examined with echocardiography before sacrifice at both 3 M and 6 M. SFN prevented T2D-induced progression of cardiac dysfunction, remodeling (hypertrophy and fibrosis), inflammation, and oxidative damage in wild-type diabetic mice, but not in AMPKα2-KO mice. Mechanistically, SFN prevented T2D-induced cardiomyopathy not only by improving AMPK-mediated lipid metabolic pathways, but also enhancing NRF2 activation via AMPK/AKT/GSK3ß pathway. However, these improving effects of SFN were abolished in AMPKα2-KO diabetic mice. CONCLUSIONS: AMPK is indispensable for the SFN-induced prevention of cardiomyopathy in T2D, and the activation of NRF2 by SFN is mediated by AMPK/AKT/GSK3ß signaling pathways.

The management of lipohypertrophy in diabetes care.

Lipohypertrophy has been a recognized complication of insulin therapy for many years, yet research shows that its prevalence in insulin-injecting patients with diabetes remains high. The problem for the patient is that the injection of insulin into a site of lipohypertrophy, although painless, may lead to erratic absorption of the insulin, with the potential for poor glycaemic control and unpredictable hypoglycaemia. Despite the important implications of this for diabetes control in insulin-injecting patients, there is a dearth of information and completed research into the condition. This article raises awareness of lipohypertrophy by reviewing the available literature on the prevention, identification and management of the condition from a nursing perspective. Recommendations for medical and nursing practice in diabetes care to improve prevention and management of lipohypertrophy are made.

Hepatic lipidosis in a black-headed python (Aspidites melanocephalus).

The number of people keeping reptiles in captivity has markedly increased, and widespread inappropriate husbandry will result in an increasing incidence of the diagnosis of hepatic lipidosis(HL). It may become apparent that some species of snake have predisposition to develop HL. In the specific instance of the genus Aspidites, alterations to the usual husbandry that limit feeding and thereby body weight should markedly lessen the chance of the animal's developing HL. It is important for clinicians to develop a more aggressive approach to these cases and to build a bank of data with which to promote understanding of this common malady.

Simvastatin ameliorates renal lipidosis through the suppression of renal CXCL16 expression in mice with adriamycin-induced nephropathy.

AIMS: To investigate the roles of CXCL16 and ox-LDL in adriamycin (ADR)-induced nephropathy mice and to explore the mechanism of simvastatin on the renal protective effects of ADR nephropathy. METHODS: Fifteen male Balb/c mice were randomly divided into normal control (NC), ADR nephropathy and simvastatin-treated ADR nephropathy (ADR-SIM) groups. ADR nephropathy was induced by a single intravenous injection of ADR into the tail vein. All mice were sacrificed at the end of the 7th week, with the blood, 24-h urine and kidneys collected. The levels of ox-LDL and total cholesterol in the serum, the serum CXCL16, ox-LDL and NF-κB expression were detected. RESULTS: Compared with the NC group, the levels of serum total cholesterol and ox-LDL in the ADR and ADR-SIM groups were significantly higher, the level of serum albumin was significantly lower and the expression of CXCL16, ox-LDL and NF-κB in the renal tissue of ADR and ADR-SIM groups was significantly increased. Compared with the ADR group, the expressions of renal CXCL16, ox-LDL and NF-κB in the ADR-SIM group were significantly decreased. Levels of serum total cholesterol and ox-LDL were not significantly different between the two groups. CONCLUSIONS: Simvastatin exerts a protective effect on renal function and structure in mice with ADR nephropathy. The beneficial effects of simvastatin might be related to the decreasing expression of CXCL16 in glomerular podocytes followed by the decreasing endocytosis of ox-LDL in podocytes and inhibition of NF-κB pathway activation.

Inhibition by vitamin E of drug accumulation and of phospholipidosis induced by desipramine and other cationic amphiphilic drugs in human cultured cells.

1. Cationic amphiphilic drugs (CADs) are widely used in chronic pharmacotherapies in spite of frequently observed side effects connected with lysosomal phospholipid (PL) storage. 2. It has recently been shown that alpha-tocopherol (alpha-Toc) inhibits drug- and PL accumulation in cell cultures chronically exposed to the CAD, amiodarone. 3. The mechanisms of alpha-Toc action on drug kinetics and PL storage were studied in human cultured fibroblasts exposed to single and repetitive doses of desipramine and other CADs. 4. alpha-Toc did not influence the initial, pH-dependent rapid phase of drug uptake. It inhibited, in a dose-dependent manner, the slow and the cumulative phases of drug uptake and coincidently the accumulation of cellular PLs. 5. The inhibitory effects of alpha-Toc on CAD and PL accumulations depends on the ratio between CAD and alpha-Toc concentrations in the medium. This points to competition between alpha-Toc and CADs for PL complex formation. 6. Effectiveness of alpha-Toc on drug uptake varies among different CADs. It depends on its structural integrity but is independent of stereoisomerism. The inhibitory action is restricted to the piggyback slow drug uptake and therefore related to the proportion of membrane-mediated transport to permeation into lysosomes (rapid uptake). This proportion differs among CADs. 7. alpha-Toc prevents lysosomal membrane-PL storage, accelerates disintegration of PL-stores and normalizes drug-related increased membrane fluidity. This strongly suggests that alpha-Toc restores membrane recycling, impaired by CAD exposure. 8. It remains to be tested in vivo whether alpha-Toc reduces CAD side effects without interfering with drug effectiveness.

Genetic counseling by the primary care physician.

This paper has presented, in a rather concise and limited form, an outline of basic genetic principles which are necessary for the primary physician to provide good genetic counseling and good patient care. The assistance of a genetic center with prenatal diagnostic facilities allows consultation to proceed in a logical and constructive manner. The primary physician is in an excellent position to determine the pedigree, especially if he has the opportunity to examine the proband's immediate family and close relatives. The diagnosis may be easily made by the primary physician or it may require the combined efforts of the genetics clinic and the primary physician. In either case, the decision to terminate future pregnancies or to limit future offspring is made by the proband and his family, not the physician. The decision-making process may be affected by the primary physician who provides a sufficient amount of relevant information to his patients and allows them to reach a rational decision. Whether the decision appears rational to the physician or not, he must help his patients deal with it.

Tay-Sachs disease, wrongful life, and preventive malpractive.

PIP: 2 recent decisions in New York concerning responsibility of physicians in genetic counseling have confused the law in New York and the legal obligations of obstetricians. In Howard v. Lecher a majority of the ''Appellate Division of the Supreme Court denied a cause of action against an obstetrician alleged to be negligent in not properly advising a couple about the dangers they were running, as potential carriers, in having a child afflicted with Tay-Sachs disease.'' The couple sued for 2 types of damages: 1) their medical, hospital, nursing bills, and funeral expenses; and 2) their own emotional distress. The defendant appealed only on the 2nd count. 2 months later the Supreme Court imposed a legal duty upon obstetricians to perform genetic counseling in a case in which a woman gave birth to a 2nd child born with polycystic kidneys. Justice Hyman determined that New York should recognize an action for ''wronged life.'' Hyman's legal logic is difficult to follow, although the result may be considered a victory to some.^ieng

Advocacy and compliance factors in a voluntary selective screening program.

To evaluate factors responsible for compliance with a voluntary selective screening program, we surveyed 495 participants and 212 nonparticipants in a screening program for Tay-Sachs disease. Knowledge about the program and motivation are the most important factors in compliance. The primary incentive for participation was to avoid having abnormal children in future generations.

Tay-Sachs disease screening and prevention in South Africa.

Tay-Sachs disease is potentially preventable in Ashkenazi Jewish communities. About 1 out of 25 individuals is a carrier of the gene and can be accurately identified by means of a simple, inexpensive blood test. 'At risk' couples, i.e. couples of whom both partners are carriers, can be enabled, by means of prenatal diagnosis and selective abortion, to have only unaffected children. Mass screening programmes have been successfully carried out in the USA, Canada and Israel. A discussion of South African Jewish deomgraphy, attitudes to health, and priorities for public health projects, provide the background to a consideration of Tay-Sachs disease prevention in South Africa.

Approaches to the control and prevention of Tay-Sachs disease.

PIP: A prototype Tay-Sachs disease prevention program is presented and di scussed. The program strategy, design, and methodology are reviewed and results and analyses of epidemiologic data, testing results, and in-prog ram evaluations of the testing method are given, along with overall program results. Psychosocial, genetic, and socioeconomic consideration s in the counseling of screenees and relatives of carriers are discussed. In the 1st year of the program, 11 couples, none of whom had previously had a Tay-Sachs child, were identified to be at risk for Tay-Sachs disease in their offspring.^ieng