Treatment with atorvastatin ameliorates hepatic very-low-density lipoprotein overproduction in an animal model of insulin resistance, the fructose-fed Syrian golden hamster: evidence that reduced hypertriglyceridemia is accompanied by improved hepatic insulin sensitivity

A novel animal model of insulin resistance, the fructose-fed Syrian golden hamster has been previously documented to exhibit considerable hepatic very-low-density lipoprotein (VLDL) overproduction concomitant with the development of whole body insulin resistance. Here, we investigated whether hepatic lipoprotein overproduction can be ameliorated by treatment with a hydroxymethyl glutaryl conenzyme A (HMG-CoA) reductase inhibitor, atorvastatin, using a series of ex vivo experiments. Hamsters were fed a fructose-enriched diet for 14 days to induce a state of insulin resistance, and then continued on a fructose-enriched diet supplemented with or without 40 mg/kg atorvastatin per day for 14 days. Fructose feeding in the first 2 weeks caused a significant increase in plasma total cholesterol and triglyceride levels. There was a significant decline in plasma triglyceride levels following supplementation with the inhibitor (50% to 59%; P <.05). Experiments with primary hepatocytes revealed a decreased VLDL-apolipoprotein B (apoB) production (37.4% +/- 10.4%; P <.05) in hamsters treated with atorvastatin. Interestingly, atorvastatin treatment partially attenuated (by 23%) the elevated hepatic level of microsomal triglyceride transfer protein (MTP) induced by fructose feeding. There was molecular evidence of improved hepatic insulin sensitivity with atorvastatin treatment based on assessment of the phosphorylation status of the insulin receptor and the expression of protein tyrosine phosphatase-1B. The improvement in insulin signaling was not mediated by a change in hepatic triglyceride accumulation as no significant difference was observed in liver triglyceride levels. Taken together, these data suggest that statins can ameliorate the VLDL-apoB overproduction state observed in a fructose-fed, insulin-resistant hamster model, and may potentially contribute to an enhanced hepatic insulin sensitivity.     

Cecal fecaloma mimicking colonic neoplasm

Summary We present the case of a young man with chronic diarrhea associated with an apparent cecal neoplasm roentgenographically. The lesion was diagnosed as a fecaloma only after the curative right hemicolectomy specimen was examined.     

Expression analysis of mTOR-associated lncRNAs in multiple sclerosis

Metabolic Brain Disease - mTOR has been shown to be involved in the regulation of immune responses and differentiation of immune cells. This protein is a candidate molecule for unraveling the...     

Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer’s disease

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.     

Isfahan Healthy Heart Programme: a comprehensive integrated community-based programme for cardiovascular disease prevention and control. Design,methods and initial experience

The Isfahan Healthy Heart Programme (IHHP) is a five to six year comprehensive integrated community-based programme for cardiovascular diseases (CVD) prevention and control via reducing CVD risk factors and improvement of cardiovascular healthy behaviour in a target population. IHHP started late in 1999 and will be finished in 2005-2006. A primary survey was done to collect baseline data from interventional (Isfahan and Najaf-Abad) and reference (Arak) communities. In a two-stage sampling method, we randomly selected 5 to 10 percent of households from randomly selected clusters. Then individuals aged > or = 19 years were selected for the survey. This way, data from 12,600 individuals (6300 in interventional counties and 6300 in the reference county) was collected and stratified according to living area (urban vs. rural) and different age and sex groups. The samples underwent a 30-minute interview to complete validated questionnaires containing questions on demography, socioeconomic status, smoking behaviour, physical activity, nutritional habits and other behaviour regarding CVD. Blood pressure and body mass index (BMI) measurements were done and fasting blood samples were taken for two hours post load plasma glucose (2 hpp), serum (total, HDL and LDL) cholesterol and triglyceride levels. A twelve-lead electrocardiogram was recorded in all persons above 35 years of age. Community-wide surveillance of deaths, hospital discharges, myocardial infarction and stroke registry was carried out in the intervention and control areas. Four to five years of interventions based on different categories such as mass media, community partnerships, health system involvement and policy and legislation have started in the intervention area while Arak will be followed without intervention. Considering the results of the baseline surveys, (assessments needed, the objectives, existing resources and the possibility of national implementation) the interventions were planned. They were set based on specific target groups like school children, women, work-site, health personnel, high-risk persons, and community leaders were actively engaged as decision makers. A series of teams was arranged for planning and implementation of the intervention strategies. Monitoring will be done on small samples to assess the effect of different interventions in the intervention area. While four periodic surveys will be conducted on independent samples to assess health behaviours related to CVD risk factors in the intervention and reference areas, the original pre-intervention subjects aged more than 35 years will be followed in both areas to assess the individual effect of interventions and outcomes like sudden death, fatal and nonfatal MI and stroke. The whole baseline survey will be repeated on the original and an independent sample in both communities at the end of the study.     

Preparation and radiolabeling of a lyophilized (kit) formulation of DOTA-rituximab with 90Y and 111In for domestic radioimmunotherapy and radioscintigraphy of Non-Hodgkin’s Lymphoma

Background

On the basis of results of our previous investigations on ⁹⁰Y-DTPA-rituximab and in order to fulfil national demands to radioimmunoconjugates for radioscintigraphy and radioimmunotherapy of Non-Hodgkin’s Lymphoma (NHL), preparation and radiolabeling of a lyophilized formulation (kit) of DOTA-rituximab with ¹¹¹In and ⁹⁰Y was investigated.

Methods

¹¹¹In and ⁹⁰Y with high radiochemical and radionuclide purity were prepared by ¹¹²Cd (p,2n)¹¹¹In nuclear reaction and a locally developed ⁹⁰Sr/⁹⁰Y generator, respectively. DOTA-rituximab immunoconjugates were prepared by the reaction of solutions of p-SCN-Bz-DOTA and rituximab in carbonate buffer (pH = 9.5) and the number of DOTA per molecule of conjugates were determined by transchelation reaction between DOTA and arsenaso yttrium(III) complex. DOTA-rituximab immunoconjugates were labeled with ¹¹¹In and ⁹⁰Y and radioimmunoconjugates were checked for radiochemical purity by chromatography methods and for immunoreactivity by cell-binding assay using Raji cell line. The stability of radiolabeled conjugate with the approximate number of 7 DOTA molecules per one rituximab molecule which was prepared in moderate yield and showed moderate immunoreactivity, compared to two other prepared radioimmunoconjugates, was determined at different time intervals and against EDTA and human serum by chromatography methods and reducing SDS-polyacrylamide gel electrophoresis, respectively. The biodistribution of the selected radioimmunoconjugate in rats was determined by measurement of the radioactivity of different organs after sacrificing the animals by ether asphyxiation.

Results

The radioimmunoconjugate with approximate DOTA/rituximab molar ratio of 7 showed stability after 24 h at room temperature, after 96 h at 4°C, as the lyophilized formulation after six months storage and against EDTA and human serum. This radioimmunoconjugate had a biodistribution profile similar to that of ⁹⁰Y-ibritumomab, which is approved by FDA for radioimmunotherapy of NHL, and showed low brain and lung uptakes and low yttrium deposition into bone.

Conclusion

Findings of this study suggest that further investigations may result in a lyophilized (kit) formulation of DOTA-rituximab which could be easily radiolabeled with ⁹⁰Y and ¹¹¹In in order to be used for radioimmunotherapy and radioscintigraphy of B-cell lymphoma in Iran.     

Linear Friction Welding of an AZ91 Magnesium Alloy and the Effect of Ca Additions on the Weld Characteristics

Solid-state welding offers distinct advantages for joining reactive materials, such as magnesium (Mg) and its alloys. This study investigates the effect of linear friction welding (LFW) on the microstructure and mechanical properties of cast AZ91 (Mg–9Al–1Zn) and AZ91–2Ca alloys, which (to the best knowledge of the authors) has not been reported in the literature. Using the same set of LFW process parameters, similar alloy joints—namely, AZ91/AZ91 and AZ91–2Ca/AZ91–2Ca—were manufactured and found to exhibit integral bonding at the interface without defects, such as porosity, inclusions, and/or cracking. Microstructural examination of the AZ91/AZ91 joint revealed dissolution of the Al-rich second phase in the weld zone, while the Mn containing phases remained and were refined. In the AZ91–2Ca/AZ91–2Ca joint, the weld zone retained Ca- and Mn-rich phases, which were also refined due to the LFW process. In both joint types, extensive recrystallization occurred during LFW, as evidenced by the refinement of the grains from ~1000 µm in the base materials to roughly 2–6 µm in the weld zone. These microstructural changes in the AZ91/AZ91 and AZ91–2Ca/AZ91–2Ca joints increased the hardness in the weld zone by 32%. The use of digital image correlation for strain mapping along the sample gage length during tensile testing revealed that the local strains were about 50% lower in the weld zone relative to the AZ91 and AZ91–2Ca base materials. This points to the higher strength of the weld zone in the AZ91/AZ91 and AZ91–2Ca/AZ91–2Ca joints due to the fine grain size, second phase refinement, and strong basal texture. Final fracture during tensile loading of both joints occurred in the base materials.     

Novel Central Nervous System Drug Delivery Systems

For decades, biomedical and pharmaceutical researchers have worked to devise new and more effective therapeutics to treat diseases affecting the central nervous system. The blood–brain barrier effectively protects the brain, but poses a profound challenge to drug delivery across this barrier. Many traditional drugs cannot cross the blood–brain barrier in appreciable concentrations, with less than 1% of most drugs reaching the central nervous system, leading to a lack of available treatments for many central nervous system diseases, such as stroke, neurodegenerative disorders, and brain tumors. Due to the ineffective nature of most treatments for central nervous system disorders, the development of novel drug delivery systems is an area of great interest and active research. Multiple novel strategies show promise for effective central nervous system drug delivery, giving potential for more effective and safer therapies in the future. This review outlines several novel drug delivery techniques, including intranasal drug delivery, nanoparticles, drug modifications, convection‐enhanced infusion, and ultrasound‐mediated drug delivery. It also assesses possible clinical applications, limitations, and examples of current clinical and preclinical research for each of these drug delivery approaches. Improved central nervous system drug delivery is extremely important and will allow for improved treatment of central nervous system diseases, causing improved therapies for those who are affected by central nervous system diseases.