Upregulation of micro RNA-146a (miRNA-146a), a marker for inflammatory neurodegeneration, in sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Straussler-Scheinker (GSS) syndrome.

A mouse- and human-brain-abundant, nuclear factor (NF)-кB-regulated, micro RNA-146a (miRNA-146a) is an important modulator of the innate immune response and inflammatory signaling in specific immunological and brain cell types. Levels of miRNA-146a are induced in human brain cells challenged with at least five different species of single- or double-stranded DNA or RNA neurotrophic viruses, suggesting a broad role for miRNA-146a in the brain's innate immune response and antiviral immunity. Upregulated miRNA-146a is also observed in pro-inflammatory cytokine-, Aß42 peptide- and neurotoxic metal-induced, oxidatively stressed human neuronal-glial primary cell cocultures, in murine scrapie and in Alzheimer's disease (AD) brain. In AD, miRNA-146a levels are found to progressively increase with disease severity and co-localize to brain regions enriched in inflammatory neuropathology. This study provides evidence of upregulation of miRNA-146a in extremely rare (incidence 1-10 per 100 million) human prion-based neurodegenerative disorders, including sporadic Creutzfeldt-Jakob disease (sCJD) and Gerstmann-Straussler-Scheinker syndrome (GSS). The findings suggest that an upregulated miRNA-146a may be integral to innate immune or inflammatory brain cell responses in prion-mediated infections and to progressive and irreversible neurodegeneration of both the murine and human brain.

Hormone replacement therapy as a risk factor for non-small cell lung cancer: results of a case-control study.

PURPOSE: It was the aim of this study to assess the risk of lung cancer in postmenopausal women who received hormone replacement therapy (HRT). EXPERIMENTAL DESIGN: This case-control study involves women who received medical services at Roswell Park Cancer Institute (RPCI) in Buffalo, New York, between 1982 and 1998, and who agreed to complete an epidemiological questionnaire. Participants with missing smoking data were excluded. The case group consisted of 595 women with primary lung cancer. Controls included 1,195 women, randomly selected from a pool of 5,845 eligible individuals, who received medical services at RPCI for non-neoplastic conditions; they had come to RPCI with a suspicion of neoplastic disease, but were diagnosed with neither benign nor malignant conditions. Controls were frequency matched 2:1 to cases on 5-year age intervals and exposure to smoking (ever/never). Cases and controls were comparable for age (means 61.3 and 61.0 years) and ever smoking (90%). RESULTS: There were more former smokers among the cases (67 vs. 59% in controls); cases were less likely to be high school educated, were thinner, and were less likely to report HRT use compared with controls. Overall, hormone use was associated with a significant reduction in risk of lung cancer (adjusted odds ratio = 0.67; 95% confidence interval 0.53-0.85). Stratified analyses showed significant reductions in lung cancer risk in former smokers and women with normal to low body mass index. CONCLUSION: This study supports the hypotheses that there is a protective effect of HRT use on lung cancer risk in women.

Evaluation of Four Elastomeric Interocclusal Recording Materials.

BACKGROUND: The fabrication of dental prosthesis requires the transfer of interocclusal records from patient's mouth to semi-adjustable articulators using different kinds of recording media. Any inaccuracy in these interocclusal records leads to occlusal errors in the final prosthesis. This study was conducted to evaluate the dimensional changes occurring in the interocclusal recording material over a given period of time and the material's resistance to compression during the cast mounting on the articulator. METHODS: In this in vitro study, the linear dimensional change and compressive resistance of four commercially available elastomeric interocclusal recording media was tested. Three were addition silicones and the fourth was a polyether material. Cylindrical samples of 10mm diameter of each material were prepared in three different thicknesses of 2, 4 and 6mm. Ten samples each of thickness of 2, 4 and 6mm for all four materials were prepared (total of 120 samples). The linear dimensional changes of the samples were evaluated after 24 hours of fabrication. The compressive resistance was measured when each of these was subjected to a constant compressive load of 25 Newtons. RESULTS: The mean linear dimensional change in a horizontal plane was minimum for Kanibite Hard, an addition silicone. Ramitec showed the maximum linear dimensional change. The mean compression distance was least for Futar D Occlusion (an addition silicone) and maximum for Ramitec (a polyether). It was observed that the samples of thickness 2mm for all the materials underwent least compression. CONCLUSION: The compressive resistance of each elastomer was inversely proportional to the thickness of the sample. This implies that minimum thickness of the recording materials should be used for recording maxillomandibular relations without sacrificing the strength of the interocclusal record.

Microbial Sources of Amyloid and Relevance to Amyloidogenesis and Alzheimer's Disease (AD).

Since the inception of the human microbiome project (HMP) by the US National Institutes of Health (NIH) in 2007 there has been a keen resurgence in our recognition of the human microbiome and its contribution to development, immunity, neurophysiology, metabolic and nutritive support to central nervous system (CNS) health and disease. What is not generally appreciated is that (i) the ~1014 microbial cells that comprise the human microbiome outnumber human host cells by approximately one hundred-to-one; (ii) together the microbial genes of the microbiome outnumber human host genes by about one hundred-and-fifty to one; (iii) collectively these microbes constitute the largest 'diffuse organ system' in the human body, more metabolically active than the liver; strongly influencing host nutritive-, innate-immune, neuroinflammatory-, neuromodulatory- and neurotransmission-functions; and (iv) that these microbes actively secrete highly complex, immunogenic mixtures of lipopolysaccharide (LPS) and amyloid from their outer membranes into their immediate environment. While secreted LPS and amyloids are generally quite soluble as monomers over time they form into highly insoluble fibrous protein aggregates that are implicated in the progressive degenerative neuropathology of several common, age-related disorders of the human CNS including Alzheimer's disease (AD). This general commentary-perspective paper will highlight some recent findings on microbial-derived secreted LPS and amyloids and the potential contribution of these neurotoxic and proinflammatory microbial exudates to age-related inflammatory amyloidogenesis and neurodegeneration, with specific reference to AD wherever possible.

Progressive inflammatory pathology in the retina of aluminum-fed 5xFAD transgenic mice.

At least 57 murine transgenic models for Alzheimer's disease (Tg-AD) have been developed to overexpress the 42 amino acid amyloid-beta (Aß42) peptide in the central nervous system (CNS). These 'humanized murine Tg-AD models' have greatly expanded our understanding of the contribution of Aß42 peptide-mediated pro-inflammatory neuropathology to the AD process. A number of independent laboratories using different amyloid-overexpressing Tg-AD models have shown that supplementation of murine Tg-AD diets and/or drinking water with aluminum significantly enhances Aß42 peptide-mediated inflammatory pathology and AD-type cognitive change compared to animals receiving control diets. In humans AD-type pathology appears to originate in the limbic system and progressively spreads into primary processing and sensory regions such as the retina. In these studies, for the first time, we assess the propagation of Aß42 and inflammatory signals into the retina of 5xFAD Tg-AD amyloid-overexpressing mice whose diets were supplemented with aluminum. The two most interesting findings were (1) that similar to other Tg-AD models, there was a significantly accelerated development of Aß42 and inflammatory pathology in 5xFAD Tg-AD mice fed aluminum; and (2) in aluminum-supplemented animals, markers for inflammatory pathology appeared in both the brain and the retina as evidenced by an evolving presence of Aß42 peptides, and accompanied by inflammatory markers - cyclooxygenase-2 (COX-2) and C-reactive protein (CRP). The results indicate that in the 5xFAD Tg-AD model aluminum not only enhances an Aß42-mediated inflammatory degeneration of the brain but also appears to induce AD-type pathology in an anatomically-linked primary sensory area that involves vision.

A Tutorial on Target-Mediated Drug Disposition (TMDD) Models.

Target-mediated drug disposition (TMDD) is the phenomenon in which a drug binds with high affinity to its pharmacological target site (such as a receptor) to such an extent that this affects its pharmacokinetic characteristics.1 The aim of this Tutorial is to provide an introductory guide to the mathematical aspects of TMDD models for pharmaceutical researchers. Examples of Berkeley Madonna2 code for some models discussed in this Tutorial are provided in the Supplementary Materials.

Evidence for the presence of -adrenoceptors in the central thermoregulatory mechanism of rabbits.

1. The effects of intracerebroventricular administration of some alpha- and beta-adrenoceptor stimulants and antagonists on the body temperature of rabbits were investigated.2. Noradrenaline produced a dose dependent rise in body temperature. Other catecholamines were less active.3. The noradrenaline response was blocked by alpha-adrenoceptor blocking agents while beta-adrenoceptor antagonists had no effect.4. alpha-Methyl-noradrenaline and metaraminol had some hyperthermic effect, but significantly reduced the response of noradrenaline.5. The possible presence of alpha-adrenoceptors in the central thermoregulatory mechanisms is suggested.

Syntheses and biologic studies of steroidal methyl sulfides and sulfones.

Reactions of cholest-5-ene (I) and its 3 beta-chloro (II) and 3 beta-acetoxy (III) analogs with trimethylchlorosilane-dimethyl sulfoxide in dry acetonitrile furnish cholest-4-en-6 beta-yl methyl sulfide (IV) and its 3 beta-chloro (V) and 3 beta-acetoxy (VI) analogs. Oxidation of (IV) with m-chloroperbenzoic acid affords cholest-4-en-6 beta-yl methyl sulfone (VII) and 4 alpha, 5-epoxy-5 alpha-cholestan-6 beta-yl methyl sulfone (VIII). Under similar reaction conditions, V furnishes 3 beta-chlorocholest-4-en-6 beta-yl methyl sulfone (IX), while VI gives 3 beta-acetoxycholest-4-en-6 beta-yl methyl sulfone (X) and 3 beta-acetoxy-4 alpha, 5-epoxy-5 alpha-cholestan-6 beta-yl methyl sulfone (XI). The structures of these compounds were established on the basis of analytic and spectral data. Some of these compounds have been evaluated for their possible biologic activities.

Nutritional and pathological changes in male and female rats fed modifications of the AIN-76A diet.

Male and female weanling Sprague-Dawley rats were fed either an AIN-76A diet or a modification of the AIN-76A diet containing no added DL-methionine but with higher levels of vitamins, fluoride and magnesium than in the AIN-76A diet. Both diets were fed, to groups of ten rats of each sex, at 18% protein or a reduced protein level of 13% for 12 wk. Within each sex, all diets produced comparable weight gains in rats at the end of 12 wk, except that the reduced-protein modified AIN-76A diet was associated with a reduction in weight gain in male rats. Both diet and protein level had statistically significant effects on the relative weights of some organs, particularly the kidney. The AIN-76A and the reduced-protein AIN-76A diets significantly increased the relative kidney weights (% body weights) of female rats, when compared with the effects of both modified AIN-76A diets (18 and 13% protein). Male rats fed both of the diets containing 18% protein had higher relative kidney weights than did those consuming both 13% protein diets. Females fed the modified diet containing 13% protein had significantly lower liver weights than the other groups. In both sexes, the two diets containing 18% protein caused significantly higher plasma urea nitrogen concentrations than did the lower protein diets. Kidney calcium concentrations varied with the diet, with dietary protein level, and with the sex of the animal. All diets caused small mineral (calcific) concretions of minimal to mild severity in the lumina of scattered renal tubules in the cortex and/or medulla of male rats. All female rats fed the AIN-76A and the reduced-protein AIN-76A diet had large, moderate or severe mineral concretions in the tubules at the corticomedullary junction and this was associated with increased renal calcium levels. The higher concentration of renal calcium at the lower dietary protein level (13%) was associated with severe corticomedullary junction mineralization. The higher protein diets were associated with an increased incidence of hyaline droplets in the cytoplasm of kidney cortical tubules in male rats.

Synthesis and pharmacological evaluation of some 2-N-alkyl-and -aralkyl-3,4:6,7-dibenzomorphans.

2-N-Alkyl or 2-aralkyl-5,9-dimethyl-3,4:6,7-dibenzomorphans 3a-c were synthesized by condensing 1-alkyl or aralkyl-3,4-dimethylquinolinium iodides 1a-c with benzyl magnesium chloride followed by subsequent cyclization of 2-benzyl-1-alkyl or aralkyl-3,4-dimethylquinolines 2a-c. Their structures were established through elemental and spectral studies. The preliminary pharmacological screening of 3a-c and other 3,4:6,7-dibenzomorphans [16] on mice showed that these compounds have a depressant action on CNS.

p-Aminobenzene sulphonyl morpholine, compound 82/208 a new anticonvulsant agent.

p-Aminobenzene sulphonyl morpholine, compound 82/208, was evaluated for acute toxicity and anticonvulsant action in mice against tonic seizures induced by supramaximal electroshock and pentylene tetrazole and strychnine induced seizures and for its effect on blood pressure and respiration in cat. Diphenyl hydantoin (DPH) was used as reference standard. Compound 82/208 exhibited anticonvulsant activity against electroshock induced seizures and PTZ induced tonic seizures in mice. The compound had several distinct advantages over DPH in experimental evaluation in mice.

Adaptogenic activity of Indian Panax pseudoginseng.

The crude extract and saponins of Indian pseudoginseng and saponins of Korean ginseng have been studied using a battery of biological tests in rats and mice. Indian pseudoginseng saponins were found to exhibit better activity than the Korean ginseng saponins in several tests employed. The results indicate a need for in-depth study of Indian pseudoginseng as an adaptogenic agent, after cultivation of the plant under controlled conditions.

Peptidergic mechanisms in feeding behaviour.

Hyperphagia was induced in mice by p.o. administration of different types of CNS depressant drugs, like chlordiazepoxide 25 mg/kg diazepam 2.5 mg/kg, cyproheptadine 2 mg/kg and phenobarbitone 25 mg/kg. Such hyperphagia was abolished by pretreatment with naloxone 0.1 mg/kg sc. Naloxone per se at this dose produced no significant effect on the food intake. This is suggestive of the role of peptidergic mechanisms in the feeding behaviour in mice.

Systems Pharmacology of the NGF Signaling Through p75 and TrkA Receptors.

The nerve growth factor (NGF) pathway has been shown to play a key role in pain treatment. Recently, a systems pharmacology model has been proposed that can aid in the identification and validation of drug targets in the NGF pathway. However, this model did not include the role of the p75 receptor, which modulates the signaling of NGF through the tropomyosin receptor kinase A (TrkA). The precise mechanism of the interaction between these two receptors has not been completely elucidated, and we therefore adopted a systems pharmacology modeling approach to gain understanding of the effect of p75 on the dynamics of NGF signal transduction. Specifically, models were developed for the so-called heterodimer and for the ligand-passing hypotheses. We used the model to compare the effect of inhibition of NGF and TrkA and its implication for drug discovery and development for pain treatment.