ASIC3 in muscle mediates mechanical, but not heat, hyperalgesia associated with muscle inflammation

Peripheral initiators of muscle pain are virtually unknown, but likely key to development of chronic pain after muscle insult. The current study tested the hypothesis that ASIC3 in muscle is necessary for development of cutaneous mechanical, but not heat, hyperalgesia induced by muscle inflammation. Using mechanical and heat stimuli, we assessed behavioral responses in ASIC3-/- and ASIC3+/+ mice after induction of carrageenan muscle inflammation. ASIC3-/- mice did not develop cutaneous mechanical hyperalgesia after muscle inflammation when compared to ASIC3+/+ mice; heat hyperalgesia developed similarly between groups. We then tested if the phenotype could be rescued in ASIC3-/- mice by using a recombinant herpes virus vector to express ASIC3 in skin (where testing occurred) or muscle (where inflammation occurred). Infection of mouse DRG neurons with ASIC3-encoding virus resulted in functional expression of ASICs. Injection of ASIC3-encoding virus into muscle or skin of ASIC3-/- mice resulted in ASIC3 mRNA in DRG and protein expression in DRG and the peripheral injection site. Injection of ASIC3-encoding virus into muscle, but not skin, resulted in development of mechanical hyperalgesia similar to that observed in ASIC3+/+ mice. Thus, ASIC3 in primary afferent fibers innervating muscle is critical to development of hyperalgesia that results from muscle insult.     

Roles of Glycoproteins and Oligosaccharides Found in Human Vaginal Fluid in Bacterial Adherence

Adherence of type 1-piliated Escherichia coli to carbohydrate structures of vaginal mucosa plays a major role in the pathogenesis of ascending urinary tract infections in women. Colonization of the vaginal introitus is influenced by interactions between pathogens, vaginal fluid, and vaginal epithelium. In this study, the type and amount of carbohydrates and glycoproteins present in vaginal fluid were determined. Free and protein-bound oligosaccharides in vaginal fluid specimens were analyzed by fluorophore-assisted carbohydrate electrophoresis (FACE) and high-pressure liquid chromatography (HPLC). Two-dimensional electrophoretic separations of vaginal fluid glycoproteins were performed together with bacterial overlay assays. The results of FACE showed that the majority of the oligosaccharides are in the free state and the bound oligosaccharides are undetectable. HPLC analysis of free sugars revealed glucose as the major sugar (3.3 +/- 0.3 mM), and the concentrations of mannose and glucosamine were 0.065 +/- 0.04 and 0.02 +/- 0.001 mM, respectively. Radiolabeled E. coli bound three vaginal fluid glycoproteins with the following molecular masses and pIs: 82 kDa and pI 5.5, 55 kDa and pI 4.5, and 55 kDa and pI 6.5. The binding was inhibited by mannose and by deglycosylation of the proteins prior to the overlay assay. One of these putative receptors was identified to be the heavy chain of secretory IgA (S-IgA). These data suggest that the free mannose in the fluid is less than that required to affect E. coli-epithelial cell binding interactions and that S-IgA may bind E. coli in the vaginal introitus.     

Initiation of a pharmacovigilance programme at a tertiary care hospital in South India

Objective India is a country with the availability of a large number of pharmaceutical preparations as branded generics. At the time of this study there was no established pharmacovigilance system at the national level except a co‐ordinating centre at the national capital. The study site was a tertiary care teaching hospital with a bed capacity of 500 and with an average of 200 outpatient visits and 50 inpatient admissions per day. The hospital did not have any system of monitoring and documenting adverse drug reactions. The objective of the study was to introduce an adverse drug reaction (ADR) monitoring programme at a tertiary care teaching hospital and assess ADR‐related issues in both inpatient and outpatient departments. Method All departments willing to report ADRs were included in the study, which was carried out for one year. Physicians and nurses filled in the notification forms when they encountered suspected ADR cases. These cases were then assessed by a panel of four judges. According to Naranjo's algorithm, the ADRs were assessed and classified based on World Health Organization (WHO) classification. Key findings A total of 288 suspected cases were reported and 264 ADRs were confirmed by the panel. According to Naranjo's probability scale, 83 cases were categorized as ‘probable’, 181 cases were classified as ‘possible’, and none were classified as ‘unlikely’ or ‘definite’. The most common classes of drugs involved were antibiotics (25%), psychotropics (20%), analgesic and cardiovascular agents (14% each). Generalised itch and rash, tremors, urticarial drug reaction, oral ulcer, gastritis and akathesia and extrapyramidal symptoms were found to be the most common ADRs observed; 2.1% of the patients in the studied departments had ADRs. Conclusion The ADR reporting system was initiated at the hospital and was well received by the physicians. Appreciable participation of physicians was noted during the study in reporting ADRs. The study also gave an insight into the awareness of physicians about ADR‐related issues. The number of ADRs reported was reasonably comparable with the findings of other authors from India.     

Synthesis and alpha 1-adrenoceptor antagonistic activity of some 4-amino-5,7-dimethyl-2-(substituted) aminopyrido (2,3-d) pyrimidines

A series of new 4-amino-5,7-dimethyl-2- (substituted)aminopyrido(2,3-d)pyrimidines (5) have been synthesized and tested for selective alpha 1-adrenoreceptor antagonistic activity. Some of the compounds were found to antagonize alpha 1-adrenoreceptor in a competitive and reversible manner. When screened on rat anococcygeus muscle some of the compounds exhibited significant alpha 1-adrenoreceptor antagonistic activity (pA2 values in the range of 5.2-7.8). The most potent compound (5j) was evaluated by an in vivo method and was found to reduce the systolic and diastolic blood pressure of spontaneously hypertensive rats. The percentage reduction in blood pressure by test compound 5j was found to be higher than that of the standard drug prazosin (CAS 19216-56-9) at the same dose level (1 mg/kg p.o.). Chemically, prazosin is a 4-aminoquinazolin derivative. Pyridopyrimidine is a known bioisostere of quinazoline. The study revealed that isosteric replacement of the benzene ring of prazosin by a pyridine ring increases the potency.     

Disparities in use of lipid-lowering medications among people with type 2 diabetes mellitus

BACKGROUND: People with diabetes are at high risk for cardiovascular events regardless of known heart disease. Physicians may underrecognize the excess cardiovascular risk conferred by diabetes alone, without a recent cardiovascular event. Other disparities in the receipt of lipid-lowering medications (LLMs) may exist. METHODS: We studied veterans with diabetes in fiscal years 1998 and 1999 cross-sectionally. We used administrative data (demographic information, International Classification of Diseases, Ninth Revision [ICD-9] codes, utilization information, medications, and laboratory tests) to evaluate associations between use of LLMs and age, ethnicity, sex, marital status, Charlson Index, heart disease ICD-9 codes, oral agents and insulin, hospitalization status, and low-density lipoprotein cholesterol levels. We constructed separate logistic regression models to evaluate associations between low-density lipoprotein cholesterol and similar predictor variables. RESULTS: Odds ratios were similar in both years. For fiscal year 1999, patients without recent ICD-9 codes in their administrative data indicating heart disease were 0.35 times less likely to be given LLMs than those with such codes. Individuals older than 75 years were 0.65 times less likely to be given LLMs than those younger than 65 years. African Americans were 0.72 times less likely than whites to be given LLMs. In fiscal years 1999 and 1998, 27% and 36% of individuals given LLMs had low-density lipoprotein cholesterol levels higher than 130 mg/dL (3.37 mmol/L). CONCLUSIONS: Veterans with diabetes but no recently coded heart disease, older individuals, and African Americans could benefit from programs targeted to introduce LLMs. Up to one third of individuals given LLMs remained above the target level of 130 mg/dL for low-density lipoprotein cholesterol.     

Absent pulmonary valve syndrome with aortic regurgitation in a 50-year-old man

A 50-year-old man was diagnosed as having absent pulmonary valve syndrome with aneurysmal dilatation of the pulmonary arteries. He also had a large subaortic ventricular septal defect and severe aortic regurgitation. He underwent successful intracardiac repair and aortic valve replacement. This case is presented in view of its rarity and controversies in the surgical management.     

Crime and Punishment (Scotland) Act 1997: a survey of sentencers' views concerning the Scottish 'hybrid order'

The Crime and Punishment (Scotland) Act 1997 introduced the hospital direction (HD), often termed the 'hybrid order' because it allows courts to simultaneously send a mentally disordered offender to hospital and impose a prison sentence, to be completed after hospital discharge. It is the first measure that explicitly allows the imposition of a prison sentence for an offender meeting criteria for detention under the Mental Health (Scotland) Act 1984. A previous survey showed that psychiatrists in Scotland favoured the principle of a hybrid order (Darjee et al., 2000). In this study all Scottish Sheriffs (n = 110) and High Court Judges (n = 26) were surveyed for their views on the HD. Of the 56 respondents 19 felt unable to participate largely due to lack of experience in sentencing mentally disordered offenders. Respondents felt the HD was a useful measure, but, in contrast to Scottish Office guidance, indicated that psychiatrists should recommend it directly if they considered that it was an appropriate disposal. Respondents viewed the HD as primarily an incapacitating measure and most respondents hoped that it would encourage psychiatrists to admit 'psychopaths'; although Scottish psychiatrists do not favour the hospitalisation of offenders with primary personality disorders. It is concluded that in its current form and with current guidance the HD is difficult to use, as there are no criteria to differentiate it from a hospital order (HO) and psychiatrists cannot recommend it. Further, recent legislation that makes public safety the primary concern when deciding on the discharge of restricted patients in Scotland, erodes the utility of the HD as an incapacitating measure. However following the Reports of the Millan and MacLean Committees in Scotland, the role of the HD may be strengthened and clarified.