Administration of low doses of MK-801 during ethanol withdrawal in the developing rat pup attenuates alcohol's teratogenic effects

BACKGROUND: Alcohol exposure during development can produce severe and long-lasting central nervous system damage and consequent behavioral alterations. Recent evidence suggests that NMDA receptor-mediated excitotoxicity during periods of withdrawal may contribute to this damage. We have demonstrated that blocking the NMDA receptor with MK-801 during alcohol withdrawal can attenuate ethanol's adverse effects on behavioral development in the rat. This study examined the dose dependency of MK-801's ability to mitigate ethanol's teratogenic effects. METHODS: Neonatal rat pups were exposed to 6.0 g/kg of ethanol in a binge-like manner on postnatal day (PD) 6, a period of brain development equivalent to a portion of the human third trimester. Alcohol administration was accomplished with an artificial rearing procedure. Twenty-one hours after ethanol treatment, pups were injected intraperitoneally with one of four doses of MK-801 (0.05, 0.1, 0.5, or 1.0 mg/kg) or saline vehicle. An artificially reared control and a normally reared control group were included. On PD 18-19, activity level was monitored, and on PD 40-42, serial spatial discrimination reversal learning was assessed. RESULTS: Alcohol exposure on PD 6 produced significant increases in activity level and deficits in reversal learning. These alcohol-induced behavioral alterations were significantly attenuated in subjects treated with one of the three lower doses (0.05-0.5 mg/kg) of MK-801 during withdrawal. The performance of ethanol-exposed subjects treated with the high dose of MK-801 (1.0 mg/kg) did not differ from that of the Ethanol Only group. CONCLUSIONS: These data suggest that alterations in NMDA receptor activation during alcohol withdrawal contribute to the neuropathology and consequent behavioral alterations associated with developmental alcohol exposure. These data have important implications for pregnant women and newborns undergoing ethanol withdrawal.     

Hypertension in a Brazilian Urban Slum Population

Low- and middle-income countries account for the majority of hypertension disease burden. However, little is known about the distribution of this illness within subpopulations of these countries, particularly among those who live in urban informal settlements. A cross-sectional hypertension survey was conducted in 2003 among 5649 adult residents of a slum settlement in the city of Salvador, Brazil. Hypertension was defined as either an elevated arterial systolic (≥140 mmHg) or diastolic (≥90 mmHg) blood pressure. Sex-specific multivariable models of systolic blood pressure were constructed to identify factors associated with elevated blood pressure. The prevalence of hypertension in the population 18 years and older was 21 % (1162/5649). Men had 1.2 times the risk of hypertension compared with women (95 % confidence intervals (CI), 1.05, 1.36). Increasing age and lack of any schooling, particularly for women, were also significantly associated with elevated blood pressure (p < 0.05). There was also a direct association between men who were black and an elevated blood pressure. Among those who were hypertensive, 65.5 % were aware of their condition, and only 36.3 % of those aware were actively using anti-hypertensive medications. Men were less likely to be aware of their diagnosis or to use medications (p < 0.01 for both) than women. The prevalence of hypertension in this slum community was lower than reported frequencies in the non-slum population of Brazil and Salvador, yet both disease awareness and treatment frequency were low. Further research on hypertension and other chronic non-communicable diseases in slum populations is urgently needed to guide prevention and treatment efforts in this growing population.     

Tuberculosis DALY-Gap: Spatial and Quantitative Comparison of Disease Burden Across Urban Slum and Non-slum Census Tracts

To quantitatively assess disease burden due to tuberculosis between populations residing in and outside of urban informal settlements in Rio de Janeiro, Brazil, we compared disability-adjusted life years (DALYs), or “DALY-gap.” Using the 2010 Brazilian census definition of informal settlements as aglomerados subnormais (AGSN), we allocated tuberculosis (TB) DALYs to AGSN vs non-AGSN census tracts based on geocoded addresses of TB cases reported to the Brazilian Information System for Notifiable Diseases in 2005 and 2010. DALYs were calculated based on the 2010 Global Burden of Disease methodology. DALY-gap was calculated as the difference between age-adjusted DALYs/100,000 population between AGSN and non-AGSN. Total TB DALY in Rio in 2010 was 16,731 (266 DALYs/100,000). DALYs were higher in AGSN census tracts (306 vs 236 DALYs/100,000), yielding a DALY-gap of 70 DALYs/100,000. Attributable DALY fraction for living in an AGSN was 25.4 %. DALY-gap was highest for males 40–59 years of age (501 DALYs/100,000) and in census tracts with <60 % electricity (12,327 DALYs/100,000). DALY-gap comparison revealed spatial and quantitative differences in TB burden between slum vs non-slum census tracts that were not apparent using traditional measures of incidence and mortality. This metric could be applied to compare TB burden or burden for other diseases in mega-cities with large informal settlements for more targeted resource allocation and evaluation of intervention programs.     

The effect of hyperthyroidism and hypothyroidism on alpha 1- and alpha 2-adrenergic responsiveness in rat aortic smooth muscle

We report the role of thyroid hormones on in vitro responsiveness of rat aortic smooth muscle to alpha-adrenergic stimulation. Four groups of rats: hypothyroid, hyperthyroid, thyroxine (0.1 mg/kg) treated hypothyroid and controls were employed. Response of alpha 1- and alpha 2-adrenoceptors was evoked with 6 incremental doses (10(-9) to 10(-4) M) of preferential alpha 1-agonist, phenylephrine and alpha 2-agonist, clonidine respectively. alpha 1-Adrenoceptors were also evoked by phenylephrine after blockade of alpha 2-adrenoceptors with 10(-7) M yohimbine. Similarly, alpha 2-adrenoceptors were stimulated with clonidine after blocking alpha 1-adrenoceptors with selective antagonists prazosin (10(-7) M). Aortic responsiveness to alpha-agonist norepinephrine was compared between the aortae of hypothyroid and euthyroid rats after blockade of alpha 2-adrenoceptors with 10(-4) M corynanthine. We report that in hypothyroid aortae, alpha 1-adrenergic response was significantly decreased, the dose response curve shifted to the right and the maximal response was 30% less than the normal; alpha 2-adrenergic response was completely inhibited in hypothyroid state; also, IP injections of 0.1 mg/kg thyroxine twice in 48 h to thyroidectomized rats reversed the effects of hypothyroidism on both alpha 1- and alpha 2-adrenergic response. Hyperthyroidism did not alter alpha 1- and alpha 2-adrenergic response. These results signify the role of thyroid hormones in the regulation of alpha-adrenergic response in rat aortae.     

Differential antibody recognition of FC27-like Plasmodium falciparum merozoite surface protein MSP2 antigens which lack 12 amino acid repeats

Three alleles of the FC27-type allelic family of the MSP2 gene of the malaria parasite Plasmodium falciparum have been sequenced from parasites from the field (The Gambia and Tanzania). These alleles lack the 12 amino acid repeat units which are usual in this family of MSP2 alleles. We have investigated the recognition by sera from an endemic area (The Gambia) of three recombinant MSP2 proteins that have 5, 1 and no copies of this repeat region. Antibody recognition of these recombinant proteins varied according to the number of repeats present. High titre antibody levels were seen with most sera using the recombinant protein with 5 × 12-mer repeats, whereas only low responses were measured using proteins containing 1 or no 12-mer repeats. Several sera entirely failed to recognise the protein which lacked 12-mer repeats. The data suggest that variation in the number of tandem repeat sequences could allow the parasite to avoid high avidity antibody binding and this may allow escape from immune recognition.     

Clonally related penicillin-nonsusceptible Streptococcus pneumoniae serotype 14 from cases of meningitis in Salvador, Brazil.

Active hospital-based surveillance in the city of Salvador, Brazil, from December 1995 through October 1998, identified 221 patients with confirmed pneumococcal meningitis. Of these 221 patients, 29 (13%) had isolates with intermediate-level resistance to penicillin. Infection with these penicillin-nonsusceptible isolates was significantly associated with age of <2 years (P<.0019), previous antibiotic use (P<.0006), and coresistance to trimethoprim-sulfamethoxazole (P<.0000). Serotype 14 was the most prevalent serotype (55.2%) of penicillin-nonsusceptible isolates. Strain typing by repetitive element BOX polymerase chain reaction (PCR) analysis showed that penicillin-nonsusceptible serotype 14 isolates had closely related BOX PCR patterns, whereas penicillin-susceptible serotype 14 isolates each had distinct, unrelated patterns. Penicillin-nonsusceptible serotype 14 isolates from Salvador and other Brazilian cities had similar BOX PCR patterns. These observations indicate that in Brazil a large proportion of cases of penicillin-nonsusceptible pneumococcal meningitis appear to be caused by a closely related group of serotype 14 strains that may have disseminated to widely separate geographic areas.     

Receptor-like function of heparin in the binding and uptake of neutral lipids

Molecular mechanisms regulating the binding, amphipathic stabilization, and metabolism of the major neutral lipids (e.g., cholesteryl esters, triglycerides, and fatty acids) are well studied, but the details of their movement from a binding compartment to a metabolic compartment deserve further attention. Since all neutral lipids must cross hydrophilic segments of plasma membranes during such movement, we postulate that a critical receptor-like site exists on the plasma membrane to mediate a step between binding and metabolism and that membrane-associated heparin is a key part of this mediator. For example, intestinal brush border membranes containing heparin bind homogeneous human pancreatic 125I-labeled cholesterol esterase (100 kDa) and 125I-labeled triglyceride lipase (52 kDa). This interaction is enzyme concentration-dependent, specific, and saturable and is reversed upon addition of soluble heparin. Scatchard analysis demonstrates a single class of receptors with a Kd of 100 nM and a Bmax of approximately 50-60 pmol per mg of vesicle protein. In contrast, enzymes associated with the hydrolysis of hydrophilic compounds such as amylase, phospholipase A2, and deoxyribonuclease do not bind to intestinal membranes in this manner. Human pancreatic cholesterol esterase also binds specifically and saturably to cultured intestinal epithelial cells (CaCo-2), and soluble heparin significantly diminishes the cellular uptake of the resultant hydrophobic reaction products (cholesterol and free fatty acids). We conclude that a physiological role for intestinal heparin is that of a mediator to bind neutral lipolytic enzymes at the brush border and thus promote absorption of the subsequent hydrolyzed nutrients in the intestine. This mechanism may be a generalizable pathway for transport of neutral lipids into endothelial and other cells.     

Superoxide dismutase mimetics

In this review we describe the potential role(s) of superoxide in inflammatory disorders.     

Mycophenolate mofetil reduces tissue damage and inflammation in an experimental model of colitis in rats

BACKGROUND: Lymphocytes are widely believed to be responsible for persistent intestinal inflammation in inflammatory bowel diseases. Mycophenolate mofetil (MMF) is a potent immunosuppressant that inhibits lymphocyte proliferation and has been shown to be effective in preventing allograft rejection after organ transplantation. The purpose of this study was to assess the modulating effects of MMF on intestinal inflammation in an experimental model of colitis in rats. METHODS: Colitis was induced by rectal instillation of trinitrobenzenesulfonic acid (TNBS) in ethanol in male Sprague-Dawley rats. One group of rats (n = 10) was treated with MMF i.p. (25 mg/kg b.w.) daily for 1 week starting 24 h after induction of colitis. A second group of rats (n = 10) was treated with MMF at the same dose 2 days, I day and 1 h prior to induction of colitis. Control animals (n = 10) received vehicle only. After being killed, colonic tissue was macroscopically evaluated for necrosis and microscopically for ulcerations. Sections were stained and examined for the presence of granulocytes. RESULTS: Administration of MMF after induction of TNBS colitis reduced macroscopic injury by 62% compared to control animals (P = 0.01). Microscopic ulcerations were reduced by 64% compared to controls (P = 0.009). In addition, posttreatment significantly reduced the number of granulocytes. MMF pretreatment did not significantly prevent macroscopic or microscopic tissue damage, or change the number of granulocytes. CONCLUSION: Systemic administration of MMF significantly ameliorates tissue damage in a model of experimental colitis in rats suggesting that this compound may play an important role as an immunosuppressant in the therapy of inflammatory bowel diseases.