Ethyl pyruvate (EP) has demonstrated neuroprotective effects against acute brain injury through its anti-inflammatory action. The nuclear protein high-mobility group box 1 (HMGB1) can activate inflammatory pathways when released from dying cells. This study was designed to investigate the protective effects of EP against secondary brain injury in rats after Traumatic Brain Injury (TBI). Adult male rats were randomly divided into three groups: (1) Sham + vehicle group, (2) TBI + vehicle group, and (3) TBI + EP group (n = 30 per group). Right parietal cortical contusion was made by using a weight-dropping TBI method. In TBI + EP group, EP was administered intraperitoneally at a dosage of 75 mg/kg at 5 min, 1 and 6 h after TBI. Brain samples were harvested at 24 h after TBI. We found that EP treatment markedly inhibited the expressions of HMGB1 and TLR4, NF-κB DNA binding activity and inflammatory mediators, such as IL-1β, TNF-α and IL-6. Also, EP treatment significantly ameliorated beam walking performance, brain edema, and cortical apoptotic cell death. These results suggest that the protective effects of EP may be mediated by the reduction of HMGB1/TLR4/NF-κB-mediated inflammatory response in the injured rat brain.

OBJECTIVE

Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia.

METHODS

English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated.

RESULTS

Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression.

CONCLUSIONS

Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.

We noninvasively measured changes in average aortic stiffness in 79 cynomolgus monkeys being fed cholesterol progression, regression, and control diets by measuring pulse wave velocity (PWV) in 260 experiments during a 30-month period. Every 6 months, a group of monkeys was studied with invasive aortic PWV techniques and with ultrasonically determined pressure-strain elastic modulus (Ep) of the carotid artery, and then the group was killed so that morphometric evaluation of atherosclerosis severity could be made. After 6 months of a cholesterol progression diet, PWV decreased slightly from 6.2 +/- 0.1 to 5.7 +/- 0.1 m/sec, followed by an approximate linear increase to 8.8 +/- 1.2 m/sec after 30 months on the diet. The corresponding ratio of intimal (plaque) area to medial area (IA/MA) measured on perfusion-fixed cross-sections of the abdominal and thoracic aortas increased from 0.16 +/- 0.07 at 6 months to 1.23 +/- 0.22 at 30 months. Monkeys in the regression groups were fed the cholesterol progression diet for 18 months, followed by a chow diet for 6 or 12 months. In the first 6 months of the cholesterol regression diet, PWV continued to increase from 7.0 +/- 0.2 to 8.1 +/- 0.4 m/sec, and IA/MA was 1.24 +/- 0.18. However, after 12 months of the cholesterol regression diet, PWV decreased to 6.8 +/- 0.4 m/sec, and IA/MA was 0.90 +/- 0.18. The variability of the data demonstrates that PWV is not a simple function of atherosclerosis severity, and the best simple correlation was r = 0.69 (r2 = 0.48) between PWV and intimal area. However, multiple regression analysis of aortic PWV, systolic (SP) and diastolic (DP) blood pressures, and total plasma cholesterol concentration (TPC), all of which can be measured with minimally invasive techniques, improved the prediction of the IA/MA ratio through the following equation: IA/MA = 0.127 PWV-0.039 DP+0.023SP+0.0003TPC-0.292 (r = 0.81, r2 = 0.66). These data suggest that arterial stiffness in combination with minimally invasive parameters can be used to predict the severity of diffuse asymptomatic atherosclerosis in monkeys. However, more widespread application of these data to humans is uncertain because of biological variability and differences between animal models and human subjects.

In a large population-based case-control study in Germany, including 3,464 breast cancer cases aged 50-74 at diagnosis and 6,657 population based and frequency matched controls, we investigated the effects of menopausal hormone therapy (HT) by type, regimen, timing and progestagenic constituent on postmenopausal breast cancer risk overall and according to histological type. Data were collected by face-to-face interviews. Logistic and polytomous logistic regression analysis were used to estimate odds ratios (OR) and 95%-confidence intervals (95% CI). Risk of invasive breast cancer was significantly elevated in current users (OR, 1.73, 95% CI, 1.55-1.94) and heterogeneous by histological type (p < 0.01), being more than 2-fold higher for lobular and tubular than for ductal cancer. Risks for current users varied significantly by type and regimen of HT, with ORs per year of use of 1.05 (95% CI, 1.04-1.06) for continuous combined estrogen-progestagen, 1.03 (95% CI, 1.02-1.04) for cyclical EP and 1.01 (95% CI, 1.00-1.03) for estrogen-only therapy. No statistically significant increase in risk was observed after 5 years of cessation of HT use for any histological type. Analyses of progestagenic content by regimen revealed a significantly higher risk for continuously administered norethisterone- or levonorgestrel-derived progestagens than for continuously administered progesterone-derived progestagens (OR, 2.27, 95% CI, 1.98-2.62 vs. 1.47, 95% CI, 1.12-1.93, respectively, p = 0.003), which may be explained by dose rather than type of progestagen. These data suggest that the risks associated with menopausal HT differ by type and regimen of HT and histological type of breast cancer and may vary by progestagenic component, depending on the effective dose.

Iron is essential for the survival as well as the proliferation and maturation of developing erythroid precursors (EP) into hemoglobin-containing red blood cells. The transferrin-transferrin receptor pathway is the main route for erythroid iron uptake. Using a two-phase culture system, we have previously shown that placental ferritin as well as macrophages derived from peripheral blood monocytes could partially replace transferrin and support EP growth in a transferrin-free medium. We now demonstrate that in the absence of transferrin, ferritin synthesized and secreted by macrophages can serve as an iron source for EP. Macrophages trigger an increase in both the cytosolic and the mitochondrial labile iron pools, in heme and in hemoglobin synthesis, along with a decrease in surface transferrin receptors. Inhibiting macrophage exocytosis, binding extracellular ferritin with specific antibodies, inhibiting EP receptor-mediated endocytosis or acidification of EP lysosomes, all resulted in a decreased EP growth when co-cultured with macrophages under transferrin-free conditions. The results suggest that iron taken up by macrophages is incorporated mainly into their ferritin, which is subsequently secreted by exocytosis. Nearby EP are able to take up this ferritin probably through clathrin-dependent, receptor-mediated endocytosis into endosomes, which following acidification and proteolysis release the iron from the ferritin, making it available for regulatory and synthetic purposes. Thus, macrophages support EP development under transferrin-free conditions by delivering essential iron in the form of metabolizable ferritin.

N-Acetyl-L-cysteine (NAC) is used in medical treatment of patients with chronic bronchitis. The positive effects of NAC treatment have primarily been attributed to the mucus-dissolving properties of NAC, as well as its ability to decrease biofilm formation, which reduces bacterial infections. Our results suggest that NAC also may be an interesting candidate for use as an agent to reduce and prevent biofilm formation on stainless steel surfaces in environments typical of paper mill plants. Using 10 different bacterial strains isolated from a paper mill, we found that the mode of action of NAC is chemical, as well as biological, in the case of bacterial adhesion to stainless steel surfaces. The initial adhesion of bacteria is dependent on the wettability of the substratum. NAC was shown to bind to stainless steel, increasing the wettability of the surface. Moreover, NAC decreased bacterial adhesion and even detached bacteria that were adhering to stainless steel surfaces. Growth of various bacteria, as monocultures or in a multispecies community, was inhibited at different concentrations of NAC. We also found that there was no detectable degradation of extracellular polysaccharides (EPS) by NAC, indicating that NAC reduced the production of EPS, in most bacteria tested, even at concentrations at which growth was not affected. Altogether, the presence of NAC changes the texture of the biofilm formed and makes NAC an interesting candidate for use as a general inhibitor of formation of bacterial biofilms on stainless steel surfaces.

In bacterial biofilms, high molecular weight, secreted exopolysaccharides can serve as a scaffold to which additional carbohydrates, proteins, lipids, and nucleic acids adhere, forming the matrix of the developing biofilm. Here we report methods to extract and purify high molecular weight (>15 kDa) exopolysaccharides from biofilms of eight human pathogens, including species of Staphylcococcus, Klebsiella, Acinetobacter, Pseudomonas, and a toxigenic strain of Escherichia coli O157:H7. Glycosyl composition analysis indicated a high total mannose content across all strains with P. aeruginosa and A. baumannii exopolysaccharides comprised of 80-90% mannose, K. pneumoniae and S. epidermidis strains containing 40-50% mannose, and E. coli with ∼10% mannose. Galactose and glucose were also present in all eight strains, usually as the second and third most abundant carbohydrates. N-acetyl-glucosamine and galacturonic acid were found in 6 of 8 strains, while arabinose, fucose, rhamnose, and xylose were found in 5 of 8 strains. For linkage analysis, 33 distinct residue-linkage combinations were detected with the most abundant being mannose-linked moieties, in line with the composition analysis. The exopolysaccharides of two P. aeruginosa strains analyzed were consistent with the Psl carbohydrate, but not Pel or alginate. The S. epidermidis strain had a composition rich in mannose and glucose, which is consistent with the previously described slime associated antigen (SAA) and the extracellular slime substance (ESS), respectively, but no polysaccharide intracellular adhesion (PIA) was detected. The high molecular weight exopolysaccharides from E. coli, K. pneumoniae, and A. baumannii appear to be novel, based on composition and/or ratio analysis of carbohydrates.

Prolonged exposure to hyperoxia results in acute lung injury (ALI), accompanied by a significant elevation in the levels of proinflammatory cytokines and leukocyte infiltration in the lungs. However, the mechanisms underlying hyperoxia-induced proinflammatory ALI remain to be elucidated. In this study, we investigated the role of the proinflammatory cytokine high mobility group box protein 1 (HMGB1) in hyperoxic inflammatory lung injury, using an adult mouse model. The exposure of C57BL/6 mice to ≥99% O2 (hyperoxia) significantly increased the accumulation of HMGB1 in the bronchoalveolar lavage fluids (BALF) prior to the onset of severe inflammatory lung injury. In the airways of hyperoxic mice, HMGB1 was hyperacetylated and existed in various redox forms. Intratracheal administration of recombinant HMGB1 (rHMGB1) caused a significant increase in leukocyte infiltration into the lungs compared to animal treated with a non-specific peptide. Neutralizing anti-HMGB1 antibodies, administrated before hyperoxia significantly attenuated pulmonary edema and inflammatory responses, as indicated by decreased total protein content, wet/dry weight ratio, and numbers of leukocytes in the airways. This protection was also observed when HMGB1 inhibitors were administered after the onset of the hyperoxic exposure. The aliphatic antioxidant, ethyl pyruvate (EP), inhibited HMGB1 secretion from hyperoxic macrophages and attenuated hyperoxic lung injury. Overall, our data suggest that HMGB1 plays a critical role in mediating hyperoxic ALI through the recruitment of leukocytes into the lungs. If these results can be translated to humans, they suggest that HMGB1 inhibitors provide treatment regimens for oxidative inflammatory lung injury in patients receiving hyperoxia through mechanical ventilation.

OBJECTIVE

In various chronic pain conditions cortical reorganization seems to play a role in the manifestations. The aim of this study was to investigate cortical reorganization in patients with pain caused by chronic pancreatitis.

METHODS

Twelve healthy subjects and 10 patients with chronic pancreatitis were included. The esophagus, stomach, and duodenum were stimulated electrically at the pain threshold using a nasal endoscope. The electroencephalogram was recorded from 64 surface electrodes and event-related brain potentials (EPs) were obtained.

RESULTS

As compared with healthy subjects, the patient group showed decreased latencies of the early EP components (N1, P < .001; P1, P = .02), which is thought to reflect the exogenous brain pain processing specifically. Source analysis showed that the dipolar activities corresponding to the early EPs were located consistently in the bilateral insula, in the anterior cingulate gyrus, and in the bilateral secondary somatosensory area. The bilateral insular dipoles were localized more medial in the patient group than in the healthy subjects after stimulation of all 3 gut segments (P < .01). There also were changes in the cingulate cortex where the neuronal source was more posterior in patients than in controls to stimulation of the esophagus (P < .05).

CONCLUSIONS

The findings indicate that pain in chronic pancreatitis leads to changes in cortical projections of the nociceptive system. Such findings also have been described in somatic pain disorders, among them neuropathic pain. Taken together with the clinical data this suggests a neuropathic component in pancreatic pain, which may influence the approach to treatment.

Eleven exopolysaccharides (EPS) isolated from different human intestinal Bifidobacterium strains were tested in fecal slurry batch cultures and compared with glucose and the prebiotic inulin for their abilities to act as fermentable substrates for intestinal bacteria. During incubation, the increases in levels of short-chain fatty acids (SCFA) were considerably more pronounced in cultures with EPS, glucose, and inulin than in controls without carbohydrates added, indicating that the substrates assayed were fermented by intestinal bacteria. Shifts in molar proportions of SCFA during incubation with EPS and inulin caused a decrease in the acetic acid-to-propionic acid ratio, a possible indicator of the hypolipidemic effect of prebiotics, with the lowest values for this parameter being obtained for EPS from the species Bifidobacterium longum and from Bifidobacterium pseudocatenulatum strain C52. This behavior was contrary to that found with glucose, a carbohydrate not considered to be a prebiotic and for which a clear increase of this ratio was obtained during incubation. Quantitative real-time PCR showed that EPS exerted a moderate bifidogenic effect, which was comparable to that of inulin for some polymers but which was lower than that found for glucose. PCR-denaturing gradient gel electrophoresis of 16S rRNA gene fragments using universal primers was employed to analyze microbial groups other than bifidobacteria. Changes in banding patterns during incubation with EPS indicated microbial rearrangements of Bacteroides and Escherichia coli relatives. Moreover, the use of EPS from B. pseudocatenulatum in fecal cultures from some individuals accounted for the prevalence of Desulfovibrio and Faecalibacterium prausnitzii, whereas incubation with EPS from B. longum supported populations close to Anaerostipes, Prevotella, and/or Oscillospira. Thus, EPS synthesized by intestinal bifidobacteria could act as fermentable substrates for microorganisms in the human gut environment, modifying interactions among intestinal populations.

Prostaglandins exert a profound influence over the adhesive, migratory, and invasive behavior of cells during the development and progression of cancer. Cyclooxygenase-2 (COX-2) and microsomal prostaglandin E(2) synthase-1 (mPGES-1) are upregulated in inflammation and cancer. This results in the production of prostaglandin E(2) (PGE(2)), which binds to and activates G-protein-coupled prostaglandin E(1-4) receptors (EP(1-4)). Selectively targeting the COX-2/mPGES-1/PGE(2)/EP(1-4) axis of the prostaglandin pathway can reduce the adhesion, migration, invasion, and angiogenesis. Once stimulated by prostaglandins, cadherin adhesive connections between epithelial or endothelial cells are lost. This enables cells to invade through the underlying basement membrane and extracellular matrix (ECM). Interactions with the ECM are mediated by cell surface integrins by "outside-in signaling" through Src and focal adhesion kinase (FAK) and/or "inside-out signaling" through talins and kindlins. Combining the use of COX-2/mPGES-1/PGE(2)/EP(1-4) axis-targeted molecules with those targeting cell surface adhesion receptors or their downstream signaling molecules may enhance cancer therapy.

OBJECTIVE

Mouse models are useful for glaucoma research, but it is unclear whether intraocular pressure (IOP) regulation in mice operates through mechanisms similar to those in humans. Our goal was to determine whether pharmacologic compounds that affect conventional outflow facility in human eyes exert similar effects in C57BL/6 mice.

METHODS

A computerized perfusion system was used to measure conventional outflow facility in enucleated mouse eyes ex vivo. Paired eyes were perfused sequentially, either immediately after enucleation or after 3 hours storage at 4°C. Three groups of experiments examined sphingosine 1-phosphate (S1P), S1P with antagonists to S1P(1) and S1P(2) receptors, and the prostanoid EP(4) receptor agonist 3,7-dithia PGE(1). We also examined whether a 24-hour postmortem delay affected the response to 3,7-dithia prostaglandin E(1) (PGE(1)).

RESULTS

S1P decreased facility by 39%, and was blocked almost completely by an S1P(2), but not S1P(1), receptor antagonist. The S1P(2) receptor antagonist alone increased facility nearly 2-fold. 3,7-dithia PGE(1) increased facility by 106% within 3 hours postmortem. By 24 hours postmortem, the facility increase caused by 3,7-dithia PGE(1) was reduced 3-fold, yet remained statistically detectable.

CONCLUSIONS

C57BL/6 mice showed opposing effects of S1P(2) and EP(4) receptor activation on conventional outflow facility, as observed in human eyes. Pharmacologic effects on facility were detectable up to 24 hours postmortem in enucleated mouse eyes. Mice are suitable models to examine the pharmacology of S1P and EP(4) receptor stimulation on IOP regulation as occurs within the conventional outflow pathway of human eyes, and are promising for studying other aspects of aqueous outflow dynamics.

An intermediate trophoblast is a distinctive trophoblastic cell population from which four trophoblastic lesions are thought to arise: exaggerated placental site (EPS), placental site nodule (PSN), placental site trophoblastic tumor (PSTT), and epithelioid trophoblastic tumor (ETT). EPSs and PSTTs are related to the differentiation of the intermediate trophoblast in the implantation site (implantation site intermediate trophoblast), whereas PSNs and ETTs are related to the intermediate trophoblast of the chorion laeve (chorionic-type intermediate trophoblast). EPSs and PSNs are nonneoplastic lesions, whereas PSTTs and ETTs are neoplasms with a potential for local invasion and metastasis. Microscopically, intermediate trophoblastic lesions can be confused with a variety of trophoblastic and nontrophoblastic tumors, but an appreciation of the morphologic features and immunophenotype allows their diagnosis to be relatively straightforward in most instances. Correct diagnosis is important because each of these lesions may require different therapeutic approaches.

We describe the heterologous expression in Escherichia coli of the proenzyme precursor to EP-B2, a cysteine endoprotease from germinating barley seeds. High yields (50 mg/l) of recombinant proEP-B2 were obtained from E. coli inclusion bodies in shake flask cultures following purification and refolding. The zymogen was rapidly autoactivated to its mature form under acidic conditions at a rate independent of proEP-B2 concentration, suggesting a cis mechanism of autoactivation. Mature EP-B2 was stable and active over a wide pH range and efficiently hydrolyzed a recombinant wheat gluten protein, alpha2-gliadin, at sequences with known immunotoxicity in celiac sprue patients. The X-ray crystal structure of mature EP-B2 bound to leupeptin was solved to 2.2 A resolution and provided atomic insights into the observed subsite specificity of the endoprotease. Our findings suggest that orally administered proEP-B2 may be especially well suited for treatment of celiac sprue.

Recent experimental evidence suggests that arterial insufficiency precedes the structural and functional changes in corpora cavernosa (CC) leading to organic erectile dysfunction (ED). The present review gives an overview of the physiological factors involved in the regulation of penile vasculature. Sympathetic nerves maintain flaccidity and tonically released noradrenaline induces vasoconstriction of both arteries and veins through alpha(1)- and alpha(2)-postsynaptic receptors and downregulates its own release and that of nitric oxide (NO) through alpha(2)-presynaptic receptors. The sympathetic cotransmitter neuropeptide Y (NPY) modulates noradrenergic vasoconstriction in penile small arteries by both enhancing and depressing noradrenaline contractions through Y(1)- and Y(2)-postsynaptic and a NO-independent atypical endothelial receptor, respectively. Activation of alpha(1)-adrenoceptors involves both Ca(2+) influx through L-type and receptor-operated Ca(2+) channels (ROC) and Ca(2+) sensitization mechanisms mediated by protein kinase C (PKC), tyrosine kinases (TKs) and Rho kinase (RhoK). In addition, RhoK can regulate Ca(2+) entry in penile arteries upon receptor stimulation. Vasodilatation of penile arteries and large veins during erection is mediated by neurally released NO. The subsequent increased arterial inflow to the cavernosal sinoids and shear stress on the endothelium lining penile arteries activates endothelial NO production through Akt phosphorylation of endothelial NO synthase (eNOS). NO stimulates guanylate cyclase and increased cyclic guanin 3'-monophosphate (cGMP) levels in turn activate protein kinase G (PKG), which enhances K(+) efflux through Ca(2+)-activated (K(Ca)) and voltage-dependent Ca(2+) (K(v)) channels in penile arteries and veins, respectively. PKG-mediated decrease in Ca(2+) sensitivity and its regulation by RhoK remains to be clarified in penile vasculature. Phosphodiesterase type 5 (PDE5) inhibitors are potent vasodilators of penile resistance arteries and increase the content and effects of basally released endothelial NO. Endothelium-dependent relaxations of penile small arteries also include an endothelium-derived hyperpolarizing factor (EDHF)-type response, which is impaired in diabetes and hypertension-associated ED. Locally produced contractile and relaxant prostanoids regulate penile venous and arterial tone, respectively. The latter activates prostaglandin I (IP) and prostaglandin E (EP) receptors coupled to adenylate cyclase and to the increase of cyclic adenosine monophosphate (cAMP) levels, which in turn stimulates K(+) efflux through ATP-sensitive K(+) (K(ATP)) channels. There is a crosstalk between the cGMP and cAMP signaling pathways in penile small arteries. Relevant issues such as the mechanisms underlying the excitation-secretion coupling of the endothelial cells, as well as those involved in cell proliferation and vascular remodeling of the penile vasculature remain to be elucidated. In addition, only few studies have investigated the changes in structure and function of penile arteries in cardiovascular risk situations leading to ED.

OBJECTIVE

We tested the hypothesis that the power output attained at the end of a 3-min all-out cycling test would be equivalent to critical power.

METHODS

Ten habitually active subjects performed a ramp test, two 3-min all-out tests against a fixed resistance to establish the end-test power (EP) and the work done above the EP (WEP), and five constant-work rate tests to establish the critical power (CP) and the curvature constant parameter (W') using the work-time and 1/time models.

RESULTS

The power output in the 3-min trial declined to a steady level within 135 s. The EP was 287 +/- 55 W, which was not significantly different from, and highly correlated with, CP (287 +/- 56 W; P = 0.37, r = 0.99). The standard error for the estimation of CP using EP was approximately 6 W, and in 8 of 10 cases, EP agreed with CP to within 5 W. Similarly, the WEP derived from the 3-min test (15.0 +/- 4.7 kJ) was not significantly different from, and correlated with, W' (16.0 +/- 3.8 kJ; P = 0.35; r = 0.84).

CONCLUSIONS

During a 3-min all-out cycling test, power output declined to a stable value in approximately the last 45 s, and this power output was not significantly different from the independently measured critical power.

Hypertension is a leading attributable risk factor for mortality in South Asia. However, a systematic review on prevalence and risk factors for hypertension in the region of the South Asian Association for Regional Cooperation (SAARC) has not carried out before.The study was conducted according to the Meta-Analysis of Observational Studies in Epidemiology Guideline. A literature search was performed with a combination of medical subject headings terms, "hypertension" and "Epidemiology/EP". The search was supplemented by cross-references. Thirty-three publications that met the inclusion criteria were included in the synthesis and meta-analyses. Hypertension is defined when an individual had a systolic blood pressure (SBP) ≥140 mm Hg and/or diastolic blood pressure (DBP) ≥90 mm Hg, was taking antihypertensive drugs, or had previously been diagnosed as hypertensive by health care professionals. Prehypertension is defined as SBP 120-139 mm Hg and DBP 80-89 mm Hg.The overall prevalence of hypertension and prehypertension from the studies was found to be 27% and 29.6%, respectively. Hypertension varied between the studies, which ranged from 13.6% to 47.9% and was found to be higher in the studies conducted in urban areas than in rural areas. The prevalence of hypertension from the latest studies was: Bangladesh: 17.9%; Bhutan: 23.9%; India: 31.4%; Maldives: 31.5%; Nepal: 33.8%; Pakistan: 25%; and Sri Lanka: 20.9%. Eight out of 19 studies with information about prevalence of hypertension in both sexes showed that the prevalence was higher among women than men. Meta-analyses showed that sex (men: odds ratio [OR] 1.19; 95% confidence interval [CI]: 1.02, 1.37), obesity (OR 2.33; 95% CI: 1.87, 2.78), and central obesity (OR 2.16; 95% CI: 1.37, 2.95) were associated with hypertension.Our study found a variable prevalence of hypertension across SAARC countries, with a number of countries with blood pressure above the global average. We also noted that studies are not consistent in their data collection about hypertension and related modifiable risk factors.

The aim of this study was to examine attention in a large, representative, contemporary cohort of children born extremely preterm (EP) and/or extremely low birth weight (ELBW). Participants included 189 of 201 surviving children born EP (<28 weeks' gestation) or ELBW (<1,000 g) in 1997 in the state of Victoria, Australia. A comparison group of 173 of 199 children born full term and normal birth weight (FT/NBW) were randomly selected matching for birth hospital, expected due date, gender, mother's country of birth, and health insurance status. Participants were assessed at 8 years of age on subtests from the Test of Everyday Attention for Children (TEA-Ch) and the Wechsler Intelligence Scale for Children-4th Edition (WISC-IV). Measures of selective attention, sustained attention, attention encoding, and executive attention (inhibition, shifting attention, and divided attention) were administered. To assess behavioral elements of inattention, the primary caregiver completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Conners' ADHD/DSM-IV Scale (CADS-P). The EP/ELBW group performed more poorly across all cognitive and behavioral measures than the FT/NBW group, with the exception of inhibition. The EP/ELBW group also had significantly elevated rates of impairment in selective, sustained, shifting and divided attention, as well as attention deficit hyperactivity disorder (ADHD) symptoms. No significant gender or gradient effects (e.g., <26 weeks' gestation vs. ≥ 26 weeks' gestation) were identified. Neonatal medical factors were not strong predictors of attention, although necrotizing enterocolitis (NEC) and cystic periventricular leukomalacia (PVL) were independent predictors of selective attention. In conclusion, our comprehensive assessment of attention provides strong evidence that children born EP/ELBW are at increased risk for attentional impairments, and as such, this population should be monitored closely during early and middle childhood with a focus on attention functioning.

Biotrophic plant pathogens encounter a postinfection basal resistance layer controlled by the lipase-like protein enhanced disease susceptibility 1 (EDS1) and its sequence-related interaction partners, senescence-associated gene 101 (SAG101) and phytoalexin deficient 4 (PAD4). Maintainance of separate EDS1 family member clades through angiosperm evolution suggests distinct functional attributes. We report the Arabidopsis EDS1-SAG101 heterodimer crystal structure with juxtaposed N-terminal α/β hydrolase and C-terminal α-helical EP domains aligned via a large conserved interface. Mutational analysis of the EDS1-SAG101 heterodimer and a derived EDS1-PAD4 structural model shows that EDS1 signals within mutually exclusive heterocomplexes. Although there is evolutionary conservation of α/β hydrolase topology in all three proteins, a noncatalytic resistance mechanism is indicated. Instead, the respective N-terminal domains appear to facilitate binding of the essential EP domains to create novel interaction surfaces on the heterodimer. Transitions between distinct functional EDS1 heterodimers might explain the central importance and versatility of this regulatory node in plant immunity.

Advances in neonatal care have resulted in increased survival of children born extremely pre-term (EP). Nevertheless the incidence of bronchopulmonary dysplasia and long-term respiratory morbidity remains high. We investigated the nature of pathophysiological changes at 11 yrs of age to ascertain whether respiratory morbidity in EP children primarily reflects alterations in the lung periphery or more centralised airway function in this population. Spirometry, plethysmography, diffusing capacity, exhaled nitric oxide, multiple-breath washout, skin tests and methacholine challenge were used during laboratory-based assessments in a subgroup of the 1995 EPICure cohort and in controls. Results were obtained in 49 EP and 52 control children. Lung function abnormalities were found in 78% of EP children, with evidence of airway obstruction, ventilation inhomogeneity, gas trapping and airway hyperresponsiveness. Levels of atopy and exhaled nitric oxide were similar between the groups. Prior wheeze was associated with significant reductions in forced flows and volumes. By contrast, abnormalities of the lung periphery appear to be mediated primarily through EP birth per se. The prevalence of lung function abnormalities, which is largely obstructive in nature and likely to have long-term implications, remains high among 11-yr-old children born EP. Spirometry proved an effective means of detecting these persistent abnormalities.

We screened for genes that, when overexpressed in the proliferating cells of the eye imaginal disc, result in a reduction in the size of the adult eye. After crossing the collection of 2296 EP lines to the ey-GAL4 driver, we identified 46 lines, corresponding to insertions in 32 different loci, that elicited a small eye phenotype. These lines were classified further by testing for an effect in postmitotic cells using the sev-GAL4 driver, by testing for an effect in the wing using en-GAL4, and by testing for the ability of overexpression of cycE to rescue the small eye phenotype. EP lines identified in the screen encompass known regulators of eye development including hh and dpp, known genes that have not been studied previously with respect to eye development, as well as 19 novel ORFs. Lines with insertions near INCENP, elB, and CG11518 were characterized in more detail with respect to changes in growth, cell-cycle phasing, and doubling times that were elicited by overexpression. RNAi-induced phenotypes were also analyzed in SL2 cells. Thus overexpression screens can be combined with RNAi experiments to identify and characterize new regulators of growth and cell proliferation.

The physiological and morphological changes resulting from acute and chronic infusion of ouabain onto the intact round-window (RW) membrane were examined in the gerbil cochlea. Osmotic pumps fitted with cannulas allowed chronic (0.5-8 days) infusions of ouabain. Acute and short-term applications of ouabain (1-24 h) induced an increase in auditory-nerve compound action potential (CAP) thresholds at high frequencies with lower frequencies unaffected. The resulting threshold shifts were basically all (no response) or none (normal thresholds), with a sharp demarcation between high and low frequencies. Survival times of 2 days or greater after ouabain exposure resulted in complete auditory neuropathy with no CAP response present at any frequency. Distortion product otoacoustic emissions (DPOAEs) and the endocochlear potential (EP) were largely unaffected by the ouabain indicating normal function of the outer hair cells (OHC) and stria vascularis. One to 3 days after short-term applications, apoptosis was evident among the spiral ganglion neurons assessed both morphologically and with TdT-mediated dUTP-biotin nick end labeling (TUNEL). With 4-8 day survival times, most spiral ganglion cells were absent; however, a few cell bodies remained intact in many ganglia profiles. These surviving neurons had many of the characteristics of type II afferents. Our working hypothesis is that the ouabain induces a spreading depression among the type I ganglion cells by blocking the Na,K-ATPase pump. Because of the constant spike activity of these cells, the ouabain rapidly alters potassium concentrations within ([K+]i) and external to ([K+]o) the ganglion cells, thereby initiating an apoptotic cascade.

The arachidonic acid (AA) cascade produces eicosanoids, such as prostaglandins (PGs), that regulate physiological and pathological functions. Although various nonsteroidal anti-inflammatory drugs have been developed, blocking upstream components (cyclooxygenase-1 and -2) of the AA cascade leads to severe side effects, including gastrointestinal ulcers and cardiovascular events, respectively, due to the complexity of the AA cascade. Here, using an AA cascade-targeted lipidomics approach, we report that microsomal PGE synthase 1 (mPGES-1) plays a key role in experimental autoimmune encephalomyelitis (EAE). Eicosanoids (mainly PGD(2)) are produced constitutively in the spinal cord of naive mice. However, in EAE lesions, the PGE(2) pathway is favored and the PGD(2), PGI(2), and 5-lipoxygenase pathways are attenuated. Furthermore, mPGES-1(-/-) mice showed less severe symptoms of EAE and lower production of IL-17 and IFN-gamma than mPGES-1(+/+) mice. Expression of PGE(2) receptors (EP1, EP2, and EP4) was elevated in EAE lesions and correlated with clinical symptoms. Immunohistochemistry on central nervous systems of EAE mice and multiple sclerosis (MS) patients revealed overt expression of mPGES-1 protein in microglia/macrophages. Thus, the mPGES-1-PGE(2)-EPs axis of the AA cascade may exacerbate EAE pathology. Our findings have important implications for the design of therapies for MS.

OBJECTIVE

Motor and cognitive function were compared in patients with Lewy body dementia, Parkinson's disease, or Alzheimer's disease, to identify features that may be clinically useful in differentiating Lewy body dementia from Alzheimer's disease and Parkinson's disease.

METHODS

A range of neuropsychological function and extrapyrimidal signs (EPS) was assessed in 16 patients with Lewy body dementia, 15 with Parkinson's disease, 25 with Alzheimer's disease, and 22 control subjects.

RESULTS

The severity of total motor disability scores increased in the following order: controls approximately = Alzheimer's disease (< Parkinson's disease < Lewy body dementia. Compared with patients with Parkinson's disease, patients with Lewy body dementia had greater scores for rigidity and deficits in the finger tapping test, but rest tremor and left/right asymmetry in EPS were more evident in Parkinson's disease. Patients with Lewy body dementia were also less likely to present with left/right asymmetry in EPS at the onset of their parkinsonism. "Sensitivity" to neuroleptic drugs was noted in 33% of patients with Lewy body dementia. Alzheimer's disease and Lewy body dementia groups had greater severity of dementia compared with the Parkinson's disease group and controls. Neuropsychological evaluation disclosed severe but similar degrees of impaired performances in tests of attention (digit span), frontal lobe function (verbal fluency, category, and Nelson card sort test) and motor sequencing in both Lewy body dementia and Alzheimer's disease groups, than Parkinson's disease and controls. In the clock face test, improved performance was noted in the "copy" compared to "draw" part of the test in controls, patients with Alzheimer's disease, and those with Parkinson's disease, but not in the patients with Lewy body dementia, who achieved equally poor scores in both parts of the test.

CONCLUSIONS

EPS in Lewy body dementia resemble those seen in idiopathic Parkinson's disease, although less rest tremor and left/right asymmetry but more severe rigidity favours a diagnosis of Lewy body dementia. The unique profile of patients with Lewy body dementia seen in the clock face test suggests that this simple and easy to administer test may be useful in the clinical setting to differentiate Lewy body dementia and Alzheimer's disease.