Surface energy changes and their relationship with the dispersibility of salmeterol xinafoate powders for inhalation after storage at high RH

This study investigated the relationship between surface energy of micronized lactose, coarse lactose and salmeterol xinafoate and dispersibility from a mixture after storage at 75% RH. Surface energies, dispersibility, morphology, and the presence of amorphous domains were determined by inverse gas chromatography, twin stage impinger, scanning electron microscope and dynamic vapour sorption, respectively. The fine particle fraction of mixture decreased significantly in 4 weeks (P < 0.05), reaching a static level in 3 months. Amorphous content was not detected in the micronized lactose, coarse lactose and salmeterol xinafoate. After conditioning stored samples at 75% RH for 2 h, dispersive surface energy of both micronized and coarse lactose significantly decreased (P < 0.05), while the polar surface energy of all significantly increased (P < 0.05) resulting in significant increase in total surface energy after storage. After conditioning stored samples at 0% RH for 2 h, no significant difference was observed in any surface energy parameter. This study concluded that the total surface energy increased during storage at high RH due to the adhered surface moisture. The mechanism of decreased dispersibility was related to increased capillary/solid bridging interactions and to possible increased interaction of contiguous particles due to increased polar surface energy.     

Risk for Infection with Highly Pathogenic Avian Influenza Virus (H5N1) in Backyard Chickens, Bangladesh

To evaluate risk factors for infection with highly pathogenic avian influenza A virus (H5N1) in backyard chickens in Bangladesh, we conducted a matched case–control study. We enrolled 25 case farms (cases March–November 2007) and 75 control farms (June–November 2007). We used a questionnaire to collect farm data, which were analyzed by matched-pair analysis and multivariate conditional logistic regression. Factors independently associated were offering slaughter remnants of purchased chickens to backyard chickens (odds ratio [OR] 13.29, 95% confidence interval [CI] 1.34–131.98, p = 0.027), having a nearby water body (OR 5.27, 95% CI 1.24–22.34, p = 0.024), and having contact with pigeons (OR 4.47, 95% CI 1.14–17.50, p = 0.032). Separating chickens and ducks at night was protective (OR 0.06, 95% CI 0.01–0.45, p = 0.006). Reducing these risks and taking protective measures might reduce the risk for influenza (H5N1) infection in backyard chickens.     

Inequalities in maternity care and newborn outcomes: one-year surveillance of births in vulnerable slum communities in Mumbai

Background  

Aggregate urban health statistics mask inequalities. We described maternity care in vulnerable slum communities in Mumbai, and examined differences in care and outcomes between more and less deprived groups.     

A Forward Chemical Screen Using Zebrafish Embryos with Novel 2‐Substituted 2H‐Chromene Derivatives

We synthesized 2‐substituted 2H‐chromene derivatives from salicylaldehyde using potassium vinylic borates in the presence of secondary amines. Our goal was to generate novel compounds that might modulate transforming growth factor‐β signaling, based on limited rational design. Potassium vinyl trifluoroborates react with salicylaldehydes at 80 °C in the presence of a secondary amine and produce 2‐substituted 2H‐chromene derivatives with a 70–90% yield. A small library of these compounds, predicted to potentially interact with transforming growth factor‐β receptors, was screened for bioactivity in living zebrafish embryos. We found that the related compounds differentially affect development, and demonstrate one compound that produces severe body axis alterations in early embryogenesis and at lower doses affects specifically cardiovascular development. This compound modulates specifically a Smad‐independent transforming growth factor‐β‐regulated mitogen‐activated protein kinase pathway, namely p‐SAPK/JNK. These compounds, as suggested by our biological assays, may prove useful to manipulate developmental programs and develop therapeutic tools.     

Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection

The inflamed liver in chronic hepatitis B virus (HBV) infection (CHB) is characterized by a large influx of non–virus-specific CD8 T cells. Little is known about the functional capacity of these lymphocytes, which could provide insights into mechanisms of failure of viral control and liver damage in this setting. We compared the effector function of total circulating and intrahepatic CD8 T cells in CHB patients and healthy donors. We demonstrated that CD8 T cells from CHB patients, regardless of their antigen specificity, were impaired in their ability to produce interleukin-2 and proliferate upon TCR-dependent stimulation. In contrast, these CD8 T cells had preserved production of the proinflammatory cytokines interferon-γ and tumor necrosis factor-α. This aberrant functional profile was partially attributable to down-regulation of the proximal T cell receptor signaling molecule CD3ζ, and could be corrected in vitro by transfection of CD3ζ or replenishment of the amino acid arginine required for its expression. We provide evidence for depletion of arginine in the inflamed hepatic microenvironment as a potential mechanism for these defects in global CD8 T cell signaling and function. These data imply that polarized CD8 T cells within the HBV-infected liver may impede proliferative antiviral effector function, while contributing to the proinflammatory cytokine environment.     

Genesis of hepatic fibrosis and its biochemical markers

Liver fibrosis is characterized by an abnormal hepatic accumulation of extracellular matrix (ECM) that results from both increased deposition and reduced degradation of collagen fibres. Fibrotic liver injury results in activation of the hepatic stellate cell (HSC). Surrogate markers are gradually being substituted for biomarkers that reflect the complex balance between synthesis and degradation of the extracellular matrix. Once the hepatic stellate cell is activated, the preceding matrix changes and recurrent injurious stimuli will perpetuate the activated state. The ECM directs cellular differentiation, migration, proliferation and fibrogenic activation or deactivation. The metabolism of the extracellular matrix is closely regulated by matrix metalloproteinases (MMP) and their specific tissue inhibitors (TIMP). Although liver biopsy combined with connective tissue stains has been a mainstay of diagnosis, there is a need for less invasive methods. These diagnostic markers should be considered in combination with liver function tests, ultrasonography and clinical manifestations.     

Antiplasmodial activity of [(aryl)arylsulfanylmethyl]Pyridine

A series of [(aryl)arylsufanylmethyl]pyridines (AASMP) have been synthesized. These compounds inhibited hemozoin formation, formed complexes (K(D) = 12 to 20 muM) with free heme (ferriprotoporphyrin IX) at a pH close to the pH of the parasite food vacuole, and exhibited antimalarial activity in vitro. The inhibition of hemozoin formation may develop oxidative stress in Plasmodium falciparum due to the accumulation of free heme. Interestingly, AASMP developed oxidative stress in the parasite, as evident from the decreased level of glutathione and increased formation of lipid peroxide, H(2)O(2), and hydroxyl radical (.OH) in P. falciparum. AASMP also caused mitochondrial dysfunction by decreasing mitochondrial potential (DeltaPsim) in malaria parasite, as measured by both flow cytometry and fluorescence microscopy. Furthermore, the generation of .OH may be mainly responsible for the antimalarial effect of AASMP since .OH scavengers such as mannitol, as well as spin trap alpha-phenyl-n-tertbutylnitrone, significantly protected P. falciparum from AASMP-mediated growth inhibition. Cytotoxicity testing of the active compounds showed selective activity against malaria parasite with selectivity indices greater than 100. AASMP also exhibited profound antimalarial activity in vivo against chloroquine resistant P. yoelii. Thus, AASMP represents a novel class of antimalarial.     

Sexual Harassment at Work in the United States

Using nationally representative data from the 1992 U.S. National Health and Social Life Survey, this study queried the prevalence and risk factors of lifetime workplace sexual harassment among both women and men. Among those aged 18-60 reporting ever having worked, 41% of women (CI, 37-44) reported any workplace harassment over their lifetime, with men's harassment prevalence significantly lower, at 32% (CI, 29-35). In the youngest age groups (those in their 20s or younger), there was no statistically significant difference between women's and men's harassment prevalence. Multivariate analysis of risk factors suggested that, in contrast to much of the harassment literature, among both genders workplace harassment seemed to have at least as much to do with a system of "routine activities" mechanisms-a victim's conscious or unconscious sexual signaling, more exposure to potential harassers, and a perpetrator's lower cost of harassment-as with unobserved differences in power between victim and perpetrator. Strikingly, both women's and men's harassment was strongly linked to markers of sexualization, whether early developmental factors or behavioral patterns in adulthood-a mechanism insufficiently emphasized in the harassment literature.     

The cytotoxic properties and preferential toxicity to tumour cells displayed by some 2,4-bis(benzylidene)-8-methyl-8-azabicyclo[3.2.1] octan-3-ones and 3,5-bis(benzylidene)-1-methyl-4-piperidones

This study demonstrated that replacement of the axial protons on the C2 and C6 atoms of various 1-methyl-3,5-bis(benzylidene)-4-piperidones 3 by a dimethylene bridge leading to series 2 lowered cytotoxic potencies. Four compounds 2a and 3a-c emerged as lead molecules based on their toxicity towards different neoplasms and their selective toxicity for malignant rather than normal cells. Some possible reasons for the disparity between the IC(50) values in the two series of compounds are presented based on molecular modeling, logP values and respiration in rat liver mitochondria.     

Amyloid precursor protein and amyloid beta-peptide bind to ATP synthase and regulate its activity at the surface of neural cells

Amyloid precursor protein (APP) and amyloid beta-peptide (Abeta) have been implicated in a variety of physiological and pathological processes underlying nervous system functions. APP shares many features with adhesion molecules in that it is involved in neurite outgrowth, neuronal survival and synaptic plasticity. It is, thus, of interest to identify binding partners of APP that influence its functions. Using biochemical cross-linking techniques we have identified ATP synthase subunit alpha as a binding partner of the extracellular domain of APP and Abeta. APP and ATP synthase colocalize at the cell surface of cultured hippocampal neurons and astrocytes. ATP synthase subunit alpha reaches the cell surface via the secretory pathway and is N-glycosylated during this process. Transfection of APP-deficient neuroblastoma cells with APP results in increased surface localization of ATP synthase subunit alpha. The extracellular domain of APP and Abeta partially inhibit the extracellular generation of ATP by the ATP synthase complex. Interestingly, the binding sequence of APP and Abeta is similar in structure to the ATP synthase-binding sequence of the inhibitor of F1 (IF(1)), a naturally occurring inhibitor of the ATP synthase complex in mitochondria. In hippocampal slices, Abeta and IF(1) similarly impair both short- and long-term potentiation via a mechanism that could be suppressed by blockade of GABAergic transmission. These observations indicate that APP and Abeta regulate extracellular ATP levels in the brain, thus suggesting a novel mechanism in Abeta-mediated Alzheimer's disease pathology.