Inappropriate peripheral blood lymphocyte responses to herpes viruses in patients with behçet's syndrome

Specific antibody production and the proliferative response of peripheral blood lymphocytes (PBLs) to a variety of viruses, including herpes simplex virus-type-1 (HSV-1) and varicella zoster (VZ), were studied in 7 patients with Behçet's syndrome. None of the patients produced an antibody response against HSV-1 or VZ. Furthermore, none of the patients showed a proliferative response to VZ, and three of them also failed to mount a response to HSV-I. These results suggest that the PBLs of patients with Behçet's syndrome make an inappropriately poor antibody and proliferative response when stimulated by HSV-1 and VZ.     

Endotoxin-induced suppression of erythropoiesis: the role of erythropoietin and a heme synthesis stimulating factor

The regulation of erythropoiesis is primarily controlled by erythropoietin (Ep). Recently, however, other factors that both stimulate and inhibit erythropoiesis have been reported. Using an in vitro liquid culture of bone marrow cells, a factor in normal mouse serum was demonstrated that markedly stimulated heme synthesis by marrow erythroid cells. In this study, the role of this heme synthesis stimulating factor (HSF) and Ep in the erythropoietic suppression caused by endotoxin administration to mice was examined. Although HSF levels did not alter appreciably after endotoxin injection, marrow erythroid cells from these animals became unresponsive to the factor. This could be reversed if Ep was added to the culture in vitro or if the hormone was injected into the mice 18 hr prior to harvesting the marrow. This marrow erythroid cell response is identical to that seen in animals in whom Ep levels are markedly reduced, such as that found in exhypoxic polycythemia, and suggest a decrease in the hormone following endotoxin administration. Additional studies demonstrated that when Ep was injected into mice 6 hr after endotoxin administration, an increase in femoral erythroid colony-forming units (CFU-E), proerythroblast number, and 59 Fe incorporation into femoral marrow cells could be demonstrated. These findings, together with the marrow erythroid cell response to the hormone, suggest that the mechanism for suppression of erythropoiesis after endotoxin injection is a reduction in the level of circulating Ep.     

Measurement of maximal inspiratory pressure in ventilated children

Maximal inspiratory pressure (PIMAX), the maximum negative pressure generated during temporary occlusion of the airway, is commonly used to measure inspiratory muscle strength in mechanically ventilated infants and children. There are, however, no guidelines as to how the PIMAX measurement should be made. We compared the maximum inspiratory pressure generated during airway occlusion (PIMAX(OCC)) to that when a unidirectional valve (PIMAX(UNI)), which allowed expiration, but not inspiration was used. Twenty-two mechanically ventilated children (mean (SD) age 4.8 (4.5) years) were studied. Three sets of end expiratory occlusions were performed for each method in random order. The expired volume during PIMAX(UNI) was assessed and related to the functional residual capacity (FRC) measured using a helium dilution technique.The mean (SD) PIMAX(UNI) (45.5 (15.2) cmH(2)O) was significantly greater than mean (SD) PIMAX(OCC) (30.9 (9.0) cmH(2)O) (P < 0.0001). The mean (SD) expired volume during PIMAX(UNI), was 98 ml (62.3), a mean reduction in FRC of 33.1% (SD 13.9). There were no significant differences between techniques in the baseline respiratory drive, the number of efforts required and the time to reach PIMAX. Regardless of technique, PIMAX was reached in 10 inspiratory efforts or 15 sec of airway occlusion.A unidirectional valve allowing expiration, but not inspiration yields greater PIMAX values in children. Occlusions should be maintained for 12 sec or eight breaths (99% CI of mean).     

Association Between Alcohol Use and HIV-Related Sexual Risk Behaviors Among Men Who Have Sex with Men (MSM): Findings from a Multi-Site Bio-Behavioral Survey in India

This paper examines the association between alcohol use and HIV-related sexual risk behaviors among men who have sex with men (MSM). A cross-sectional bio-behavioral survey was conducted among 3,880 MSM, recruited using time-location cluster sampling from cruising sites in three Indian states. Nearly three-fifths of the participants reported alcohol use. Among frequent users (40 % of the sample), defined as those who consumed alcohol daily or at least once a week, 66 % were aged 25 years and above, 53 % self-identified as kothi (feminine/receptive), and 63 % consistently used condoms with male paying partners. Multivariate logistic regression demonstrated that frequent users were more likely to be aged 25 years and above, less likely to self-identify as kothi, and less likely to consistently use condoms with male paying (AOR = 0.7; 95 % CI 0.5–0.9) and male regular (AOR = 0.7; 95 % CI 0.6–0.9) partners. HIV prevention interventions for MSM need to provide tailored information on alcohol use-related sexual risk, especially for MSM in sex work and MSM with male regular partners.     

Clinical investigation of human alpha interferon in chronic myelogenous leukemia

Fifty-one patients with previously untreated or minimally treated chronic myelogenous leukemia in chronic phase received human alpha interferon 3 to 9 X 10(6) units intramuscularly (IM) daily until complete hematologic remission, then at doses ranging from 3 X 10(6) units every other day to 9 X 10(6) units daily. Forty-one (80%) patients achieved a hematologic response, 36 (71%) of them attaining a complete hematologic remission with normal peripheral WBC and differential counts. Responding patients showed continuous but slow normalization of several other blood and marrow parameters including platelet counts, serum lactic dehydrogenase and B12 levels, and marrow cellularity and maturation index. Suppression of the Philadelphia chromosome on serial cytogenetic studies of marrow metaphases was documented in 20 of the 36 patients who achieved complete hematologic remission (56%; 39% of total group), eight of whom (22%) had a decrease of the Philadelphia chromosome-positive metaphases to less than 35%. These changes were persistent for 6 months or longer in 18 patients, seven of whom had continuous suppression of the Philadelphia chromosome to less than 90% for a median of 30+ months (range 21+ to 39+ months). After a median follow-up period of 37 months, 25 patients remain in continued disease control with interferon therapy. The projected 3-year survival rate is 76%, with a yearly death rate of 6%, 9%, and 9% in the first 3 years. Response, Philadelphia chromosome suppression, and survival were significantly better among patients in the low-risk category compared to intermediate- and high-risk categories, as defined by a multivariate analysis-derived prognostic model. The projected 3- year survival rate was 94% for patients who achieved a complete hematologic remission on interferon therapy and 45% for those who did not. Thirteen patients have developed blastic crisis, six with lymphoid and three with undifferentiated morphology. We conclude that human leukocyte alpha interferon effectively controls chronic myeloid leukemia and allows reappearance of diploid hemopoietic cells in some patients.     

Evaluation of drugs for elimination of leukemic cells from the bone marrow of patients with acute leukemia

Relatively nonmyelotoxic drugs and drug combinations were investigated for their ability to eliminate malignant cells from human bone marrow. In vitro 90% inhibitory concentration (IC90) doses were established on granulocyte macrophage colony-forming units (GM-CFU) in culture of bone marrow by using the GM-CFU assay for the following drugs: 4- hydroperoxycyclophosphamide (4-HC), Adriamycin, L-asparaginase, bleomycin, hydrocortisone, VP-16, spirogermanium, Taxol, and vincristine. The leukemic cell kill efficiency of these drugs at IC90 doses was compared with that of 4-HC on acute lymphoid leukemia (ALL) cell lines by using the limiting-dilution assay. Under these conditions, no single drug was superior to 4-HC. To increase the in vitro effect in leukemic cell kill, combinations of vincristine with hydrocortisone, Adriamycin, VP-16, and 4-HC were investigated. Vincristine at 1 to 5 micrograms/mL increased the marrow cytotoxicity of hydrocortisone, Adriamycin, and VP-16, but it was protective (subadditive) with 4-HC. Vincristine and 4-HC in combination was additive to supraadditive on ALL cell lines, increased the leukemic cell kill by one to two logs above 4-HC alone at IC90 doses (P less than .05), and was not affected by the addition of excess marrow cells. The recommended doses for chemopurging in clinical studies are vincristine, 1 to 5 micrograms/mL, plus 4-HC, 5 micrograms/mL.     

Efficient Denoising Framework for Mammogram Images with a New Impulse Detector and Non-Local Means

Objective: The survival rates of breast cancer are increasing as screening and diagnosis improve. The removal of noise is revealed to be a significant step for automatic - computer aided detection (CAD) of microcalcification in digital mammography. Methods: In this paper, a combined approach for eradicating impulse noise from digital mammograms is proposed. The process is achieved in two stages, detection of noise followed by filtering of noise. The detection of noise is carried out by using Modified Robust Outlyingness Ratio (mROR) trailed by an extended NL (Non-Local)-means filter for filtering mechanism. Results: According to the value of mROR, all pixels in mammogram images are divided into four distinct groups. In each cluster, many decision rules are then applied for detecting the impulse noise. Filtering is done with NL-means filter by providing a reference mammogram image. Conclusion: The comparative analysis and evaluated results are compared with some existing filters which indicate that the proposed structure outperforms the analysed result of others.     

Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery

The glucagon-like peptide-1 receptor (GLP-1R) is a family B G protein-coupled receptor and an important drug target for the treatment of type II diabetes, with activation of pancreatic GLP-1Rs eliciting glucose-dependent insulin secretion. Currently, approved therapeutics acting at this receptor are peptide based, and there is substantial interest in small molecule modulators for the GLP-1R. Using a variety of resonance energy transfer techniques, we demonstrate that the GLP-1R forms homodimers and that transmembrane helix 4 (TM4) provides the primary dimerization interface. We show that disruption of dimerization using a TM4 peptide, a minigene construct encoding TM4, or by mutation of TM4, eliminates G protein-dependent high-affinity binding to GLP-1(7-36)NH₂ but has selective effects on receptor signaling. There was <10-fold decrease in potency in cAMP accumulation or ERK1/2 phosphorylation assays but marked loss of intracellular calcium mobilization by peptide agonists. In contrast, there was near-complete abrogation of the cAMP response to an allosteric agonist, compound 2, but preservation of ERK phosphorylation. Collectively, this indicates that GLP-1R dimerization is important for control of signal bias. Furthermore, we reveal that two small molecule ligands are unaltered in their ability to allosterically modulate signaling from peptide ligands, demonstrating that these modulators act in cis within a single receptor protomer, and this has important implications for small molecule drug design.     

Migraine and the hypothalamus

Migraine is a complex brain disorder where several neuronal pathways and neurotransmitters are involved in the pathophysiology. To search for a specific anatomical or physiological defect in migraine may be futile, but the hypothalamus, with its widespread connections with other parts of the central nervous system and its paramount control of the hypophysis and the autonomic nervous system, is a suspected locus in quo. Several lines of evidence support involvement of this small brain structure in migraine. However, whether it plays a major or minor role is unclear. The most convincing support for a pivotal role so far is the activation of the hypothalamus shown by positron emission tomography (PET) scanning during spontaneous migraine attacks. A well-known theory is that the joint effect of several triggers may cause temporary hypothalamic dysfunction, resulting in a migraine attack. If PET scanning had consistently confirmed hypothalamic activation prior to migraine headache, this hypothesis would have been supported. However, such evidence has not been provided, and the role of the hypothalamus in migraine remains puzzling. This review summarizes and discusses some of the clues.