Expression and shedding of intercellular adhesion molecule 1 and lymphocyte function–associated antigen 3 by normal and scleroderma fibroblasts.

Objective. To examine intercellular adhesion molecule 1 (ICAM-1) and lymphocyte function-associated antigen 3 (LFA-3) in cultures of normal and systemic sclerosis (SSc) dermal fibroblasts. Methods. The surface and soluble forms of ICAM-1 and LFA-3 were measured by flow cytometry and capture enzyme-linked immunosorbent assay, respectively. Results. Surface ICAM-1 was significantly higher on SSc fibroblasts compared with normal controls. β-estradiol did not directly enhance ICAM-1 or LFA-3 expression in either normal or SSc cells, but significantly augmented the cytokine-induced increase in ICAM-1. Soluble ICAM-1 (sICAM-1) and sLFA-3 were detected in fibroblast cultures. While no difference was found in the level of sLFA-3, the shedding of sICAM-1 was significantly increased (P < 0.001) in cells from SSc patients. Conclusion. SSc fibroblasts express intrinsically elevated levels of surface ICAM-1 and release higher levels of sICAM-1 in vitro. Increased expression of ICAM-1 by interferon-γ and tumor necrosis factor α alone, and the further induction in combination with β-estradiol may underlie an aspect of fibroblast dysfunction in SSc and the female predisposition to the disease.     

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors

This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.     

Acute lower respiratory tract infection due to Chlamydia species in children under five years of age

BACKGROUND: The contribution of Chlamydia spp in respiratory tract infections in paediatric population from India has not been studied in detail. METHODS: Sixty children under five years of age who were admitted with acute lower respiratory tract infection during a one year period were investigated for Chlamydial aetiology of respiratory infection. Diagnosis was based on antigen detection by direct immunofluorescence (DIF) in throat swab along with anti-Chlamydial immunoglobulin G (IgG) antibody demonstration by solid phase enzyme immunoassay (EIA). RESULTS: Chlamydia spp antigen was detected in seven (11.6%) cases, C. pneumoniae in six (10%) and C. trachoniatis in one (1.6%). Chlamydia spp IgG antibody in serum was demonstrated in 24 (40%) cases, of which C. pneumoniae IgG was denconstrated in 18 (30%) cases. Taking the criteria of antigen detection (n=7) and high IgG antibody titre of > or = 1:512 (n=5) for a positive case, 12 (20%) children were found to be suffering from recent Chlamydial infection. CONCLUSION: Chlamydia spp plays a significant role in respiratory tract infections in Indian paediatric population. Diagnostic procedure like antigen detection in throat swab is rapid, less cumbersome and feasible and should be more widely used along with antibody demonstration to determine the aetiological agent early in the course of illness.     

Antiinflammatory and antinociceptive activities of gossypin and procumbentin – cyclooxygenase‐2 (COX‐2) inhibition studies

In the present study the antiinflammatory and antinociceptive activities of a few selected flavonoids were investigated. Procumbentin, gossypin, chrysin and methylhespiridin were studied for antiinflammatory and antinociceptive activities using in vitro enzymatic assays and in animal models utilizing acetic acid‐induced writhing in mice and hind paw edema in rats. In vitro studies were performed using TMPD (NNN′N′‐tetramethyl‐p‐phenylene diamine) and oxygraphic methods for COX‐1 (cyclooxygenase‐1), COX‐2, 5‐LOX (5‐lipoxygenase) and 15‐LOX. Gossypin and procumbentin showed COX‐2 inhibitory activity and exhibited IC₅₀ (COX‐2/COX‐1) ratios of 0.14 and 0.11, respectively. None of the flavonoids tested in this study showed LOX inhibitory activity. Four groups were studied for each test compound following intraperitoneal (i.p.) administration of doses of 10, 30 and 100 mg/kg. Antiinflammatory activity was measured by the carrageenin‐induced rat hind paw edema model and antinociceptive activity by acetic acid‐induced writhing. Procumbentin and gossypin showed antinociceptive activity at the 100 mg/kg dose. Gossypin showed antiinflammatory activity at doses of 10, 30, 100 mg/kg. Procumbentin and gossypin exhibited COX‐2 inhibitory activity when tested by in vitro methods. Procumbentin and gossypin showed antinociceptive, and gossypin showed antiinflammatory, activities. Copyright © 2008 John Wiley & Sons, Ltd.     

Efficacy of HIV/STI Behavioral Interventions for Heterosexual African American Men in the United States: A Meta-Analysis

This meta-analysis estimates the overall efficacy of HIV prevention interventions to reduce HIV sexual risk behaviors and sexually transmitted infections (STIs) among heterosexual African American men. A comprehensive search of the literature published during 1988-2008 yielded 44 relevant studies. Interventions significantly reduced HIV sexual risk behaviors and STIs. The stratified analysis for HIV sexual risk behaviors indicated that interventions were efficacious for studies specifically targeting African American men and men with incarceration history. In addition, interventions that had provision/referral of medical services, male facilitators, shorter follow-up periods, or emphasized the importance of protecting family and significant others were associated with reductions in HIV sexual risk behaviors. Meta-regression analyses indicated that the most robust intervention component is the provision/referral of medical services. Findings indicate that HIV interventions for heterosexual African American men might be more efficacious if they incorporated a range of health care services rather than HIV/STI-related services alone.     

DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on the surface of monocyte-derived immature dendritic cells

C1q modulates the differentiation and function of cells committed to the monocyte-derived dendritic cell (DC) lineage. Because the 2 C1q receptors found on the DC surface-gC1qR and cC1qR-lack a direct conduit into intracellular elements, we postulated that the receptors must form complexes with transmembrane partners. In the present study, we show that DC-SIGN, a C-type lectin expressed on DCs, binds directly to C1q, as assessed by ELISA, flow cytometry, and immunoprecipitation experiments. Surface plasmon resonance analysis revealed that the interaction was specific, and both intact C1q and the globular portion of C1q bound to DC-SIGN. Whereas IgG reduced this binding significantly, the Arg residues (162-163) of the C1q-A chain, which are thought to contribute to the C1q-IgG interaction, were not required for C1q binding to DC-SIGN. Binding was reduced significantly in the absence of Ca(2+) and by preincubation of DC-SIGN with mannan, suggesting that C1q binds to DC-SIGN at its principal Ca(2+)-binding pocket, which has increased affinity for mannose residues. Antigen-capture ELISA and immunofluorescence microscopy revealed that C1q and gC1qR associate with DC-SIGN on blood DC precursors and immature DCs. The results of the present study suggest that C1q/gC1qR may regulate DC differentiation and function through the DC-SIGN-mediated induction of cell-signaling pathways.     

Flow cytometry antifungal susceptibility testing of Aspergillus fumigatus and comparison of mode of action of voriconazole vis-à-vis amphotericin B and itraconazole

Aspergillus fumigatus isolates were tested with three antifungals by flow cytometry (FC) and fluorescence-activated cell sorting. FC results after 4 h correlated well with MICs obtained by the NCCLS M38-A method; voriconazole exhibited fungicidal activity, albeit to a lesser extent than amphotericin B, but to a greater extent than itraconazole.     

Role of Periductal and Ductular Epithelial Cells of the Adult Rat Pancreas in Pancreatic Hepatocyte Lineage: A Change in the Differentiation Commitment

Development of pancreatic hepatocytes in adult rats maintained on copper deficient diet containing 0.6% trien (CuDT) has been reported recently. To elucidate the histogenesis of hepatocytes a sequential study was undertaken using morphologic, histochemical, immunochemical, in situ hybridization, and Northern blot analysis. Male F-344 rats weighing 80 to 90 g were fed CuDT for 8 weeks and returned to normal rat chow. Beginning from 4 weeks of copper depletion, there was a progressive loss of acinar cells and by 8 weeks more than 90% of the acinar tissue was lost. During this period, there was an increase in the number of adipocytes in the interstitium, and in the number of interstitial and ductular cells. Morphologic observations were confirmed by immunoblot and Northern blot analysis, in which the amount of pancreatic proteins and their mRNAs decreased between 5 and 8 weeks. During this period, a progressive increase in the level of albumin mRNA was observed. In situ hybridization, performed at 7 weeks of copper deficiency, showed localization of albumin mRNA over interstitial and ductular cells. Pancreatic hepatocytes were identified immediately after the rats were returned to a normal diet and gradually increased in number. The hepatocytes occupied almost 60% of the pancreatic volume by 8 weeks. During the early recovery phase, hepatocytes were identified in ductules as well as in the interstitium. Based on these studies, it is concluded that both the ductular cells and interstitial cells, which resemble oval cells of liver, are capable of transforming into pancreatic hepatocytes and these cells may be considered stem-cell equivalent.     

Outcome after decompressive craniectomy in patients with dominant middle cerebral artery infarction: A preliminary report

Introduction:

Life-threatening, space occupying, infarction develops in 10-15% of patients after middle cerebral artery infarction (MCAI). Though decompressive craniectomy (DC) is now standard of care in patients with non-dominant stroke, its role in dominant MCAI (DMCAI) is largely undefined. This may reflect the ethical dilemma of saving life of a patient who may then remain hemiplegic and dysphasic. This study specifically addresses this issue.

Materials and Methods:

This retrospective analysis studied patients with DMCAI undergoing DC. Patient records, operation notes, radiology, and out-patient files were scrutinized to collate data. Glasgow outcome scale (GOS), Barthel index (BI) and improvement in language and motor function were evaluated to determine functional outcome.

Results:

Eighteen patients between 22 years and 72 years of age were included. 6 week, 3 month, 6 month and overall survival rates were 66.6% (12/18), 64% (11/17), 62.5% (10/16) and 62.5% (10/16) respectively. Amongst ten surviving patients with long-term follow-up, 60% showed improvement in GOS, 70% achieved BI score >60 while 30% achieved full functional independence. In this group, motor power and language function improved in 9 and 8 patients respectively. At last follow-up, 8 of 10 surviving patients were ambulatory with (3/8) or without (5/8) support. Age <50 years corresponded with better functional outcome amongst survivors (P value –0.0068).

Conclusion:

Language and motor outcomes after DC in patients with DMCAI are not as dismal as commonly perceived. Perhaps young patients (<50 years) with DMCAI should be treated with the same aggressiveness that non-DMCAI is currently dealt with.Key Words: Craniectomy, dominant, middle cerebral artery, outcome, stroke