WHO Clinical Staging of HIV Infection and Disease, Tuberculosis and Eligibility for Antiretroviral Treatment: Relationship to CD4 Lymphocyte Counts.

SETTING: Thyolo district, Malawi. OBJECTIVES: To determine in HIV-positive individuals aged over 13 years CD4 lymphocyte counts in patients classified as WHO Clinical Stage III and IV and patients with active and previous tuberculosis (TB). DESIGN: Cross-sectional study. METHODS: CD4 lymphocyte counts were determined in all consecutive HIV-positive individuals presenting to the antiretroviral clinic in WHO Stage III and IV. RESULTS: A CD4 lymphocyte count of < or = 350 cells/microl was found in 413 (90%) of 457 individuals in WHO Stage III and IV, 96% of 77 individuals with active TB, 92% of 65 individuals with a history of pulmonary TB (PTB) in the last year, 91% of 89 individuals with a previous history of PTB beyond 1 year, 81% of 32 individuals with a previous history of extra-pulmonary TB, 93% of 107 individuals with active or past TB with another HIV-related disease and 89% of 158 individuals with active or past TB without another HIV-related disease. CONCLUSIONS: In our setting, nine of 10 HIV-positive individuals presenting in WHO Stage III and IV and with active or previous TB have CD4 counts of < or = 350 cells/microl. It would thus be reasonable, in this or similar settings where CD4 counts are unavailable for clinical management, for all such patients to be considered eligible for antiretroviral therapy

A phase I clinical and pharmacological study evaluating vinflunine in combination with doxorubicin as first line treatment in metastatic breast cancer

Vinfunine (VFL) is a novel bifluorinated tubulin-targeted agent of the vinca alkaloids class active in advanced stage breast cancer. We conducted a phase I study combining VFL with doxorubicin (DXR) to define the recommended dose (RD), safety, pharmacokinetic (PK) interaction and efficacy. Two schedules (day 1 every 3weeks; days 1 and 8 every 3weeks) were investigated as first line chemotherapy in metastatic breast cancer patients. Thirty-two patients received a total of 162 cycles of the VFL-DXR combination (median 6). The RDs were VFL 250mg/m2/DXR 40mg/m2 every 3weeks for schedule 1 and VFL 120mg/m2/DXR 25mg/m2 days 1 and 8 every 3weeks for schedule 2. The main dose-limiting toxicity was neutropenia. The most frequent non-hematological adverse events were nausea, fatigue, constipation, vomiting, anorexia, stomatitis and dyspnea. Objective response rate was reached in 47.1% of the patients. No PK interaction was observed. VFL-DXR combination is feasible with manageable toxicity. The antitumor activity was promising and supports further evaluatio

Azacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease

Background The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Tregs). Objective We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo. Methods In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice. Results AZA successfully improved both survival (p&lt;0.0001) and xGVHD scores (p&lt;0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Conclusion These findings emphasize a potential role for AZA as prevention or treatment of GVHD

Antimicrobial Resistance of Escherichia coli Isolated from Chickens in West of Algeria

Modern poultry flocks undergo strong microbial pressure. Antibiotics can contribute to reduce bacterial infections. Their use increased these last years. Studies performed in Morocco and Algeria highlighted the importance of antibioresistance after excessive use of antibiotics in poultry breeding. In western Algeria, 240 strains of enterobacteriaceae were isolated according to usual bacteriological procedures. In order to assess antimicrobial resistance, the disc diffusion method for antibiotic susceptibility (tetracycline (TE), enrofloxacin (ENR), trimethoprim+sulfamethoxazole (SXT), amoxicillin+clavulanic acid (AMC), ceftiofur (KF), colistin (CT), neomycin (N), gentamicin (GN) and chloramphenicol (C) was applied (Antibioresistance Committee of the French Microbiology Society, 2010). All enterobacteriaceae strains isolated presented at least one resistance to those antibiotics. Escherichia coli counted for 47.5% of these strains (N=114). By omitting intermediate resistances, 28% of E. coli presented a resistance to at least 6 antibiotics and 31.6% to 5 antibiotics. In general, 90.35%, 79.82%, 70.17%, 92.10%, 62.28%, 31.57% and 21.05% of E. coli were resistant to, respectively, TE, ENR, SXT, AMC, KF, CT and N. Considering such a high resistance rate, it is strongly advised to implement epidemiological survey of bacterial resistances at the regional level

Resonance expansions in quantum mechanics

The goal of this contribution is to discuss various resonance expansions that have been proposed in the literature.Comment: 10 pages and 1 figure; presented at the Istanbul workshop on pseudo-Hermitian Hamiltonian

Probabilistic Interpretation of Resonant States

We provide probabilistic interpretation of resonant states. This we do by showing that the integral of the modulus square of resonance wave functions (i.e., the conventional norm) over a properly expanding spatial domain is independent of time, and therefore leads to probability conservation. This is in contrast with the conventional employment of a bi-orthogonal basis that precludes probabilistic interpretation, since wave functions of resonant states diverge exponentially in space. On the other hand, resonant states decay exponentially in time, because momentum leaks out of the central scattering area. This momentum leakage is also the reason for the spatial exponential divergence of resonant state. It is by combining the opposite temporal and spatial behaviors of resonant states that we arrive at our probabilistic interpretation of these states. The physical need to normalize resonant wave functions over an expanding spatial domain arises because particles leak out of the region which contains the potential range and escape to infinity, and one has to include them in the total count of particle number.Comment: 11 pages, 5 figures, to appear in Pramana Journal of Physics as an article in the proceedings of Homi Bhabha Centenary Conference on Non-Hermitian Hamiltonians in Quantum Physics PHHQP VIII; this version are with added references as well as some rewording after reviewer's suggestion

regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomized, placebo-controlled, phase 3 trial.

Summary Background No treatment options are available for patients with metastatic colorectal cancer that progresses after all approved standard therapies, but many patients maintain a good performance status and could be candidates for further therapy. An international phase 3 trial was done to assess the multikinase inhibitor regorafenib in these patients. Methods We did this trial at 114 centres in 16 countries. Patients with documented metastatic colorectal cancer and progression during or within 3 months after the last standard therapy were randomised (in a 2:1 ratio; by computer-generated randomisation list and interactive voice response system; preallocated block design (block size six); stratified by previous treatment with VEGF-targeting drugs, time from diagnosis of metastatic disease, and geographical region) to receive best supportive care plus oral regorafenib 160 mg or placebo once daily, for the first 3 weeks of each 4 week cycle. The primary endpoint was overall survival. The study sponsor, participants, and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT01103323. Findings Between April 30, 2010, and March 22, 2011, 1052 patients were screened, 760 patients were randomised to receive regorafenib (n=505) or placebo (n=255), and 753 patients initiated treatment (regorafenib n=500; placebo n=253; population for safety analyses). The primary endpoint of overall survival was met at a preplanned interim analysis; data cutoff was on July 21, 2011. Median overall survival was 6·4 months in the regorafenib group versus 5·0 months in the placebo group (hazard ratio 0·77; 95% CI 0·64–0·94; one-sided p=0·0052). Treatment-related adverse events occurred in 465 (93%) patients assigned regorafenib and in 154 (61%) of those assigned placebo. The most common adverse events of grade three or higher related to regorafenib were hand-foot skin reaction (83 patients, 17%), fatigue (48, 10%), diarrhoea (36, 7%), hypertension (36, 7%), and rash or desquamation (29, 6%). Interpretation Regorafenib is the first small-molecule multikinase inhibitor with survival benefits in metastatic colorectal cancer which has progressed after all standard therapies. The present study provides evidence for a continuing role of targeted treatment after disease progression, with regorafenib offering a potential new line of therapy in this treatment-refractory population