Novel 5-(1-aryl-1H-pyrazol-3-yl)-1H-tetrazoles as glycogen phosphorylase inhibitors: An in vivo antihyperglycemic activity study

In this study, we report the ring transformation of 3-arylsydnone into 1-aryl-1H-pyrazole-3-carbonitriles via [3 + 2] cycloaddition with acrylonitrile. 1-Aryl-1H-pyrazole-3-carbonitrile underwent [2 + 3] cycloaddition with sodium azide to afford 5-(1-aryl-1H-pyrazol-3-yl)-1H-tetrazoles which were further subjected to N-alkylation with aryl/heteroaryl alkyl halides to afford 1,5- and 2,5-disubstituted tetrazoles. Furthermore, the title compounds were screened for in vivo antihyperglycemic activity using albino Wistar rats of either sex. Compounds 4a , 6b , 7a , 7b , 8b , and 9b showed maximum fall in the blood glucose levels in streptozotocin-induced diabetic rats after 5–7 days of administration. In support of antidiabetic activity, we also performed the experimental in vivo studies, namely, effect of compounds on enzymes (serum glutamic oxaloacetic transaminase, serum glutamic-pyruvic transaminase, creatinine, urea, and total protein), antihyperlipidemic, and histopathology. Moreover, the molecular docking study has been performed for potent molecules among the series with glycogen phosphorylase as target enzyme, and this study corroborated the experimental in vivo results.     

Modified Tat peptide with cationic lipids enhances gene transfection efficiency via temperature-dependent and caveolae-mediated endocytosis

The HIV-1 Tat peptide has been successfully used for intracellular gene delivery. Likewise, various lipid-based methods have shown increased endocytosis and can influence endosomal escape. This study combines the favorable properties of Tat peptide with that of lipid systems for DNA delivery. We combined the lipid FuGENE HD (FH) with the Tat peptide sequence modified with histidine and cysteine residues (mTat). mTat/FH transfection was evaluated by luciferase expression plasmid in five cell types. mTat/FH produced significant improvement in transfection efficiency of all cell lines when compared to FH or mTat. Treatment with chloroquine, associated with energy-dependent endocytosis, significantly increased transfection efficiency with mTat/FH while incubation at low temperature decreased it. The zeta potential of mTat/FH/DNA was significantly higher compared to FH, mTat, or their DNA combination in the presence of serum, and it was correlated with transfection efficiency. The particle size of the FH/DNA complex was significantly reduced by addition of mTat. Filipin III, an inhibitor of caveolae-mediated endocytosis, significantly inhibited mTat/FH transfection, but transfection was increased by chlorpromazine, an inhibitor of clathrin-mediated endocytosis. These findings demonstrated the feasibility of using a combination of mTat with lipids, utilizing temperature-dependent and caveolae-mediated endocytosis, as a potentially attractive non-viral gene vector.     

Influence of cancer treatment on the <Emphasis Type="Italic">Candida albicans</Emphasis> isolated from the oral cavities of cancer patients

Purpose

Cancer treatment causes mucositis and the manifestation of oral candidiasis. This study investigated the virulence properties and antifungal susceptibilities of Candida albicans isolated from cancer patients undergoing therapy.

Methods

C. albicans were isolated from 49 patients on cancer treatment and 21 healthy individuals and their virulence attributes measured. A correlation was determined between the length of treatment and the fungal counts and their virulence factors.

Results

Although Candida carriage was similar in all the study groups, high quantities of C. albicans and variety of Candida were found in cancer patients. Germ tubes were produced by all the strains. Significantly high number of yeast isolated from radiotherapy and chemotherapy produced large quantities of phospholipase compared to healthy individuals (p?<?0.01). The length of chemotherapy was associated with an increase in the phospholipase production (p?=?0.03) by the C. albicans. Proteinase production was seen in a significant number of isolates from the radiotherapy group (p?<?0.01). Type of cancer treatment had no effect. Resistance to antifungal agents was low.

Conclusions

High quantities of phospholipase were produced by C. albicans in cancer patients on therapy which also increased with the length of chemotherapy suggesting enhanced risk of oral and systemic infection. Therefore, during treatment, prophylactic topical antifungal therapy may be considered.

     

Prone ventilation reduces mortality in patients with acute respiratory failure and severe hypoxemia: systematic review and meta-analysis

Background

Prone position ventilation for acute hypoxemic respiratory failure (AHRF) improves oxygenation but not survival, except possibly when AHRF is severe.

Objective

To determine effects of prone versus supine ventilation in AHRF and severe hypoxemia [partial pressure of arterial oxygen (PaO₂)/inspired fraction of oxygen (FiO₂) <100 mmHg] compared with moderate hypoxemia (100 mmHg ≤ PaO₂/FiO₂ ≤ 300 mmHg).

Design

Systematic review and meta-analysis.

Data Sources

Electronic databases (to November 2009) and conference proceedings.

Methods

Two authors independently selected and extracted data from parallel-group randomized controlled trials comparing prone with supine ventilation in mechanically ventilated adults or children with AHRF. Trialists provided subgroup data. The primary outcome was hospital mortality in patients with AHRF and PaO₂/FiO₂ <100 mmHg. Meta-analyses used study-level random-effects models.

Results

Ten trials (N = 1,867 patients) met inclusion criteria; most patients had acute lung injury. Methodological quality was relatively high. Prone ventilation reduced mortality in patients with PaO₂/FiO₂ <100 mmHg [risk ratio (RR) 0.84, 95% confidence interval (CI) 0.74–0.96; p = 0.01; seven trials, N = 555] but not in patients with PaO₂/FiO₂ ≥100 mmHg (RR 1.07, 95% CI 0.93–1.22; p = 0.36; seven trials, N = 1,169). Risk ratios differed significantly between subgroups (interaction p = 0.012). Post hoc analysis demonstrated statistically significant improved mortality in the more hypoxemic subgroup and significant differences between subgroups using a range of PaO₂/FiO₂ thresholds up to approximately 140 mmHg. Prone ventilation improved oxygenation by 27–39% over the first 3 days of therapy but increased the risks of pressure ulcers (RR 1.29, 95% CI 1.16–1.44), endotracheal tube obstruction (RR 1.58, 95% CI 1.24–2.01), and chest tube dislodgement (RR 3.14, 95% CI 1.02–9.69). There was no statistical between-trial heterogeneity for most clinical outcomes.

Conclusions

Prone ventilation reduces mortality in patients with severe hypoxemia. Given associated risks, this approach should not be routine in all patients with AHRF, but may be considered for severely hypoxemic patients.     

Calculating the required transfusion volume in children

BACKGROUND: The traditional method of calculating blood volume for pediatric transfusion in the UK is weight (kg) x aimed increment in hemoglobin concentration (Hb; g/dL) x the transfusion factor, usually quoted at 3 or 4. This equation is without evidence base. The aim was to assess how the volume of red cells (RBCs) affects the increase in serum Hb in children and to devise a formula that allows accurate volume calculation. STUDY DESIGN AND METHODS: All pediatric intensive care charts for 2 years were examined retrospectively. The immediate pre- and posttransfusion Hb estimations and the precise volumes of RBC transfused were recorded. Fluid boluses and hemorrhagic loss during the transfusion were documented. RESULTS: A total of 7679 patient charts were examined with a total of 564 transfusions. All patients who were bleeding, had drain losses, or had concurrent colloid infusions were excluded, giving 379 data points. The correlation gradient between mL per kg blood transfused and increase in Hb was 5.02. There was no significant association between effect and patient weight, age, starting Hb, transfusion time, or sex. No significant difference was found in Hb at 1 and 7 hours posttransfusion. CONCLUSIONS: The following equation should be used to calculate transfusion volumes: weight (kg) x increment in Hb (g/dL) x 3/(hematocrit [Hct] level of RBCs). This predicts that with a UK standard Hct of 0.6, 10 mL/kg gives an increment of 2 g/dL. Care must be taken not to risk hypervolemia, while minimizing donor exposure. Hb estimation 1 hour after transfusion is the same as 7 hours after transfusion.