Direct observation of intermediates formed during steady-state electrocatalytic O2 reduction by iron porphyrins

Heme/porphyrin-based electrocatalysts (both synthetic and natural) have been known to catalyze electrochemical O₂, H⁺, and CO₂ reduction for more than five decades. So far, no direct spectroscopic investigations of intermediates formed on the electrodes during these processes have been reported; and this has limited detailed understanding of the mechanism of these catalysts, which is key to their development. Rotating disk electrochemistry coupled to resonance Raman spectroscopy is reported for iron porphyrin electrocatalysts that reduce O₂ in buffered aqueous solutions. Unlike conventional single-turnover intermediate trapping experiments, these experiments probe the system while it is under steady state. A combination of oxidation and spin-state marker bands and metal ligand vibrations (identified using isotopically enriched substrates) allow in situ identification of O₂-derived intermediates formed on the electrode surface. This approach, combining dynamic electrochemistry with resonance Raman spectroscopy, may be routinely used to investigate a plethora of metalloporphyrin complexes and heme enzymes used as electrocatalysts for small-molecule activation.     

Superficial Temporal Fascia Pedicled V-Y Advancement Flap for Scalp Reconstruction

Repair of scalp defects using local hair bearing scalp is technically challenging. Transposition or rotation of local flaps to close the defect has its own disadvantages. Reconstruction of scalp defect using superficial temporal fascia pedicled V-Y advancement flap using both frontal and parietal branches of superficial temporal artery following the excision of a benign and a malignant pathology is reported here. It is possible to reconstruct the defect with hair bearing scalp in a single stage along with primary closure of the donor site using this technique.     

Tumor-infiltrating Foxp3-CD4+CD25+ T cells predict poor survival in renal cell carcinoma.

PURPOSE: Regulatory T cells (Tregs) have been implicated as inhibitors of antitumoral immunity, and evidence suggests that elimination of Tregs may augment natural and pharmacologic immunity. We tested for the presence of putative Tregs within renal cell carcinoma (RCC) tumors. EXPERIMENTAL DESIGN: We identified 170 patients who underwent radical or partial nephrectomy for clear cell RCC between 2000 and 2002. Specimens were stained with anti-CD4, anti-CD25, and anti-Foxp3 antibodies and examined using confocal microscopy. Associations of CD4(+)CD25(+)Foxp3(-) and CD4(+)CD25(+)Foxp3(+) T cells with death from RCC were evaluated using Cox proportional hazards regression models. RESULTS: At last follow-up, 46 of 170 patients had died; of these, 37 died from RCC at a median of 1.4 years following nephrectomy (range, 0-4.4). Among the 124 remaining patients, median follow-up was 3.7 years (range, 0-5.7). Forty-three (25.3%) tumors harbored CD4(+)CD25(+)Foxp3(+) T cells. The presence of Foxp3(+) T cells was not significantly associated with RCC death univariately. One hundred forty-three (84.1%) tumors harbored CD4(+)CD25(+)Foxp3(-) T cells. The indicator for >or=10% CD4(+)CD25(+)Foxp3(-) T cells was significantly associated with RCC death univariately [risk ratio (RR), 2.60; 95% confidence interval (95% CI), 1.35-4.98; P = 0.004], after adjusting for tumor B7-H1 expression (RR, 2.53; 95% CI, 1.32-4.85; P = 0.005) and lymphocytic infiltration (RR, 2.53; 95% CI, 1.32-4.87; P = 0.005). CONCLUSIONS: Increased presence of CD4(+)CD25(+)Foxp3(+) T cells was not significantly associated with RCC death. In contrast, CD4(+)CD25(+)Foxp3(-) T cells, which may represent a unique set of Tregs or activated helper T cells, was significantly associated with outcome.     

Routine Screening of Gynaecological and Obstetric Patients for Chlamydia Trachomatis

Chlamydia trachomatis infection of the cervix uteri was diagnosed in 9% of 221 gynaecological and obstetric patients. Infection occurred more commonly among obstetric (12.6%) than gynaecological patients (5.5%). In obstetric patients chlamydial infection was commoner in those complaining of excessive vaginal discharge or spontaneous premature rupture of the membranes. Chlamydial infection in gynaecological patients occurred in those with previous pelvic infection, menstrual disorders or excessive vaginal discharge. No cases of chlamydial infection were detected among intrauterine device users. The enzyme immunoassay we used is an easy and relatively quick method of diagnosis for genital chlamydial infection.     

Effects of oral contraceptive norethindrone on blood-lipid and lipid peroxidation parameters

Considering importance of the lipophilicity of norethindrone (log P=2.97), a significant contributor to its mechanism of action, interaction of the drug with total lipids of goat whole blood have been investigated using phospholipid binding, fatty acid composition and peroxidation phenomena as the parameters under investigation. The objective was to derive an insight into the pharmacodynamic behavior of the drug by correlating biological activity with drug induced changes in lipid constituents. Significant loss in phospholipid along with changes in fatty acid cotmposition was observed after incubation of whole blood with norethindrone at 56 ng/ml (effective contraceptive concentration in blood) in varying periods of time. This may be ascribed to binding affinity of norethindrone with lipid constituents in blood. Lipid binding potential of the drug may have a role in its therapeutic effect. Lipid peroxidation induction potential of norethindrone was quantitatively measured in the context of its toxicity. The results reveal that northindrone caused significant extent of lipid peroxidation. Ascorbic acid, a promising antioxidant, at equivalent human dose levels of 250 mg and 500 mg could significantly reduce norethindrone induced lipid peroxidation.     

Effect of desogestrel on blood-lipid in relation to its biological activities

Desogestrel (DG), a 19-nor progestin, is widely used in replacement therapy as a contraceptive steroidal hormone. Considering the importance of its partition coefficient parameter (log P = 5.68), a significant contributor to its action mechanism, interactions of the drug with blood-lipids had been investigated using phospholipid binding, fatty acid composition and peroxidation phenomena as the parameters under investigation to explain its pharmacodynamic behavior. From the present investigation, it was observed that lipid loss after incubation of whole blood with DG (80 ng/ml, effective contraceptive concentration in blood) for varying periods of time was accompanied with significant changes in fatty acid composition, which may be ascribed to binding affinity of DG with lipid constituents in blood that may have a role in the mediation of its therapeutic effect. Lipid peroxidation induction potential of DG has been quantitatively measured in the context of its toxicity. The results reveal that DG caused significant extent of lipid peroxidation. Ascorbic acid, an antioxidant, at equivalent human dose of 250 mg could significantly reduce DG-induced lipid peroxidation.     

Pharmacogenetic applications of the post genomic era

The human genome sequence has given us the view of the internal genetic scaffold around which human life is molded. We have inherited this heritage from our ancestors and through it we are connected to all life on earth. The sequencing of the human genome, amongst others, has led to the newer areas of healthcare and medicine. The human population is heterogeneous and consists of populations of immense ethnic diversity. There are considerable allelic differences between human populations as well as individuals within each ethnic group as a result of molecular heterogeneity of the genome. This, in turn, is responsible for differential allelic expression of genes endowing them with polymorphic characters. The molecular diversity within genes is responsible amongst others, of disease resistance or susceptibility or for that matter drug response. The objective of this article is to understand the nuances of the genetic repertoire and correlate it with disease gene identification, genes that have been or can be used as drug targets, identify candidate genes for drug development and recent trends in drug discovery. As regular clinical trials for drugs does not take into account the ethnic variations, it sometimes results in the differential response with respect to the efficacy and/or adverse reaction of the drug. Therefore the diverse ethnic populations of the world pose a challenge to the pharma industry. The concept of the personal medicine seems to be the answer to this problem. But it is a Herculean task requiring immense innovation in technology, is time consuming and is not a financially viable proposition at this point of time. An alternate approach would be to divide the populations in genetic cohorts and design drugs according to their genetic profile and haplotype. In addition, the ethical and legal bindings have also to be taken into consideration.