Rosiglitazone reverses tenofovir-induced nephrotoxicity

Tenofovir disoproxil fumarate (TDF) is a first-line drug used in patients with highly active retroviral disease; however, it can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Because rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist induces the expression of many of these same transporters, we tested if the nephrotoxicity can be ameliorated by its use. High doses of TDF caused severe renal failure in rats accompanied by a reduction in endothelial nitric-oxide synthase and intense renal vasoconstriction; all of which were significantly improved by rosiglitazone treatment. Low-dose TDF did not alter glomerular filtration rate but produced significant phosphaturia, proximal tubular acidosis, polyuria and a reduced urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. A Fanconi's-like syndrome was ruled out as there was no proteinuria or glycosuria. Rosiglitazone reversed TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. These studies suggest that rosiglitazone treatment might be useful in patients presenting with TFV-induced nephrotoxicity especially in those with hypophosphatemia or reduced glomerular filtration rate.     

Is DARPP-32 a potential therapeutic target?

Signaling pathways play important roles in the coordination and integration of a myriad cellular functions. Because of widespread interest in the dopaminergic pathways, the protein dopamine and cyclic adenosine 3',5'-monophosphate-regulated phosphoprotein with molecular weight of 32 kDa, known by the acronym DARPP-32, occupies a central role in the biology of dopaminoceptive neurons in the central and peripheral nervous system (PNS). Its involvement has been demonstrated in many neural phenomena, including physiologic and pathologic neuroplasticity to drug effects and cognition. However, DARPP-32 has also been identified in non-neuronal tissues and its level of expression has been associated with the malignant level of some types of cancer, via modulation of cell survival and differentiation. This review considers some of these apparently compartmentalized functions of DARPP-32 and its potential as a therapeutic target.     

Recent progress in discovery and development of antimitotic agents

This review highlights structural diversity of antimitotic agents. In particular, we emphasized current antimitotic therapies based on modulation of microtubule dynamics. With several successful anticancer drugs on the market and numerous compounds in clinical developments, tubulin-binding agents remain among the most important categories of anticancer agents. Compounds targeting mitotic kinases and kinesins are also discussed.     

Inhibition of HIV replication: a powerful antiviral strategy by IFN-beta gene delivery in CD4+ cells

In this study, we demonstrated the efficiency and feasibility of a gene therapy protocol against HIV infection using the antiviral effects of IFN-beta expression. Lentiviral vectors containing the human or the simian IFN-beta sequences under the influence of the murine moderate H2-kb promoter were constructed. To examine the capacity of IFN-beta to inhibit the replication of HIV in human CD4(+) cells, a transduction protocol permitting to efficiently transduce CD4(+) cells or PBMC (85+/-12% of CD4(+)-transduced cells) with a moderate expression of IFN-beta was developed. Results indicate that enforced expression of IFN-beta has no negative effects in terms of apoptosis and proliferation. In human CD4(+) cells, it drastically inhibits (up to 99.9%) replication after challenging with different strains of HIV-1. The expression of exogenous IFN-beta leads to an amplification of the CD4(+) cells (11-fold) and to a drastic decrease of the p24 protein. Micro-array analyses indicated that antiviral effect of IFN-beta could be due to a major regulation of the inflammatory response. These results are encouraging for the development of a clinical study of gene therapy against AIDS using IFN-beta.     

Immediate skin-sparing mastectomy reconstruction with deep inferior epigastric perforator (DIEP) flap. Technical aspects and outcome

Although breast reconstruction with deep inferior epigastric perforator (DIEP) flap is a well-described technique, few publications have specifically reported the technical aspects and the outcome following skin-sparing mastectomy (SSM). The aim of this study is to analyse the feasibility of its immediate application and to describe the operative planning, outcome and complications after SSM. 27 patients underwent 30 DIEP flap breast reconstructions with all immediate and 3 bilateral. Mean time of follow-up was 29 months. Breast skin, DIEP Flap and donor-site complications were evaluated. Information on patient satisfaction was collected. 70% had tumors measuring 2 cm or less (T1) and 74% were stage 0 and I according to American Joint Committee on Cancer. Breast skin complications occurred in 7.4%, all represented by small areas of skin necrosis. Partial losses were observed in two (7.4%) patients (less than 15% of total area) and total DIEP loss in 1 (3.7%). Donor-site complications represented by bulging occurred in only one patient (3.7%). The majority of patients were either very satisfied or satisfied. One local recurrence was observed. All complications except 2 were treated by a conservative approach. The DIEP flap is a reliable technique for SSM reconstruction. Success depends on patient selection, coordinated planning with the oncologic surgeon and careful intraoperative and postoperative management. The main advantage is that patients can safely undergo dual procedures with the added aesthetic benefits in breast and abdominal donor site.     

Fluctuating prostate-specific antigen levels in patients with initial negative biopsy: should we be reassured?

OBJECTIVE: To evaluate whether the risk of having a positive repeat prostate biopsy is lower in patients with fluctuating prostate-specific antigen (PSA) levels than in patients with a steady or steadily increasing PSA level. PATIENTS AND METHODS: Files were extracted from the 2000-2003 databases of two teaching hospitals; 191 patients who had a first negative biopsy followed by one or more sets of biopsies and at least two PSA measurements were included. A 'fluctuating PSA level' in a patient was defined as a PSA series including at least one PSA value lower than the one immediately preceding it. RESULTS: The median PSA level at the first biopsy was 7 ng/mL, while that for the second, third and fourth biopsies were 8.0, 8.0 and 8.7 ng/mL, respectively. The median time between the first and second, and the second and third PSA tests was 290 and 317 days, respectively. Prostate cancer was eventually detected in 53 men (27.7%) in whom 39 it was at the first repeat biopsy. Among the 79 patients with a fluctuating PSA level, 17 (22%) had prostate cancer, vs 36 (32%) among the 112 with a 'steady' PSA level; the difference was not significant (P=0.14). When considering the 53 patients diagnosed with prostate cancer, the 17 with a fluctuating PSA level and the 36 others had no significant difference in age, T stage, first PSA level and Gleason score. CONCLUSION: In the present study, by contrast with the common and unfounded view, the risk of having a positive repeat prostate biopsy was no lower in men with a fluctuating PSA level than in those with a steady or steadily increasing PSA level. The practical and economical implications warrant further studies to confirm these findings.     

Patients with renal cell carcinoma nodal metastases can be accurately identified: external validation of a new nomogram

Outcome of patients with renal cell carcinoma nodal metastases (NM) is substantially worse than that of patients with localized disease. This justifies more thorough staging and possibly more aggressive treatment in those at risk of or with established NM. We developed and externally validated a nomogram capable of highly accurately predicting renal cell carcinoma NM in patients without radiographic evidence of distant metastases. Age, symptom classification, tumour size and the pathological nodal stage were available for 4,658 individuals. The data of 2,522 (54.1%) individuals from 7 centers were used to develop a multivariable logistic regression model-based nomogram predicting the individual probability of NM. The remaining data from 2,136 (45.9%) patients from 5 institutions were used for external validation. In the development cohort, 107/2,522 (4.2%) had lymph node metastases vs. 100/2,136 (4.7%) in the external validation cohort. Symptom classification and tumour size were independent predictors of NM in the development cohort. Age failed to reach independent predictor status, but added to discriminant properties of the model. A nomogram based on age, symptom classification and tumour size was 78.4% accurate in predicting the individual probability of NM in the external validation cohort. Our nomogram can contribute to the identification of patients at low risk of NM. This tool can help to risk adjust the need and the extent of nodal staging in patients without known distant metastases. More thorough staging can hopefully better select those in whom adjuvant treatment is necessary. (c) 2007 Wiley-Liss, Inc.