Identification of a novel zinc finger gene, zf5-3, as a potential mediator of neuroblastoma differentiation.

We established a unique parental neuroblastoma cell line, NUB-7, which mimics the bipotentiality of neuroblastoma in vivo along neuronal and Schwann cell lineages following dibutyryl cAMP and retinoic acid treatments, respectively. Differential display identified a putative novel zinc finger gene as a potential differentiation-responsive gene coincident with retinoic acid treatment of NUB-7. This cDNA clone, now designated zf5-3, was mapped to chromosome 19 using somatic cell hybrids, and a larger cDNA clone further localized this gene to band 13.1-13.2 by fluorescent in situ hybridization. zf5-3 possesses 4 characteristic zinc finger DNA-binding motifs as determined by its nucleic acid and proposed amino acid sequence. Expression of zf5-3 is restricted to fetal neuronal, hepatic and renal tissues and their tumor-derived cell lines, including 8/9 neuroblastomas and 2/2 malignant rhabdoid tumors of kidney. The restricted expression in the kidney of zf5-3 to collecting tubules and ureter epithelium is suggestive of an ectodermal histogenesis of malignant rhabdoid tumors of kidney. During development of the fetal human brain, high levels of zf5-3 mRNA are restricted to the mitotically active, undifferentiated neuroblasts. Morphological evidence of overt differentiation was generally accompanied by a marked loss in zf5-3 expression. Therefore, the neuronal tissue expression profile and the down-regulation coincident with retinoic acid-induced neuroblastoma maturation implicate zf5-3 as a potential mediator of their differentiation.     

Antioxidant properties of methanolic extracts from leaves of Rhazya stricta

Because of increased safety concerns about synthetic antioxidants, exploitation of cheaper and safer sources of antioxidants based on natural origin is the focus of research nowadays. Rhazya stricta is a medicinally important plant native to South Asia. Extraction of antioxidants was carried out in different solvent systems, i.e., water, 80% methanol, 70% ethanol, and diethyl ether. The methanolic extract exhibited the highest total phenolic content among the extracts; therefore for further studies the methanolic extract was employed. Antioxidant activity measurement in the linoleic acid system, metal chelating activity, reducing power, scavenging effect on 1,1-diphenyl-2-picrylhydrazyl free radical, and superoxide anion radical scavenging activity were taken as the parameters for assessment of antioxidant potential of methanolic extracts. Results were compared with alpha-tocopherol and the synthetic antioxidant butylated hydroxyanisole. The antioxidant potential of methanolic extracts of R. stricta leaves was comparable with previously exploited potent antioxidants and is strongly concentration dependent.     

Preferential expression of insulin-like growth factor binding proteins-1, -3, and -5 during early diabetic renal hypertrophy in rats

The renal insulin-like growth factor-I (IGF-I) system has been implicated in the pathogenesis of renal hypertrophy, altered hemodynamics, and extracellular matrix expansion associated with early diabetes. The relative abundance of IGF binding proteins (IGFBPs) in the renal microenvironment may modulate IGF-I actions. However, the precise IGFBPs expressed in the glomerular and tubulointerstitial compartments during diabetic renal growth have not been characterized. In the present study, in situ hybridization studies were performed to examine the expression of IGFBP-1 to -6 messenger RNAs (mRNAs) 3, 7, and 14 days after streptozotocin (STZ) injection in rats. In control, nondiabetic kidneys, all six IGFBP mRNAs were differentially expressed with a predominance of IGFBP-5. The onset of renal hypertrophy in STZ-induced diabetes was associated with a rapid and site-specific induction of IGFBP-1, -3, and -5 mRNAs. In contrast, basal expression of IGFBP-2, -4, and -6 mRNAs was not altered in diabetic rats. IGFBP-5 mRNA expression increased in diabetic glomeruli, cortical, and inner medullary peritubular interstitial cells at days 3, 7, and 14. Although normal glomeruli failed to express IGFBP-3, it was induced concomitantly with IGFBP-5 in diabetic glomeruli and cortical peritubular interstitial cells. IGFBP-1 mRNA levels also increased in cortical tubular cells at each time point tested. Peak induction of IGFBP-3 and -5 was observed at day 3, whereas IGFBP-1 was delayed until day 7. IGFBP-1, -3, and -5 mRNA levels declined by day 14, but remained persistently elevated above control. By immunoperoxidase staining, similar alterations in the pattern of IGFBP-3 and -5 protein expression were observed at each time point. The preferential and site-specific increase in IGFBP-1, -3, and -5 suggest that these IGFBPs may regulate the local autocrine and/or paracrine actions of IGF-I and contribute to the pathogenesis of the early manifestations of diabetic nephropathy.     

Regulation of neutrophil migration and superoxide production by recombinant tumor necrosis factors-alpha and -beta: comparison to recombinant interferon-gamma and interleukin-1 alpha

We compared the ability of recombinant human tumor necrosis factor- alpha (rHuTNF-alpha) and tumor necrosis factor-beta (rHuTNF-beta) to stimulate polymorphonuclear neutrophil (PMN) migration and superoxide production. Significant PMN migration occurred across polycarbonate filters after stimulation with rHuTNF-alpha at concentrations ranging from 10(-7) to 10(-10) mol/L and at 10(-7) to 10(-8) mol/L for rHuTNF- beta and N-formylmethionyl-leucyl phenylalanine (FMLP), whereas recombinant human interferon-gamma was only minimally active at 10(-7) mol/L and recombinant human interleukin-1 alpha was inactive at the doses tested. In addition, antibodies to rHuTNF-alpha completely inhibited rHuTNF-alpha but not rHuTNF-beta or FMLP-induced PMN migration. Combinations of rHuTNF-alpha and rHuTNF-beta (at similar molar concentrations) stimulated PMN migration levels comparable to that obtained with rHuTNF-alpha alone. Checkerboard analyses performed by placing different concentrations of rHuTNF-alpha and rHuTNF-beta above and below polycarbonate filters of microchemotaxis chambers demonstrated that rHuTNF-alpha and rHuTNF-beta stimulated both chemotactic and chemokinetic responses by PMN. Additional studies demonstrated that 1 X 10(-8) mol/L rHuTNF-alpha and 3 X 10(-9) mol/L rHuTNF-beta (which represents 10(4) U/mL of each cytokine) were similar in their ability to induce superoxide production by PMNs; however, at ten- to 100-fold lower molar concentrations (10(3) and 10(2) units), rHuTNF-alpha was significantly more active than rHuTNF-beta. At the doses tested, both cytokines were less active than phorbol myristate acetate at stimulating O2- release. The results demonstrate that rHuTNF- alpha and rHuTNF-beta differ quantitatively but not qualitatively in their effects on PMN functions in vitro and suggest that rHuTNF-beta may be less toxic than rHuTNF-alpha in vivo.     

Student quality-of-life declines during third year surgical clerkship

INTRODUCTION: Choosing surgery as a career is declining among U.S. medical students. The 8-wk third year surgery clerkship at our institution can be an intense learning experience, and we hypothesized that during this clerkship medical student quality-of-life would drop significantly from baseline, and that this drop would be greater among certain subgroups, such as women students not interested in pursuing a surgical career, and those who place a high value on a controllable lifestyle. METHODS: At clerkship orientation (baseline), students were asked to complete a survey that measured quality-of-life on an 84-point scale, and depression on a 40-point scale. The quality-of-life scale was composed of select questions from the Medical Outcomes Study, and the Harvard Department of Psychiatry/NDSD brief screening instrument was used to measure depression. Students were also asked the typical number of hours they slept per night. Demographics, attitude toward a controllable lifestyle, and top three specialties of interest were also gathered at baseline. On week 6 of the clerkship, students were surveyed on the same quality-of -life and depression scales, and asked average hours of sleep per night for the previous week. RESULTS: From June 2005 through December 2006, 143 of 177 (81%) students agreed to participate, and after exclusions for missing data, 137 students were included in the analysis. Sixty-nine students were women (51%), and the average age was 25.8 (sd 2.6). Mean quality-of-life at baseline was 57.0 (sd 11.3) and at week 6 was 50.4 (sd 10.1) representing a statistically significant average decline of 6.6 points (P < 0.0001). Mean depression at baseline was 14.4 (sd 3.8) and at week 6 was 15.1 (sd 3.6), representing a small but significant average decline of 0.7 points (P = 0.0155). Mean sleep at baseline was 6.3 h/night (sd 0.9) and at week 6 was 5.7 h/night (sd 1.2), representing a statistically significant average decline of 0.6 h/night (P < 0.0001). Declines were similar on all outcomes between men versus women, those who ranked surgery in their top three career choices versus those who did not, and those who ranked controllable lifestyle as "very important" versus all other categories. CONCLUSION: Quality-of-life and sleep declines and depression increases significantly in third-year medical students from orientation to week 6 of their surgery clerkship at our institution. We look forward to studying quality-of-life on other clerkships for comparison, assessing whether the magnitude of this decline in quality-of-life predicts students avoiding a future career in surgery, and testing interventions to prevent this decline in quality-of-life during the clerkship.     

Evaluation of a culturally adapted cognitive behavior therapy-based,third-wave therapy manual

BACKGROUND Recommendations for psychotherapy have evolved over the years, with cognitive behavioral therapy(CBT) taking precedence since its inception within clinical guidelines in the United Kingdom and United States. The use of CBT for severe mental illness is now more common globally.AIM To investigate the feasibility and acceptability of a culturally adapted, CBT-based, third-wave therapy manual using the Comprehend, Cope, and Connect approach with individuals from a diverse population prese...     

Influence of accurate and inaccurate ‘split-time’ feedback upon 10-mile time trial cycling performance

The objective of the study is to examine the impact of accurate and inaccurate ‘split-time’ feedback upon a 10-mile time trial (TT) performance and to quantify power output into a practically meaningful unit of variation. Seven well-trained cyclists completed four randomised bouts of a 10-mile TT on a SRM™ cycle ergometer. TTs were performed with (1) accurate performance feedback, (2) without performance feedback, (3) and (4) false negative and false positive ‘split-time’ feedback showing performance 5% slower or 5% faster than actual performance. There were no significant differences in completion time, average power output, heart rate or blood lactate between the four feedback conditions. There were significantly lower (p < 0.001) average [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} (ml min⁻¹) and [(V)\dot]\textE \dot{V}{\text{E}}  (l min⁻¹) scores in the false positive (3,485 ± 596; 119 ± 33) and accurate (3,471 ± 513; 117 ± 22) feedback conditions compared to the false negative (3,753 ± 410; 127 ± 27) and blind (3,772 ± 378; 124 ± 21) feedback conditions. Cyclists spent a greater amount of time in a ‘20 watt zone’ 10 W either side of average power in the negative feedback condition (fastest) than the accurate feedback (slowest) condition (39.3 vs. 32.2%, p < 0.05). There were no significant differences in the 10-mile TT performance time between accurate and inaccurate feedback conditions, despite significantly lower average [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} and [(V)\dot]\textE \dot{V}{\text{E}} scores in the false positive and accurate feedback conditions. Additionally, cycling with a small variation in power output (10 W either side of average power) produced the fastest TT. Further psycho-physiological research should examine the mechanism(s) why lower [(V)\dot]\textO₂ \dot{V}{\text{O}}_{2} and [(V)\dot]\textE \dot{V}{\text{E}} scores are observed when cycling in a false positive or accurate feedback condition compared to a false negative or blind feedback condition.     

The place of premedication in pediatric practice

Behind the multiple arguments for and against the use of premedication, sedative drugs in children is a noble principle that of minimizing psychological trauma related to anesthesia and surgery. However, several confounding factors make it very difficult to reach didactic evidence-based conclusions. One of the key confounding issues is that the nature of expectations and responses for both parent and child vary greatly in different environments around the world. Studies applicable to one culture and to one hospital system (albeit multicultural) may not apply elsewhere. Moreover, the study of hospital-related distress begins at the start of the patient's journey and ends long after hospital discharge; it cannot be focused completely on just the moment of anesthetic induction. Taking an example from actual practice experience, the trauma caused by the actual giving of a premedication to a child who absolutely does not want it and may struggle may not be recorded in a study but could form a significant component of overall effect and later psychological pathology. Clearly, attitudes by health professionals and parents to the practice of routine pediatric premedication, vary considerably, often provoking strong opinions. In this pro–con article we highlight two very different approaches to premedication. It is hoped that this helps the reader to critically re-evaluate a practice, which was universal historically and now in many centers is more selective.