Expression of cyclin D1 and retinoblastoma protein in Paget’s disease of the vulva and breast: an immunohistochemical study of 108 cases

Aims: Loss of retinoblastoma protein expression and overexpression of cyclin D1 have been implicated in the development and progression of some cancers. Paget’s disease of the vulva (PDV) and Paget’s disease of the breast (PDB) are uncommon conditions and the pathogenesis of these diseases is still unclear. The aim was to examine the expression of the retinoblastoma and cyclin D1 proteins in PDV and PDB and to correlate any differences between PDV and PDB, and in the presence or absence of an underlying carcinoma. Methods and results: Seventy‐two archival cases of PDV including 10 with invasive disease and 36 cases of PDB were evaluated immunohistochemically for the expression of cyclin D1 and retinoblastoma protein. Forty‐four percent (32/72) of cases of PDV showed loss of expression of the retinoblastoma protein, compared with 67% (24/36) of PDB cases. Fifty‐nine percent (41/69) of PDV overexpressed cyclin D1. In PDB, 8% (3/34) overexpressed cyclin D1. There were no significant differences in the expression of retinoblastoma and cyclin D1 in PDV cases with or without underlying invasive disease. There were significant differences between the expression of retinoblastoma (P = 0.03) and cyclin D1 (P < 0.001) in PDV compared with PDB. Conclusions: The differences in the expression of cyclin D1 and retinoblastoma may indicate the differences in the pathogenesis of PDV and PDB.     

The Vermont Diabetes Information System: A Cluster Randomized Trial of a Population Based Decision Support System

BACKGROUND  

Optimal care for patients with diabetes is difficult to achieve in clinical practice.     

Femoral nerve block with ropivacaine or bupivacaine in day case anterior crucial ligament reconstruction

Background/Objective: Our aim was to evaluate analgesia, motor block and pharmacokinetics of ropivacaine 0.2% and 0.75% in a femoral nerve block (FNB) in day case patients for anterior crucial ligament (ACL)‐reconstruction compared with bupivacaine 0.25% and placebo. Methods: Following ethics committee approval and informed consent, 280 patients were randomly allocated to four groups for single‐shot FNB [30 ml ropivacaine 0.2% (group RO2.0), 0.75% (RO7.5), bupivacaine 0.25% (BU2.5) and NaCl 0.9% (NaCl)]. Analgesia (pain scores, primary outcome) and motor block were assessed at 4 h (dismissal) and up to 24 h. Plasma concentration was determined up to 240 min thereafter. Results: Pain scores at 4 h were significantly higher for NaCl 4 (0–8) (median, range) (vs.) BU2.5 2 (0–8), RO2.0 3 (0–9) and RO7.5 2 (0–8) (NS within the LA groups). Patients of the NaCl group needed analgesics significantly more often (93%) within 4 h after surgery vs. 16% of group RO2.0, 19% of group RO7.5 and 19% of group BU2.5. Motor block was significantly increased with all local anesthetics without a significant difference within the LA groups 3 (0–5) in RO2.0, 3 (0–5) in RO7.5 and 3 (0–4) in BU2.5 vs. 0 (0–3) in group NaCl (median (range); scale from 0=full strength to 5=complete paralysis). Peak plasma concentrations differed significantly: RO7.5: 1.4 ± 0.4 (0.73–2.6) [μg/ml, mean ± SD (range)] after 33 ± 14 (10–40) min, RO2.0: 0.6 ± 0.3 (0.13–1.0) after 22+17 (10–60) and BU2.5: 0.3 ± 0.16 (0.05–0.62) at 31 ± 17 (10–60), respectively. Conclusion: FNB for ACL reconstruction with ropivacaine or bupivacaine provided better post‐operative analgesia than placebo without reaching toxic plasma concentrations. Significant motor block was observed after 4 h in all groups including the lowest concentration of ropivacaine but occurred even with placebo.     

Monitoring the retention of a protein antigen in complete Freund's adjuvant, alum, and pluronic F-127 gel formulations by X-ray fluorescence.

Adjuvants function by protecting antigens from rapid degradation or dispersal. The effectiveness of experimental adjuvants can be assessed by measuring antibody titers to the antigen of interest or, less frequently, by evaluating the retention and distribution of antigen at the application site. In this study, we used X-ray fluorescence (XRF) to monitor the release of an iodinated protein (I-bovine serum albumin) from several adjuvant formulations after its subcutaneous injection in rats. The interaction of the tagged antigen with an external Am-241 source leads to the emission of iodine X-rays from the application site; the number of these X-rays is proportional to the concentration of the protein remaining at the injection site. The disappearance of the iodine X-rays, and hence the antigen, from the injection site followed first-order kinetics for all adjuvant formulations tested; mean half-life values were as follows: in 50% Freund's adjuvant, 17.1 +/- 1.1 h; in 4-hour-old 25% Alum, 11.78 +/- 0.08 h; in 4-h-old 50% Alum, 13.2 +/- 2 h; in 3-day-old 50% Alum, 15.8 +/- 1.5 h; and in 240 mg/mL Pluronic F-127, 7.9 +/- 0.7 h. We conclude that XRF is an easy, reliable, noninvasive method to monitor the retention of antigens in these adjuvant solutions.     

幽门螺杆菌对人胃癌MKN45细胞p38MAPK信号转导通路激活作用的研究

背景与目的: 环氧合酶2(cyelooxygenase-2,COX-2)是花生四烯酸转化为前列腺素(prostaglandins,PGs)代谢中重要的限速酶,幽门螺杆菌(Helicobacterpylori,Hp)感染诱导胃黏膜COX-2的过度表达是胃癌发生的重要环节,但Hp感染胃黏膜细胞COX-2表达的机制尚不清楚.本研究旨在揭示Hp对人胃癌MKN45细胞COX-2表达和p38MAPK信号通路的影响,探讨COX-2表达的可能机制.方法: 采用实时荧光定量PCR(real time-PCR)检测Hp标准株NCTC11637感染对人胃痛MKN45细胞COX-2 mRNA转录的影响,Western blot检测坳COX-2蛋白表达的影响和p38MAPK信号通路的激活及其下游因子ATF-2的表达.结果: Hp感染人胃癌MKN45细胞后,COX-2 mRNA的表达明显上调,Hp感染3、6、9、12 h后COX-2 mRNA的表达量分别为正常值的3倍、7.2倍、5.1倍和4.3倍,各时间组COX-2 mRNA表达均明显高于对照组(P＜0.01);Up与MKN45细胞共培养24 h后,COX-2蛋白的表达亦显著增加(P＜0.01).Hp感染MKN45 20 min后,p38MAPK信号通路被激活,60 min达峰值;p38MAPK下游因子ATF-2的表达也明显增加,2 h达高峰,随着作用时间的延长,表达逐渐下降,24 h仍有表达.结论: Hp感染能诱导人胃癌MKN45细胞COX-2的表达;激活p38MAPK信号通路,增加其下游因子ATF-2的表达,可能是其诱导COX-2表达的机制.     

Phase I targeted combination trial of sorafenib and erlotinib in patients with advanced solid tumors.

PURPOSE: Sorafenib and erlotinib are potent, orally administered receptor tyrosine kinase inhibitors with antiproliferative and antiangiogenic activities. Given their inhibitory target profile and efficacy as single agents, the combination of these drugs is of considerable interest in solid malignancies. This study aimed to determine the recommended phase II dose of this targeted combination, their toxicity profile, pharmacokinetic interaction, and preliminary clinical activities. EXPERIMENTAL DESIGN: Sorafenib was administered alone for a 1-week run-in period, and then both drugs were given together continuously, with every 28 days considered as a cycle. Three dose levels were assessed. RESULTS: Seventeen patients with advanced solid tumors received 75 cycles of treatment. The most frequent adverse events of all grades were constitutional and gastrointestinal in nature followed by electrolytes and dermatologic toxicities. Fatigue was the most common adverse event (17 patients; 100%) followed by diarrhea (15 patients; 88%), hypophosphatemia (13 patients; 76%), and acneiform rash (12 patients; 71%). These adverse events were predominantly mild to moderate. The recommended phase II dose of this combination was determined as 400 mg twice daily sorafenib and 150 mg daily erlotinib. Pharmacokinetic analysis revealed no significant effect of erlotinib on the pharmacokinetic profile of sorafenib. Among 15 evaluable patients, 3 (20%) achieved a confirmed partial response and 9 (60%) had stable disease as best response. CONCLUSIONS: Sorafenib and erlotinib are well tolerated and seem to have no pharmacokinetic interactions when administered in combination at their full single-agent recommended doses. This well tolerated combination resulted in promising activity that needs further validation in phase II studies.     

Assessment of condoms as probe covers for transvaginal sonography

PURPOSE: This prospective study assessed the incidence of transvaginal probe contamination and breakage of condoms used to cover those probes during transvaginal sonography. METHODS: Over a 9-month period, 214 women underwent transvaginal sonography with probes that had been coated with gel and then covered with a latex condom. Condom defects were detected after the scans by inspection, by adding hydrogen peroxide, and by filling the condoms with 500 ml of water. After the condoms were removed, the probe was either wiped with a dry tissue (during the first 18 weeks of the study) or wiped first with a dry tissue and then with a 70% isopropyl alcohol wipe. Probe head contamination was assessed by periodic swab sampling and culturing for bacteria and herpes simplex virus. Samples of the sonographic gel also were tested for bacterial contamination at approximately weekly intervals. RESULTS: A total of 217 condoms were used, 3 of which broke and were discarded while being applied to the probe. Two of the 214 condoms used (0.9%) were found upon visual inspection to have perforations. None of the other 212 condoms leaked upon being filled with water; none of the 204 condoms tested with hydrogen peroxide showed bubbles. Only 1 of the 46 probe swab samples was positive for bacteria (Acinetobacter species); none of the 26 probe swab samples cultured for viruses or the 25 gel samples cultured for bacteria were positive. CONCLUSIONS: Condoms used to cover transvaginal probes showed a low rate of perforation. Disinfection of the probe with isopropyl alcohol wipes further reduced the risk of contamination.     

The importance of parents' concerns about their child's development

Parents are often concerned about their child's development, but it is unknown whether concerns indicate actual developmental problems. Pilot studies within 96 families showed that parents' concerns about their children's development took the form of value judgments, could be classified into commonly accepted developmental domains, and related to performance on screening tests. In our study, 100 families seeking pediatric care were asked to list any concerns about their child's development while their children received developmental screening. Eighty percent of the children who failed screening had parents with concerns about articulation, language, fine-motor skills, or global development. Ninety-four percent of the children who passed screening had parents with no concerns or concerns in other developmental areas. The types of concerns parents raised did not vary significantly with level of education, experience in child rearing, or other demographic variables. These results suggest that parental concerns may be a helpful adjunct to standardized developmental screening.