The cholinomimetic agent carbachol induces headache in healthy subjects

The parasympathetic nervous system is likely to be involved in migraine pathogenesis. We hypothesized that the cholinomimetic agonist carbachol would induce headache and vasodilation of cephalic and radial arteries. Carbachol (3 µg/kg) or placebo was randomly infused into 12 healthy subjects in a double-blind crossover study. Headache was scored on a verbal rating scale from 0–10. Velocity in the middle cerebral artery (V_MCA) and diameter of the superficial temporal artery (STA) and radial artery (RA) were recorded. Nine participants developed headache after carbachol compared with three after placebo. The area under the curve for headache was increased after carbachol compared with placebo both during infusion (0–30 min) ( P  = 0.042) and in the postinfusion period (30–90 min) ( P  = 0.027). Carbachol infusion caused a drop in V_MCA ( P  = 0.003) and an increase in STA diameter ( P  = 0.006), but no increase in the RA diameter ( P  = 0.200). In conclusion, the study demonstrated that carbachol caused headache and dilation of cephalic arteries in healthy subjects.     

The development of an intervention programme to reduce whole-body vibration exposure at work induced by a change in behaviour: a study protocol

Background  

Whole body vibration (WBV) exposure at work is common and studies found evidence that this exposure might cause low back pain (LBP). A recent review concluded there is a lack of evidence of effective strategies to reduce WBV exposure. Most research in this field is focussed on the technical implications, although changing behaviour towards WBV exposure might be promising as well. Therefore, we developed an intervention programme to reduce WBV exposure in a population of drivers with the emphasis on a change in behaviour of driver and employer. The hypothesis is that an effective reduction in WBV exposure, in time, will lead to a reduction in LBP as WBV exposure is a proxy for an increased risk of LBP.     

Tobacco use and prostate cancer in Blacks and Whites in the United States

Prostate cancer occurs more frequently in Blacks than Whites in the United States. A population-based case-control study which investigated the association between tobacco use and prostate cancer risk was carried out among 981 pathologically confirmed cases (479 Blacks, 502 Whites) of prostate cancer, diagnosed between 1 August 1986 and 30 April 1989, and 1,315 controls (594 Blacks, 721 Whites). Study subjects, aged 40 to 79 years, resided in Atlanta (GA), Detroit (MI), and 10 counties in New Jersey, geographic areas covered by three, population-based, cancer registries. No excesses in risk for prostate cancer were seen for former cigarette smokers, in Blacks (odds ratio [OR]=1.1, 95 percent confidence interval [CI]=0.7–1.5) and in Whites (OR=1.2, CI=0.9–1.6), or for current cigarette smokers, in Blacks (OR=1.0, CI=0.7–1.4) and in Whites (OR=1.2, CI=0.8–1.7). Increases in risk were noted for smokers of 40 or more cigarettes per day, among former (OR=1.4, CI=1.0–1.5) and current (OR=1.5, CI=1.0–2.4) smokers. Duration of cigarette use and cumulative amount of cigarette use (pack-years) were not associated with prostate cancer risk for Blacks or Whites. By age, only the youngest subjects, aged 40 to 59 years, showed excess risk associated with current (OR=1.5, CI=1.0–2.3) and former (OR=1.7, CI=1.1–2.6) use of cigarettes, but there were no consistent patterns in this group according to amount or duration of smoking. Risks also were not elevated for former or current users of pipes, cigars, or chewing tobacco, but the risk associated with current snuff use was OR=5.5 (CI=1.2–26.2). This subgroup finding may have been due to chance. The results of the present study may be consistent with a small excess risk for prostate cancer associated with tobacco use, but the lack of consistent findings in population subgroups and the lack of a clear dose-response relationship argue more strongly that no causal association exists. The data do not indicate that the Black-White difference in prostate cancer risk is related to tobacco use.This research was performed under contracts: NO1-CP-51090, NO1-CN-0522, NO1-CP-51089, NO1-CN-31022, NO1-CP-51092, and NO1-CN-5227.     

Serum lycopene,other serum carotenoids,and risk of prostate cancer in US Blacks and Whites

Epidemiologic studies investigating the relation between individual carotenoids and risk of prostate cancer have produced inconsistent results. To further explore these associations and to search for reasons prostate cancer incidence is over 50% higher in US Blacks than Whites, the authors analyzed the serum levels of individual carotenoids in 209 cases and 228 controls in a US multicenter, population-based case-control study (1986-1989) that included comparable numbers of Black men and White men aged 40-79 years. Lycopene was inversely associated with prostate cancer risk (comparing highest with lowest quartiles, odds ratio (OR) = 0.65, 95% confidence interval (CI): 0.36, 1.15; test for trend, p = 0.09), particularly for aggressive disease (comparing extreme quartiles, OR = 0.37, 95% CI: 0.15, 0.94; test for trend, p = 0.04). Other carotenoids were positively associated with risk. For all carotenoids, patterns were similar for Blacks and Whites. However, in both the controls and the Third National Health and Nutrition Examination Survey, serum lycopene concentrations were significantly lower in Blacks than in Whites, raising the possibility that differences in lycopene exposure may contribute to the racial disparity in incidence. In conclusion, the results, though not statistically significant, suggest that serum lycopene is inversely related to prostate cancer risk in US Blacks and Whites.     

贴报-P2临床毒理学、药理学和疗效研究

5-Flourouracil（5-FU） is one of well known anti-cancer drugs, but its toxicity in normal lymphocytes remains a major problem in chemotherapy. The eastern traditional drug, Bupleuri radix（BR）, has been used for the treatment of liver diseases and contains series of triterpene saponins.     

Nomograms provide improved accuracy for predicting survival after radical cystectomy.

AIMS: To develop multivariate nomograms that determine the probabilities of all-cause and bladder cancer-specific survival after radical cystectomy and to compare their predictive accuracy to that of American Joint Committee on Cancer (AJCC) staging. METHODS: We used Cox proportional hazards regression analyses to model variables of 731 consecutive patients treated with radical cystectomy and bilateral pelvic lymphadenectomy for bladder transitional cell carcinoma. Variables included age of patient, gender, pathologic stage (pT), pathologic grade, carcinoma in situ, lymphovascular invasion (LVI), lymph node status (pN), neoadjuvant chemotherapy (NACH), adjuvant chemotherapy (ACH), and adjuvant external beam radiotherapy (AXRT). Two hundred bootstrap resamples were used to reduce overfit bias and for internal validation. RESULTS: During a mean follow-up of 36.4 months, 290 of 731 (39.7%) patients died; 196 of 290 patients (67.6%) died of bladder cancer. Actuarial all-cause survival estimates were 56.3% [95% confidence interval (95% CI), 51.8-60.6%] and 42.9% (95% CI, 37.3-48.4%) at 5 and 8 years after cystectomy, respectively. Actuarial cancer-specific survival estimates were 67.3% (62.9-71.3%) and 58.7% (52.7-64.2%) at 5 and 8 years, respectively. The accuracy of a nomogram for prediction of all-cause survival (0.732) that included patient age, pT, pN, LVI, NACH, ACH, and AXRT was significantly superior (P=0.001) to that of AJCC staging-based risk grouping (0.615). Similarly, the accuracy of a nomogram for prediction of cancer-specific survival that included pT, pN, LVI, NACH, and AXRT (0.791) was significantly superior (P=0.001) to that of AJCC staging-based risk grouping (0.663). CONCLUSIONS: Multivariate nomograms provide a more accurate and relevant individualized prediction of survival after cystectomy compared with conventional prediction models, thereby allowing for improved patient counseling and treatment selection.     

Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs

The present study applied a receiver operating characteristic (ROC) analysis to assess the role of intraindividual variability of cyclosporin A (CsA) drug exposure in predisposing renal transplant recipients to the occurrence of chronic rejection, as well as to increased health care costs using a resource-based economic analysis. Two hundred and four adult renal transplant recipients were treated with tapering doses of prednisone (Pred) and with a concentration-controlled strategy that selected doses of the olive oil-based formulations of CsA (Sandimmune(R)) that achieved target concentrations based on serial pharmacokinetic profiles. The ROC analysis revealed an inflection point of plots of the coefficient of variation (%CV) of CsA exposure versus the risk of chronic rejection at >/=28.4% for the average concentration (C(av)), i.e., the dosing interval-corrected area under the concentration-time curves, and >/=36% for the trough concentration (C(0)). The incidence of chronic rejection over a period of 5 yr was 24% among the less variable (LV) versus 40% among the variable (V) cohort. The economic analysis revealed that the total mean facility and physician costs per patient were $48,789 versus $60,998, respectively (P < 0.01). The degree of variability displayed by any individual could only be predicted by serial measurements of CsA concentrations, and not by demographic features, laboratory determinations, clinical characteristics, individual or mean values of any observed CsA concentration, or other pharmacokinetic parameters calculated following a single drug exposure. Thus, strategies that reduce intrapatient variability of CsA exposure over time may lead to reductions in chronic allograft loss and in treatment costs.     

Correlation of hemodynamic impact and morphologic degree of renal artery stenosis in a canine model

In a noninvasive comprehensive magnetic resonance (MR) examination, the morphologic degree of renal artery stenosis was correlated to corresponding changes in renal artery flow dynamics. Different degrees of stenosis were created with the use of a chronically implanted inflatable arterial cuff in seven dogs. For each degree of stenosis, an ultrafast three-dimensional gadolinium MR angiography with high spatial resolution was performed, followed by cardiac-gated MR flow measurements with high temporal resolution for determination of pulsatile flow profiles and mean flow. Flow was also measured by a chronically implanted flow probe. In three of the dogs, trans-stenotic pressure gradients (DeltaP) also were measured via implanted catheters. Five different degrees of stenosis could be differentiated in the MR angiograms (0%, 30%, 50%, 80%, >90%). The MR flow data agreed with the flow probe within +/-20%. Stenoses between 30 and 80% gradually reduced the early systolic peak (Max(1)) of the flow profile but only minimally affected the midsystolic peak (Max(2)) or mean flow. Stenoses of more than 90% significantly depressed mean flow by more than 50%. The ratio between Max(1) and Max(2) (Rmax(1/2)) gradually fell with the degree of stenosis. The onset of significant mean flow reduction and DeltaP was indicated by a drop of Rmax(1/2) below 1 to 1.2. Thus, the analysis of high-resolution flow profiles allows detection of early hemodynamic changes even at degrees of stenoses not associated with a reduction of mean flow. Rmax(1/2) allows differentiation of the grade of hemodynamic compromise for a given morphologic stenosis independent of mean flow in a single comprehensive MR examination.     

Vena-mesenterica-superior-Syndrom – eine Duodenalstenose, bedingt durch eine atypisch verlaufende V. mesenterica superior

Cases in which mesenteric vessels lead to stenosis of the duodenum are very rare. Several cases have been reported of patients suffering from stenosis of the last third of the duodenum due to a malpositioning of the superior mesenteric artery or the left renal vein. We report a 78-year-old patient who was suffering from dyspepsia, pain in the upper abdominal region, nausea, and vomiting. The medical history revealed that the patient had undergone a subtotal gastrectomy according to Billroth II at the age of 19 because of similar complaints. In the last 20 years the patient had to be laparotomized several times for ileus of the small intestine. Now the patient presented abdominal complaints with nausea and pressure in the upper abdominal region. Assuming an efferent-loop syndrome and adhesions, the patient was laparotomized. We discovered malpositioning of the superior mesenteric vein, leading to stenosis of the superior part of the duodenum. In fact, 60 years ago surgeons performed a duodenojejunostomy, circumvening the stenosis of the duodenum. With a "delay of 60 years", we then performed a subtotal gastrectomy according to Billroth II. The postoperative course was uneventful; the patient had no complaints and increased in body weight. To our knowledge, this is the first time that a stenosis of the duodenum due to malpositioning of the superior mesenteric vein has been observed.