Patients with Lynch Syndrome Mismatch Repair Gene Mutations Are at Higher Risk for Not Only Upper Tract Urothelial Cancer but Also Bladder Cancer

Background

Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse.

Objective

To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations.

Design, setting, and participants

Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2).

Outcome measurements and statistical analysis

Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors.

Results and limitations

Eleven of 177 patients with MSH2 mutations (6.21%, p < 0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p > 0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p < 0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias.

Conclusions

LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.     

Separate effects of sex hormones and sex chromosomes on brain structure and function revealed by high-resolution magnetic resonance imaging and spatial navigation assessment of the Four Core Genotype mouse model

Males and females exhibit several differences in brain structure and function. To examine the basis for these sex differences, we investigated the influences of sex hormones and sex chromosomes on brain structure and function in mice. We used the Four Core Genotype (4CG) mice, which can generate both male and female mice with XX or XY sex chromosome complement, allowing the decoupling of sex chromosomes from hormonal milieu. To examine whole brain structure, high-resolution ex vivo MRI was performed, and to assess differences in cognitive function, mice were trained on a radial arm maze. Voxel-wise and volumetric analyses of MRI data uncovered a striking independence of hormonal versus chromosomal influences in 30 sexually dimorphic brain regions. For example, the bed nucleus of the stria terminalis and the parieto-temporal lobe of the cerebral cortex displayed steroid-dependence while the cerebellar cortex, corpus callosum, and olfactory bulbs were influenced by sex chromosomes. Spatial learning and memory demonstrated strict hormone-dependency with no apparent influence of sex chromosomes. Understanding the influences of chromosomes and hormones on brain structure and function is important for understanding sex differences in brain structure and function, an endeavor that has eventual implications for understanding sex biases observed in the prevalence of psychiatric disorders.     

Barriers and facilitators of evidence-based practice perceived by behavioral science health professionals

Progress in implementing evidence-based behavioral practices has been slow. A qualitative study was performed to characterize the major facilitators and barriers to evidence-based practice (EBP) perceived by behavioral professionals. Members of professional e-mail listservs were queried and 84 barriers and 48 facilitators were nominated by 37 respondents. Thematic analysis revealed seven themes to describe both barriers and facilitators: (a) training, (b) attitudes, (c) consumer demand, (d) logistical considerations, (e) institutional support, (f) policy, and (g) evidence. Most frequently cited barriers included negative attitudes about EBP and lack of training. Barriers also reflected confusion between EBP and the products of EBP (i.e., empirically supported treatments [ESTs]). Main facilitators included a growing evidence base. Results suggest that uptake of EBP may be facilitated by education and training.     

The effects of isoproterenol on abnormal electrical and contractile activity and diastolic calcium are attenuated in myocytes from aged Fischer 344 rats

We investigated whether the age-related decrease in sensitivity of the heart to catecholamines was accompanied by changes in Ca(2+) homeostasis and abnormal electrical and contractile activity caused by beta-adrenergic receptor (beta-AR) stimulation. Ventricular myocytes were isolated from young adult (3 months) and aged (24 months) male Fischer 344 rats. Unloaded cell shortening was measured in field-stimulated myocytes (2Hz, 37 degrees C); membrane currents and action potentials were measured with microelectrodes. Contractile responses to the non-selective beta-AR agonist, isoproterenol were significantly decreased in aged myocytes compared to younger myocytes and aged myocytes were less sensitive to isoproterenol. In contrast, Ca(2+) transients measured simultaneously with contractions were similar between groups. Isoproterenol increased sarcoplasmic reticulum Ca(2+) stores in both groups, but the increase was larger in aged cells. However, signs of Ca(2+) overload induced by isoproterenol were reduced with age. Diastolic Ca(2+) accumulation, contracture and the incidences of transient inward current, oscillatory afterpotentials (OAPs), aftertransients and aftercontractions induced by isoproterenol also were reduced with age. These results demonstrate that aged myocytes exhibit fewer signs of Ca(2+) overload in response to isoproterenol than young adult myocytes. These age-related changes in intracellular Ca(2+) may protect the aging heart against induction of arrhythmias initiated by OAPs.(1).     

脑血管病偏瘫上肢的康复治疗

脑血管病偏瘫上肢的恢复较下肢困难,我们必须尽早开始早期康复治疗,保持肢体功能位,定期更换体位和被动运动,以预防感染、褥疮和深静脉炎;急性期过后,尽早开始功能锻炼,在康复治疗中避免新的损伤。在恢复后期,随着上肢功能的恢复,要进行精细技巧和协调的动作训练,以进一步促进肢体神经功能的恢复。实践证明:针灸、音乐电疗和温泉疗法,对脑血管病偏瘫有较好的疗效。此外还应始终坚持心理康复、理疗和对各种慢性病的治疗。     

Monoclonal antibodies recognizing epitopes on the extracellular face and intracellular N-terminus of the human erythrocyte anion transporter (band 3) and their application to the analysis of South East Asian ovalocytes

This report describes the production and characterization of 13 rodent monoclonal antibodies to the human erythrocyte anion transport protein AE1 (syn. band 3). Eleven antibodies (4 murine and 7 rat) recognize epitopes dependent on the integrity of the third extracellular loop of the protein. Two antibodies (1 murine and 1 rat) recognize epitopes on the N-terminal cytoplasmic domain. Quantitative binding studies using radioiodinated IgG and Fab fragments of antibodies to extracellular epitopes on AE1 ranged from 77,000 to 313,000 (IgG) and from 241,000 to 772,000 (Fab) molecules bound at saturation. The results indicate that the epitopes recognized by different antibodies vary in their accessibility and suggest that there is heterogeneity in the organization of individual AE1 molecules in the red blood cell membrane. Quantitative binding studies on South East Asian ovalocytes using several antibodies to AE1 and an anti-Wrb show a marked reduction in the number of antibody molecules bound at saturation. These results are consistent with the existence of highly cooperative interactions between transmembrane domains of AE1 in normal erythrocytes and the disruption of these interactions in the variant AE1 found in South East Asian ovalocytes.     

Echocardiographic test of dipyridamole in recognition of coronary artery disease]

To assess the feasibility, safety and usefulness of dipyridamole stress echocardiography for the detection of coronary artery disease we evaluated 194 patients (124 men, 70 women) with effort chest pain. All patients underwent electrocardiographic submaximal bicycle exercise testing and 2-dimensional echocardiography after dipyridamole injection. Echocardiographic test was considered positive when new wall motion abnormalities were observed after dipyridamole i.v. injection (0.56 mg/kg b.m.). Sensitivity and specificity of electrocardiographic exercise test and dipyridamole stress echocardiography were assessed in 37 persons who underwent selective coronary angiography. The sensitivity and specificity of dipyridamole stress echocardiography, were respectively 85.0% and 91.7% and were higher than those of exercise electrocardiography. 2-dimensional echocardiography after dipyridamole injection is a well tolerated, feasible and effective test in the diagnosis of coronary artery disease.     

Peak oxygen consumption and the minute ventilation/carbon dioxide production relation slope in morbidly obese men and women: influence of subject effort and body mass index

The authors evaluated the minute ventilation/carbon dioxide production relation (VE/VCO2 slope) as a complementary measure to peak oxygen consumption (peak VO2) in 76 patients (mean +/- SD age = 44.3+/-10.8 years, 69.7% female) with morbid obesity (mean +/- SD body mass index [BMI] = 49.4+/-7.0 kg/m(2)), as it is not limited by effort. Nearly one-half (43%) of the patients achieved a peak respiratory exchange ratio <1.10. Mean peak VO2 and VE/VCO2 slope were 17.0+/-3.7 mL/kg/min and 27.8+/-4.0, respectively. Peak VO2 correlated with BMI (r=-0.45, P<.0001), while VE/VCO2 slope did not (r=-0.04, P=.73). There was a linear trend for declining mean peak VO2 (P=.001) but not for VE /VCO2 slope (P=.59) with increasing BMI quintiles. The VE/VCO2 slope is an effort-independent measure that is also independent of BMI and may serve as an adjunctive cardiorespiratory variable when evaluating morbidly obese men and women.