Increased leukotriene and prostaglandin release,and overactivity in the chronically ischemic bladder

PURPOSE: Chronic ischemia has been shown to alter bladder contractility. We studied the roles of cyclooxygenase (COX) and lipoxygenase products in ischemia induced bladder overactivity in the rabbit. MATERIALS AND METHODS: A total of 28 male New Zealand White rabbits were divided into 2 groups. In group 1 atherosclerotic occlusion of the iliac arteries was induced by balloon endothelial injury, followed by a short period of a high cholesterol diet. Group 2 received a regular diet alone. After 12 weeks blood flow measurements and cystometry were performed. Bladder tissues were processed for enzyme immunoassay of leukotrienes and prostaglandins (PGs), Western blotting of COX and lipoxygenase, isometric tension measurement and histology. RESULTS: Atherosclerotic occlusion of the iliac arteries significantly decreased bladder blood flow. Moderate ischemia caused bladder overactivity, while severe ischemia inhibited bladder contractions. Ischemia increased leukotriene B4, E4 and C4 release by 141%, 132% and 254%, and increased PG F2alpha and thromboxane A2 release by 95% and 93%, respectively, although it did not alter PG E2 release. Western blotting showed increased 5-lipoxygenase, COX-1 and COX-2 protein levels in ischemic bladder tissues. Moderate ischemia increased bladder smooth muscle contraction in response to carbachol and electrical field stimulation. Tissue treatment with the COX inhibitor indomethacin significantly increased control tissue contraction but had no effect on ischemic tissues. Treatment with the 5-lipoxygenase inhibitor REV5901 abolished this effect of indomethacin in control tissues. Treatment with REV5901 significantly decreased the contraction of ischemic tissues but had no significant effect on control tissues. The effect of indomethacin plus REV5901 was similar to the effect of REV5901 alone. Histology showed urothelial thickening and mild fibrosis in the moderately ischemic bladder. CONCLUSIONS: Chronic ischemia increased bladder 5-lipoxygenase, and COX-1 and COX-2 protein expression, and altered leukotriene and PG production. Treatment with COX and lipoxygenase inhibitors produced completely different effects in the ischemic bladder compared with the control bladder. Functional changes in the ischemic bladder were concurrent with structural changes in the urothelium. PGs modulate smooth muscle contractility in the healthy bladder. However, under ischemic conditions leukotrienes dominate bladder tone and appear to have a leading role in increased smooth muscle contraction and bladder overactivity.     

MLN0905, a Small-Molecule PLK1 Inhibitor, Induces Antitumor Responses in Human Models of Diffuse Large B-cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin lymphomas, accounting for up to 30% of all newly diagnosed lymphoma cases. Current treatment options for this disease are effective, but not always curative; therefore, experimental therapies continue to be investigated. We have discovered an experimental, potent, and selective small-molecule inhibitor of PLK1, MLN0905, which inhibits cell proliferation in a broad range of human tumor cells including DLBCL cell lines. In our report, we explored the pharmacokinetic, pharmacodynamic, and antitumor properties of MLN0905 in DLBCL xenograft models grown in mice. These studies indicate that MLN0905 modulates the pharmacodynamic biomarker phosphorylated histone H3 (pHisH3) in tumor tissue. The antitumor activity of MLN0905 was evaluated in three human subcutaneous DLBCL xenograft models, OCI LY-10, OCI LY-19, and PHTX-22L (primary lymphoma). In each model, MLN0905 yielded significant antitumor activity on both a continuous (daily) and intermittent dosing schedule, underscoring dosing flexibility. The antitumor activity of MLN0905 was also evaluated in a disseminated xenograft (OCI LY-19) model to better mimic human DLBCL disease. In the disseminated model, MLN0905 induced a highly significant survival advantage. Finally, MLN0905 was combined with a standard-of-care agent, rituximab, in the disseminated OCI LY-19 xenograft model. Combining rituximab and MLN0905 provided both a synergistic antitumor effect and a synergistic survival advantage. Our findings indicate that PLK1 inhibition leads to pharmacodynamic pHisH3 modulation and significant antitumor activity in multiple DLBCL models. These data strongly suggest evaluating PLK1 inhibitors as DLBCL anticancer agents in the clinic. Mol Cancer Ther; 11(9); 2045-53. ?2012 AACR.     

Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation

The tumour suppressor gene PTEN , which maps to 10q23.3 and encodes a 403 amino acid dual specificity phosphatase (protein tyrosine phosphatase; PTPase), was shown recently to play a broad role in human malignancy. Somatic PTEN deletions and mutations were observed in sporadic breast, brain, prostate and kidney cancer cell lines and in several primary tumours such as endometrial carcinomas, malignant melanoma and thyroid tumours. In addition, PTEN was identified as the susceptibility gene for two hamartoma syndromes: Cowden disease (CD; MIM 158350) and Bannayan-Zonana (BZS) or Ruvalcaba-Riley-Smith syndrome (MIM 153480). Constitutive DNA from 37 CD families and seven BZS families was screened for germline PTEN mutations. PTEN mutations were identified in 30 of 37 (81%) CD families, including missense and nonsense point mutations, deletions, insertions, a deletion/insertion and splice site mutations. These mutations were scattered over the entire length of PTEN , with the exception of the first, fourth and last exons. A 'hot spot' for PTEN mutation in CD was identified in exon 5 that contains the PTPase core motif, with 13 of 30 (43%) CD mutations identified in this exon. Seven of 30 (23%) were within the core motif, the majority (five of seven) of which were missense mutations, possibly pointing to the functional significance of this region. Germline PTEN mutations were identified in four of seven (57%) BZS families studied. Interestingly, none of these mutations was observed in the PTPase core motif. It is also worthy of note that a single nonsense point mutation, R233X, was observed in the germline DNA from two unrelated CD families and one BZS family. Genotype-phenotype studies were not performed on this small group of BZS families. However, genotype-phenotype analysis inthe group of CD families revealed two possible associations worthy of follow-up in independent analyses. The first was an association noted in the group of CD families with breast disease. A correlation was observed between the presence/absence of a PTEN mutation and the type of breast involvement (unaffected versus benign versus malignant). Specifically and more directly, an association was also observed between the presence of a PTEN mutation and malignant breast disease. Secondly, there appeared to be an interdependent association between mutations upstream and within the PTPase core motif, the core motif containing the majority of missense mutations, and the involvement of all major organ systems (central nervous system, thyroid, breast, skin and gastrointestinal tract). However, these observations would need to be confirmed by studying a larger number of CD families.      

Modalities of Empowerment and Strengthening of Ex-servicemen

Background

Older people including ex-servicemen (ESM) in India are left to fend for themselves due to nuclear family system. Most children are not staying with them due to reasons such as acquiring of education or employment at distant places. These factors, coupled with deteriorating health with advancing age, change in value system and attitude amongst children who give more importance to materialism, it was felt necessary to find modalities to empower and strengthen ESM by available methods of including progressive weight training, yoga and meditation.

Methods

An interventional “Before and After” study was planned for a period of three months for in-patient ESM of a military hospital for common lifestyle diseases namely stroke, diabetes, senile depression, acute myocardial infarction and hypertension. Data of anthropometry, laboratory investigations and Hamilton rating scale for depression (HRSD) were taken before the study. These cases were then subjected to interventions (progressive weight training and spiritual health enhancement by yoga with meditation for three months) followed by same measurements again.

Result

Statistically significant differences were observed before and after study with respect to pulse, respiratory rate, blood pressure, blood glucose, total cholesterol, low density lipoproteins (LDL), very low density lipoproteins (VLDL) and Hamilton depression score (p<0.05). The sleep pattern, sense of well being and posture while sitting to standing and walking with degree of support (stick/other person''s help) improved considerably after the interventions.

Conclusion

ESM are recommended to be trained much before retirement on progressive weight training and yoga in regimental centre/station institute. Provision to be made in existing ex-servicemen contributory health scheme (ECHS) polyclinics for employment of part time trainers for weight training and yoga. The physical and spiritual strengthening results in better capability to deal with old age and its problems.Key Words: Ex-servicemen, Progressive weight training, Yoga, Spiritual health     

BRCA2与LIM结构域蛋白FHL2的相互作用

目的：应用酵母双杂交方法筛选BRCA2相互作用蛋白编码基因，验证其相互作用并研究其功能联系。方法：以BRCA2基因3′端片段构建酵母双杂交质粒，筛选正常人乳腺上皮细胞cDNA库，获得编码相互作用蛋白的基因，采用免疫共沉淀、哺乳细胞双杂交和荧光酶测定等方法进一步验证蛋白间相互作用和功能联系．结果：采用酵母双杂交系统筛选，获得了多个编码BRCA2相互作用蛋白的基因，其中包括已知的FHL2蛋白；免疫共沉淀和哺乳动物细胞双杂交试验显示BRCA2和FHL2在体内特异性结合，并证实FHL2在体内形成同源二聚体；转录活性分析发现BRCA2与FHL2有协同转录激活作用。结论：发现BRCA2与FHL2蛋白间相互作用和功能联系，为BRCA2功能研究提供了新的方向。     

Response from lieberman and colleagues

Respond on comments on Lieberman's article: Cyclosiloxanes Produce Fatal Liver and Lung Damage in Mice. Environ Health Perspect 107:161-165     

Risk Factors and Hospitalization Costs of Dementia Patients: Examining Race and Gender Variations

Aims:

To examine the variation in risk factors and hospitalization costs among four elderly dementia cohorts by race and gender.

Materials and Methods:

The 2008 Tennessee Hospital Discharged database was examined. The prevalence, risk factors and cost of inpatient care of dementia were examined for individuals aged 65 years and above, across the four race gender cohorts - white males (WM), black males (BM), white females (WF), and black females (BF).

Results:

3.6% of patients hospitalized in 2008 had dementia. Dementia was higher among females than males, and higher among blacks than whites. Further, BF had higher prevalence of dementia than WF; similarly, BM had a higher prevalence of dementia than WM. Overall, six risk factors were associated with dementia for the entire sample including HTN, DM, CKD, CHF, COPD, and stroke. These risk factors varied slightly in predicting dementia by race and gender. Hospital costs were 14% higher among dementia patients compared to non-dementia patients.

Conclusions:

There exist significant race and gender disparities in prevalence of dementia. A greater degree of co-morbidity, increased duration of hospital stay, and more frequent hospitalizations, may result in a higher cost of inpatient dementia care. Aggressive management of risk factors may subsequently reduce stroke and cost of dementia care, especially in the black population. Race and gender dependent milestones for management of these risk factors should be considered.