Citations

Abstract The Nijmegen breakage syndrome 1 (NBS1) gene, which participates in DNA double strand break repair, has been postulated to be a susceptibility factor for a number of cancers, including prostate cancer. Numerous mutations have been identified in NBS1, including the founder mutation 657del5. In this study, a number of analyses were done to determine whether mutations in NBS1 are associated with an increased risk for prostate cancer. The frequency of the 657del5 mutation in both familial prostate cancer cases (1,819 affected men among 909 families) and sporadic prostate cancer cases (1,218 affected men) collected from five centers participating in the International Consortium for Prostate Cancer Genetics were compared with that found in 697 normal controls. Seven individuals were identified to carry the mutation among the 3,037 cases screened: four in the familial group (three from one family and one from another) and three in the sporadic cases. The carrier frequency was 0.22% (2 of 909) for the probands and 0.25% (3 of 1,218) for the sporadic cases of prostate cancer. The 657del5 mutation was not detected in either the 293 unaffected members of the prostate cancer families or in the 697 control samples tested. The entire NBS1 gene was also sequenced in 20 of the youngest affected individuals from the Finnish group of familial cases to identify the presence of possible mutations in this high-risk group. One rare (D95N) and one common (E185Q) missense alteration was identified. More detailed analyses of the E185Q polymorphism, along with a third rare variant (R215W), failed to show an association with prostate cancer. Because the 657del5 mutation was absent from the control population, we are unable to determine if this alteration predisposes to prostate cancer. However, our data does suggest that mutations within NBS1, and in particular, 657del5, do not significantly contribute to the overall prostate cancer burden within our patient samples. (Cancer Epidemiol Biomarkers Prev 2006;15(5):935–8)

Abstract Previous studies have suggested that the proinflammatory cytokine, TNF-α, contributes to airway hyperresponsivness by altering airway smooth muscle (ASM) Ca2+ responses to agonist stimulation. The present study examined the effects of TNF-α on Ca2+ influx pathways in cultured human ASM cells (HASMCs). Proteins encoded by the transient receptor potential (TRP) gene family function as channels through which receptor-operated and store-operated Ca2+ entry (SOCE) occur. In the present study, the presence of TRPC1, TRPC3, TRPC4, TRPC5, and TRPC6 mRNA and protein expression was confirmed in cultured HASMCs using RT-PCR and Western blot analysis. TNF-α treatment significantly increased TRPC3 mRNA and protein levels in HASMCs as well as SOCE. TNF-α treatment also increased both the peak and plateau intracellular Ca2+ concentration responses in HASMCs elicited by acetylcholine and bradykinin. The effects of TNF-α treatment on SOCE and agonist-induced intracellular Ca2+ concentration responses were attenuated using small interfering RNA transfection, which knocked down TRPC3 expression. Thus, in inflammatory airway diseases, TNF-α treatment may result in increased myocyte activation due to altered Ca2+ influx pathways. These results suggest that TRPC3 may be an important therapeutic target in inflammatory airway diseases such as asthma and chronic obstructive pulmonary disease.

Abstract Background: Mitochondrial respiratory chain complex (RCC) disorders may occur as commonly as 1 in 8500 individuals. Because of the great variability of phenotypic presentations, measurement of individual RCC enzyme activities is a crucial diagnostic process. Current assay methods are time-consuming and labor-intensive and thus constitute a major impediment to clinical practice. A method with a faster turnaround time would therefore be beneficial. Method: We developed an automated spectrophotometric method for measuring the respiratory chain enzyme activities of complex I, complex II + III, and complex IV with the Hitachi 912, an automated spectrophotometer. Mitochondrial citrate synthase was also determined for normalization of the RCC activities. Results: A blinded method comparison with samples from an external testing center yielded a 91% concordance of interpretations. Mean intraassay imprecision (as CV; n = 20) in a single batch analysis of each RCC was 5.9%. Interassay imprecision, evaluated on 2 samples harvested and analyzed 3 times each, gave mean CVs of 10%–18%. Conclusions: With this automated method, a panel of RCC enzyme activities can be determined in <2 h. In addition, an immunoblot assay using monoclonal antibodies against specific subunits of RCC enzyme complexes can be informative in cases of borderline enzyme activity. Our results suggest that in vitro diagnosis of RCC enzyme deficiencies in skin fibroblasts is an effective alternative to invasive muscle biopsy.

Purpose Patients with newly diagnosed, advanced-stage, follicular grade 1 non-Hodgkin's lymphoma (NHL) are often asymptomatic and can be observed without immediate chemotherapy. The goals of this study were to assess the overall response rate (ORR) to rituximab in this patient population and to determine the time-to-progression (TTP) and time-to-subsequent-chemotherapy (TTSC). Patients and Methods Eligible patients had untreated follicular grade 1 NHL, and measurable stage III/IV disease. Patients received rituximab 375 mg/m2 intravenous weekly × 4 doses and were then followed for response and progression; no maintenance therapy was provided. Results Thirty-seven patients were accrued; one patient was ineligible. The median age was 59 years (range, 29 to 83 years). Six patients (18%) had elevated lactate dehydrogenase levels. The ORR was 72%, with 36% complete remissions. Fourteen (39%) of 36 patients remain in unmaintained remission, two died without disease progression, and three died with disease progression. Twenty (56%) of 36 patients have disease progression. The median TTP was 2.2 years (95% CI, 1.3 to not yet reached). Eighteen patients have subsequently been treated with chemotherapy, with a median TTSC of 2.3 years (95% CI, 1.6 to not yet reached). Patients with a high lactate dehydrogenase level had a lower ORR of 33% and a short TTP of only 6 months. Conclusion Rituximab can be safely administered to patients with advanced-stage follicular grade 1 NHL with efficacy and minimal toxicity. This therapy is highly active and offers an acceptable alternative to observation in this patient population. Patients with high LDH should not be considered for rituximab monotherapy.

Markers of inflammation are predictive of cardiovascular events but their association with atherosclerotic burden remains poorly defined. We hypothesized that markers of inflammation, including C-reactive protein (CRP), white blood cell (WBC) count, and lipoprotein-associated phospholipase A2 (Lp-PLA2), would be associated with the ankle-brachial index (ABI), a marker of atherosclerotic burden. Subjects were 247 patients referred for lower extremity arterial evaluation to the non-invasive vascular laboratory excluding those with active infection or lower extremity revascularization within the previous year. ABI was measured at two sites in both legs and the lowest of four measurements was used in the analyses. CRP was measured by a high-sensitivity immunoturbidimetric assay and Lp-PLA2 was measured by ELISA. The mean patient age was 68±11 years, and 54% were men. Mean ABI was 0.84-0.31 and 49% had an ABI < 0.9. Age, hypertension, fasting plasma glucose, and ‘ever’ smoking were independently associated with the ABI. Spearman correlation coefficients of inflammatory markers with the ABI were: CRP (r 1/4-0.15, p 1/4-0.02), WBC count (r 1/4-0.27, p 1/4-0.001), and Lp-PLA2 (r 1/4-0.09, p 1/4-0.21). In a multiple regression model that included conventional risk factors and statin use, CRP and WBC count were no longer significantly associated with ABI, whereas Lp-PLA2 was a borderline-significant predictor of lower ABI (p 1/4-0.05). These data indicate that CRP and WBC count are not independently associated with ABI, a marker of atherosclerotic burden in subjects referred for non-invasive lower extremity arterial evaluation. The association of Lp-PLA2 with ABI merits further study.

Long QT syndrome is a malfunction of cardiac ion channels resulting in impaired ventricular repolarization that can lead to a characteristic polymorphic ventricular tachycardia known as torsades de pointes. Stressors, by increasing sympathetic tone, and drugs can provoke torsade de pointes, leading to syncope, seizures, or sudden cardiac death in these patients. Beta blockade, implantation of cardioverter defibrillators, and left cardiac sympathetic denervation are used in the treatment of these patients. However, these treatment modalities do not guarantee the prevention of sudden cardiac death. Certain drugs, including anesthetic agents, are known to contribute to QT prolongation. After reviewing the literature the authors give recommendations for the anesthetic management of these patients in the perioperative period.

Abstract One hundred fifty‐six arthroscopic transglenoid multiple suture repairs were performed for chronic anterior shoulder instability. In 150 shoulders (96% follow‐up), the outcome with respect to recurrence of instability and the Bankart Score was determined a minimum of 2 years and a mean of 4.1 years after surgery (range, 2 to 8.2 years). During the follow‐up interval, 11 shoulders (7.3%) redislocated. Fourteen other shoulders (9.3%) had at least one episode that we interpreted as recurrent subluxation. Shoulders with a Bankart lesion and younger patients had a higher probability of recurrent instability ( P < .05). We concluded that this method is most effective in shoulders without a Bankart lesion and in patients older than 25 years of age (regardless of pathology).