Citations

Background and Purpose— Meta-analyses of extant genome-wide data illustrate the need to focus on subtypes of ischemic stroke for gene discovery. The National Institute of Neurological Disorders and Stroke SiGN (Stroke Genetics Network) contributes substantially to meta-analyses that focus on specific subtypes of stroke. Methods— The National Institute of Neurological Disorders and Stroke SiGN includes ischemic stroke cases from 24 genetic research centers: 13 from the United States and 11 from Europe. Investigators harmonize ischemic stroke phenotyping using the Web-based causative classification of stroke system, with data entered by trained and certified adjudicators at participating genetic research centers. Through the Center for Inherited Diseases Research, the Network plans to genotype 10 296 carefully phenotyped stroke cases using genome-wide single nucleotide polymorphism arrays and adds to these another 4253 previously genotyped cases, for a total of 14 549 cases. To maximize power for subtype analyses, the study allocates genotyping resources almost exclusively to cases. Publicly available studies provide most of the control genotypes. Center for Inherited Diseases Research–generated genotypes and corresponding phenotypes will be shared with the scientific community through the US National Center for Biotechnology Information database of Genotypes and Phenotypes, and brain MRI studies will be centrally archived. Conclusions— The Stroke Genetics Network, with its emphasis on careful and standardized phenotyping of ischemic stroke and stroke subtypes, provides an unprecedented opportunity to uncover genetic determinants of ischemic stroke.

SummaryThere is a remarkable dearth of information about the various therapies used, often widely so, to control refractory or super‐refractory status epilepticus despite its high mortality and morbidity. As pointed out by recent literature reviews, there are no controlled studies, and information is based almost entirely on open, often small and retrospective, case series or case reports. Randomized or controlled studies that are sufficiently powered are not feasible in relation to the many therapies and treatment approaches available. For this reason, we proposed an international case registry of therapies used in refractory and super‐refractory cases and their outcome. Clinicians from different countries will be asked to complete an online questionnaire when they treat a patient with refractory or super‐refractory status epilepticus. Information gathered from this database will summarize the spectrum of etiologies, treatments, and outcomes of this challenging condition and may even form the bases for treatment guidelines or future targeted treatment trials.

Abstract Purpose: Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%–39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer. Clin Cancer Res; 19(19); 5505–12. ©2013 AACR.

ABSTRACT To assess recent trends in fracture incidence from all causes at all skeletal sites, we used the comprehensive (inpatient and outpatient) data resources of the Rochester Epidemiology Project to estimate rates for Olmsted County, MN, USA, residents in 2009 to 2011 compared with similar data from 1989 to 1991. During the 3-year study period, 2009 to 2011, 3549 residents ≥50 years of age experienced 5244 separate fractures. The age- and sex-adjusted (to the 2010 US white population) incidence of any fracture was 2704 per 100,000 person-years (95% confidence interval [CI] 2614 to 2793) and that for all fractures was 4017 per 100,000 (95% CI 3908 to 4127). Fracture incidence increased with age in both sexes, but age-adjusted rates were 49% greater among the women. Overall, comparably adjusted fracture incidence rates increased by 11% (from 3627 to 4017 per 100,000 person-years; p = 0.008) between 1989 to 1991 and 2009 to 2011. This was mainly attributable to a substantial increase in vertebral fractures (+47% for both sexes combined), which was partially offset by a decline in hip fractures (−25%) among the women. There was also a 26% reduction in distal forearm fractures among the women; an increase in distal forearm fractures among men aged 50 years and over was not statistically significant. The dramatic increase in vertebral fractures, seen in both sexes and especially after age 75 years, was attributable in part to incidentally diagnosed vertebral fractures. However, the fall in hip fracture incidence, observed in most age groups, continues the steady decline observed among women in this community since 1950. More generally, these data indicate that the dramatic increases in the incidence of fractures at many skeletal sites that were observed decades ago have now stabilized. © 2014 American Society for Bone and Mineral Research.

Objective To evaluate survival in patients after radical cystectomy ( RC ) who presented with non‐muscle‐invasive urothelial carcinoma and progressed to muscle invasion during surveillance. Our secondary objective was to evaluate the association between clinical factors before RC and survival. Patients and Methods In all, 981 consecutive M ayo C linic RC patients without a history of radiation or systemic chemotherapy were reviewed. Of these, 190 had RC after they progressed from non‐muscle invasive disease to muscle invasion (progressed to ≥ pT2 ). These patients were compared to 310 patients who had RC before muscle invasion (≤ pT1 ), and 481 patients who had muscle invasion at initial presentation (presented with ≥ pT2 ). Survival estimates were generated using the K aplan– M eier method and compared using the log‐rank test, while adjusted analyses were performed using C ox proportional hazard regression models. Results Patients who progressed to muscle invasion on surveillance had a higher risk of death than patients who initially presented with muscle invasion (overall survival hazard ratio [ HR ] 1.3; 95% confidence interval [ CI ] 1.0, 1.5). The estimated 5‐year cancer‐specific survival was 85.4% for patients presenting with ≤ pT1 , 52.9% for patients who progressed to ≥ pT2 , and 62.4% for patients who presented with ≥ pT2 ( P < 0.001). The corresponding 5‐year overall survival rates were 70.0%, 42.1%, and 49.5% ( P < 0.001). Of the patients who initially presented with non‐muscle‐invasive disease, progression to muscle invasion was associated with increased risk of cancer‐specific death (adjusted HR 2.38; 95% CI 1.6, 3.5). Lack of information about patients who presented without muscle invasion and never received RC is the major limitation of this study. Conclusions Despite close surveillance, many patients who progress to muscle invasion will die from bladder cancer. Patients who progress to muscle invasion on surveillance seem to have particularly aggressive disease and may benefit from multimodal treatments.

SummaryMutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS+) in multiplex families and accounts for 70–80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS+ families could be explained by highly penetrant SCN9A mutations.

Collaborative care management (CCM) for depression has been demonstrated to improve clinical outcomes. The impetus for this study was to determine if outpatient utilization patterns would be associated with depression outcomes. The hypothesis was that depression remission would be independently correlated with outpatient utilization at 6 and 12 months after enrollment into CCM. The study was a retrospective chart review analysis of 773 patients enrolled into CCM with 6- and 12-month follow-up data. The data set comprised baseline demographic data, patient intake self-assessment scores (Patient Health Questionnaire [PHQ-9], Generalized Anxiety Disorder-7, Mood Disorder Questionnaire, and Alcohol Use Disorders Identification Test), the number of outpatient visits, and follow-up PHQ-9 scores. To control for individual patient complexity and pattern of usage, the number of outpatient visits for 6 months prior to enrollment also was measured. With a logistic regression model for outpatient visit outlier status as the dependent variable, remission at 6 months (odds ratio [OR] 0.519, CI [confidence interval] 0.349–0.770, P =0.001) and remission at 12 months (OR 0.573, CI 0.354–0.927, P =0.023) were predictive. With this inverse relationship between remission and outlier status, those patients who were not in remission had an OR of 1.928 for outpatient visit outlier status at 6 months after enrollment and an OR of 1.745 at 12 months. Patients who improved clinically to remission while in CCM had decreased odds of outlier status for outpatient utilization at 6 and 12 months when controlling for all other study variables. Improvement in health care outcomes by CCM could translate into decreased outpatient utilization for depressed patients. ( Population Health Management 2014;17:48–53)

Human sperm centrosome reconstitution and the parental contributions to the zygotic centrosome are examined in mammalian zygotes and after exposure of spermatozoa to Xenopus laevis cell-free extracts. The presence and inheritance of the conserved centrosomal constituents γ-tubulin, centrin, and MPM-2 (which detects phosphorylated epitopes) are traced, as is the sperm microtubule-nucleating capability on reconstituted centrosomes. γ-Tubulin is biparentally inherited in humans (maternal >> than paternal): Western blots detect the presence of paternal γ-tubulin. Recruitment of maternal γ-tubulin to the sperm centrosome occurs after sperm incorporation in vivo or exposure to cell-free extract, especially after sperm “priming” induced by disulfide bond reduction. Centrin is found in the proximal sperm centrosomal region, demonstrates expected calcium sensitivity, but appears absent from the zygotic centrosome after sperm incorporation or exposure to extracts. Sperm centrosome phosphorylation is detected after exposure of primed sperm to egg extracts as well as during the early stages of sperm incorporation after fertilization. Finally, centrosome reconstitution in cell-free extracts permits sperm aster microtubule assembly in vitro. Collectively, these results support a model of a blended zygotic centrosome composed of maternal constituents attracted to an introduced paternal template after insemination.

Abstract Growing evidence supports a role for the unfolded protein response (UPR) in carcinogenesis; however, the precise molecular mechanisms underlying this phenomenon remain elusive. Herein, we identified the circadian clock PER1 mRNA as a novel substrate of the endoribonuclease activity of the UPR sensor IRE1α. Analysis of the mechanism shows that IRE1α endoribonuclease activity decreased PER1 mRNA in tumor cells without affecting PER1 gene transcription. Inhibition of IRE1α signaling using either siRNA-mediated silencing or a dominant-negative strategy prevented PER1 mRNA decay, reduced tumorigenesis, and increased survival, features that were reversed upon PER1 silencing. Clinically, patients showing reduced survival have lower levels of PER1 mRNA expression and increased splicing of XBP1, a known IRE-α substrate, thereby pointing toward an increased IRE1α activity in these patients. Hence, we describe a novel mechanism connecting the UPR and circadian clock components in tumor cells, thereby highlighting the importance of this interplay in tumor development. Cancer Res; 73(15); 4732–43. ©2013 AACR.