Bestrophin-3 Expression in a Subpopulation of Astrocytes in the Neonatal Brain After Hypoxic-Ischemic Injury

Bestrophin-3, a potential candidate for a calcium-activated chloride channel, recently was suggested to have cell-protective functions. We studied the expression and alternative splicing of bestrophin-3 in neonatal mouse brain and after hypoxic-ischemic (HI) injury and in human neonatal brain samples. HI brain injury was induced in 9-day old mice by unilateral permanent common carotid artery occlusion in combination with exposure to 10% oxygen for 50 min. Endoplasmic reticulum stress was induced by thapsigargin treatment in primary culture of mouse brain astrocytes. We also investigated expression of bestrophin-3 protein in a sample of human neonatal brain tissue. Bestrophin-3 protein expression was detected with immunohistochemical methods and western blot; mRNA expression and splicing were analyzed by RT-PCR. HI induced a brain tissue infarct and a pronounced increase in the endoplasmic reticulum-associated marker CHOP. Three days after HI a population of astrocytes co-expressed bestrophin-3 and nestin in a penumbra-like area of the injured hemisphere. However, total levels of Bestrophin-3 protein in mouse cortex were reduced after injury. Mouse astrocytes in primary culture also expressed bestrophin-3 protein, the amount of which was reduced by endoplasmic reticulum stress. Bestrophin-3 protein was detected in astrocytes in the hippocampal region of the human neonatal brain which had patchy white matter gliosis and neuronal loss in the Sommer’s sector of the Ammon’s horn (CA1). Analysis of bestrophin-3 mRNA in mouse brain with and without injury showed the presence of two truncated spliced variants, but no full-length mRNA. Total amount of bestrophin-3 mRNA increased after HI, but showed only minor injury-related change. However, the splice variants of bestrophin-3 mRNA were differentially regulated after HI depending on the presence of tissue injury. Our results show that bestrophin-3 is expressed in neonatal mouse brain after injury and in the human neonatal brain with pathology. In mouse brain bestrophin-3 protein is upregulated in a specific astrocyte population after injury and is co-expressed with nestin. Splice variants of bestrophin-3 mRNA respond differently to HI, which might indicate their different roles in tissue injury

Obstructive Sleep Apnea Severity Affects Amyloid Burden in Cognitively Normal Elderly. A Longitudinal Study

Rationale: Recent evidence suggests that obstructive sleep apnea (OSA) may be a risk factor for developing mild cognitive impairment and Alzheimer’s disease. However, how sleep apnea affects longitudinal risk for Alzheimer’s disease is less well understood. Objectives: To test the hypothesis that there is an association between severity of OSA and longitudinal increase in amyloid burden in cognitively normal elderly. Methods: Data were derived from a 2-year prospective longitudinal study that sampled community-dwelling healthy cognitively normal elderly. Subjects were healthy volunteers between the ages of 55 and 90, were nondepressed, and had a consensus clinical diagnosis of cognitively normal. Cerebrospinal fluid amyloid β was measured using ELISA. Subjects received Pittsburgh compound B positron emission tomography scans following standardized procedures. Monitoring of OSA was completed using a home sleep recording device. Measurements and Main Results: We found that severity of OSA indices (AHIall [F1,88 = 4.26; P < 0.05] and AHI4% [F1,87 = 4.36; P < 0.05]) were associated with annual rate of change of cerebrospinal fluid amyloid β42 using linear regression after adjusting for age, sex, body mass index, and apolipoprotein E4 status. AHIall and AHI4% were not associated with increases in ADPiB-mask (Alzheimer’s disease vulnerable regions of interest Pittsburg compound B positron emission tomography mask) most likely because of the small sample size, although there was a trend for AHIall (F1,28 = 2.96, P = 0.09; and F1,28 = 2.32, not significant, respectively). Conclusions: In a sample of cognitively normal elderly, OSA was associated with markers of increased amyloid burden over the 2-year follow-up. Sleep fragmentation and/or intermittent hypoxia from OSA are likely candidate mechanisms. If confirmed, clinical interventions for OSA may be useful in preventing amyloid build-up in cognitively normal elderly

Rapidly changing myeloma epidemiology in the general population: increased incidence, older patients, and longer survival

The incidence of multiple myeloma is characterized by a steep increase with advancing age. Dramatic improvements in survival have been reported in clinical trials; however, elderly patients are generally underrepresented in these. The aims of this study are to review patterns of incidence and survival in multiple myeloma in the general population. We searched PubMed for population-based studies on trends in incidence and survival published between January 1, 2000 and June 30, 2017 and based on regional or national cancer registries and report the following results of the review. The age-adjusted incidence of multiple myeloma has increased during the second half of the 20th Century in some countries but remained stable in areas with high case ascertainment and access to universal medical care. The crude incidence is increasing globally due to an ageing population. Survival rates have improved and 5-year relative survival rates are now around 50% and over 60% in patients 65–70 years or younger. Preliminary data suggest a 3-fold increase in the prevalence of multiple myeloma. We conclude that the number of multiple myeloma patients is increasing in the general population due to (1) aging populations and (2) more patients living longer due to modern drugs

Factors Influencing Successful Lumbar Puncture in Alzheimer Research

Lumbar puncture (LP) is increasingly common in Alzheimer disease research; however, agreement to undergo LP varies. We sought to determine factors influencing LP consent at Alzheimer's Disease Centers (ADCs) in the United States. A 3-part survey was distributed to each ADC: (1) ADC LP Experience; (2) LP Requestor Experience; and (3) Patient LP Experience (both Initial and Follow-up). In all, 64 LP Requestor, 579 Patient/Initial, and 404 Patient/Follow-up surveys were collected. Logistic regression analyses with generalized estimating equations were used to assess factors associated with LP agreement and post-LP complications. Asians and those viewing LP negatively were less likely to agree to LP. Three hundred fifty-two participants had an LP; LP headache occurred in 11.9% (blood patch required in 1.4%) and 9.9% reported other complications. Younger individuals, women, those diagnosed with mild cognitive impairment, use of a Quincke needle, ≤20 mL cerebrospinal fluid drawn, and hemorrhage during LP were associated with LP headache. Use of gravity flow during LP was associated with fewer other complications (nausea, dizziness, vasovagal response, back pain, neck stiffness, and/or nerve root pain). LP in Alzheimer disease research is generally safe and well tolerated. Factors influencing LP agreement potentially could be studied to advance participant acceptance of the procedure

Seven days ex vivo perfusion of whole ewe ovaries with follicular maturation and oocyte retrieval: towards the development of an alternative fertility preservation method

Fertility preservation methods for prepubertal women about to undergo gonadotoxic chemo and/or radiation therapy are limited. Therefore, the aim of this study was to investigate the feasibility to develop an alternative fertility preservation method based on an ex vivo perfusion platform for whole ewe ovaries. Thirteen ewe ovaries were divided into two groups (group 1 and 2) that were perfused in a bioreactor for up to 7days. Group 1 (n =3) were stimulated with human menopausal gonadotropin (hMG) administered in single daily dose, while group 2 (n =10) were stimulated continuously for 24h. The perfused ovaries in group 1 showed no significant differences in follicular density, sub-follicular morphology and oocyte quality after ischaemia and after ex vivo perfusion compared with non-perfused control ovaries. The perfused ovaries in group 2 showed a significant decrease in the follicular reserve and oocyte quality compared with the control group. In total, 16 GV-MI oocytes were retrieved from both groups. This study describes for the first time the ex vivo maintenance of viable follicles of ewe ovaries with oocyte integrity and the retrieval of oocytes after ex vivo hormonal perfusion with two different protocols for up to 7days

Effects of telmisartan, irbesartan, valsartan, candesartan, and losartan on cancers in 15 trials enrolling 138 769 individuals

Background: Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARBs) reduce cardiovascular disease (CVD) events, but a recent meta-analysis of selected studies suggested that ARBs may increase cancer risks. Objective: Candesartan, irbesartan, telmisartan, valsartan, and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants. Patients and methods: Individuals at high CVD risk were randomized to telmisartan (three trials, n = 51 878), irbesartan (three trials, n = 14 859), valsartan (four trials, n = 44 264), candesartan (four trials, n = 18 566), and losartan (one trial, n = 9193) and followed for 23-60 months. Incident cancer cases were compared in patients randomized to ARBs versus controls. In five trials (n = 42 403), the ARBs were compared to ACEi and in 11 trials (n = 63 313) to controls without ACEi. In addition, in seven trials (n = 47 020), the effect of ARBs with ACEi was compared to ACEi alone and in two trials ARBs with ACEi versus ARB alone (n = 25 712). Results: Overall, there was no excess of cancer incidence with ARB therapy compared to controls in the 15 trials [4549 (6.16%) cases of 73 808 allocated to ARB versus 3856 (6.31%) of 61 106 assigned to non-ARB controls; odds ratio (OR) 1.00, 95% confidence interval (CI) 0.95-1.04] overall or when individual ARBs were examined. ORs comparing combination therapy with ARB along with ACEi versus ACEi was 1.01 (95% CI 0.94-1.10), combination versus ARB alone 1.02 (95% CI 0.91-1.13), ARB alone versus ACEi alone 1.06 (95% CI 0.97-1.16) and ARB versus placebo/control without ACEi 0.97 (95% CI 0.91-1.04). There was no excess of lung, prostate or breast cancer, or overall cancer deaths associated with ARB treatment. Conclusion: There was no significant increase in the overall or site-specific cancer risk from ARBs compared to controls. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins

Comorbidities in multiple myeloma and implications on survival: A population-based study.

To access publisher's full text version of this article click on the hyperlink belowHigh proportion of patients with multiple myeloma suffer from comorbidities which may alter clinical management. Therefore, our aims were to evaluate the prevalence of comorbidities and their impact on survival. We included patients diagnosed with multiple myeloma 1990-2013 in Sweden and all diagnoses from each patient from 1985. A total of 13 656 patients with multiple myeloma were included in the study, thereof 7404 (54%) had comorbidity at diagnosis. The risk of death was increased for those with one comorbidity at diagnosis compared to those without any comorbidity (hazard ratio = 1.19; 95% confidence interval:1.14-1.25); this risk was higher for those with two (1.38; 1.30-1.47) and three or more comorbidities (1.72; 1.62-1.83). Furthermore, the risk of death was increased in patients with prior history of cancer, arrhythmia, heart failure, diabetes mellitus, cerebrovascular disease, chronic lung disease, psychological disease, peptic ulcer, neurological disease, peripheral vascular disease, chronic kidney disease, dementia, and inflammatory bowel disease. This large study shows that over 50% of multiple myeloma patients have a comorbidity at diagnosis and survival decreased with increasing numbers of comorbidities. This emphasizes the importance of comorbidities when evaluating patients and deciding on treatment strategies for individuals with multiple myeloma. Keywords: comorbidities; multiple myeloma; survival.Research Fund of Landspitali, University Hospital of Iceland, The Nordic Cancer Union Icelandic Centre for Researc

Swallowing function in Parkinson’s patients following Zona Incerta deep brain stimulation

Objective The purpose of the present study was to examine if there was a negative effect of caudal Zona Incerta deep brain stimulation (cZI DBS) on pharyngeal swallowing function in Parkinson’s patients (PD). There are no former reports on swallowing and cZI DBS. Methods Eight patients (aged 49 to 71 years; median 62) were evaluated pre- and postoperatively, at six and 12 months after DBS surgery. Evaluation tools were Fiberoptic Endoscopic Evaluation of Swallowing examinations and patients’ self-assessments of the swallowing function including a visual analogue scale and quality of life related questions. The swallowing protocol included Rosenbeck’s Penetration-Aspiration Scale, Secretion Severity Scale and parameters for pre-swallow spillage, pharyngeal residue and pharyngeal clearance. Results There was no clear-cut effect of neurostimulation postoperatively at six and 12 months on any of the swallowing parameters except for pre-swallow spillage which was slightly worsened in the stimulation on condition 12m postoperatively. The answers to the self assessment questions did not vary significantly. Conclusions The effect of the stimulation on swallowing function varied among individuals but the overall outcome was that cZI DBS did not seem to have a negative influence on swallowing function in the eight patients studied

The Relationship between Prostate-Specific Antigen and Prostate Cancer Risk: The Prostate Biopsy Collaborative Group

PURPOSE: The relationship between prostate specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesize that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study. EXPERIMENTAL DESIGN: We used data from 5 European and 3 US cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally-weighted scatterplot smoothing. RESULTS: The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased risk of cancer (odds ratio for >6 vs. 6 core biopsy 1.35; 95% C.I. 1.18, 1.54; p<0.0005); recent screening led to a smaller increase in risk per unit change in PSA (p=0.001 for interaction term) and US cohorts had higher risk than the European cohorts (2.14; 95% C.I. 1.99, 2.30; p<0.0005). CONCLUSIONS: Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated

Taking stock: A multistakeholder perspective on improving the delivery of care and the development of treatments for Alzheimer's disease

AbstractHealth-care stakeholders increasingly recognize that the scientific and economic challenges associated with Alzheimer's disease (AD) are simply too great for individual stakeholder groups to address solely from within their own silos. In the necessary spirit of collaboration, we present in this perspective a set of multicountry multistakeholder recommendations to improve the organization of existing AD and dementia care and the development of new treatments. In brief, the five recommendations are (1) health-care systems must make choices regarding the patient populations to be diagnosed and treated, (2) health-care systems should use an evidence-based standard of care, (3) increased collaboration between public and private institutions is needed to enhance research, (4) reimbursement end points need to be agreed on and validated, and (5) innovative business models should be used to spur the introduction of new medicines