Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease

Apolipoprotein E (apoE) alleles are important genetic risk factors for Alzheimer's disease (AD), with the epsilon4 allele increasing and the epsilon2 allele decreasing risk for developing AD. ApoE has been shown to influence brain amyloid-beta peptide (Abeta) and amyloid burden, both in humans and in transgenic mice. Here we show that direct intracerebral administration of lentiviral vectors expressing the three common human apoE isoforms differentially alters hippocampal Abeta and amyloid burden in the PDAPP mouse model of AD. Expression of apoE4 in the absence of mouse apoE increases hippocampal Abeta(1-42) levels and amyloid burden. By contrast, expression of apoE2, even in the presence of mouse apoE, markedly reduces hippocampal Abeta burden. Our data demonstrate rapid apoE isoform-dependent effects on brain Abeta burden in a mouse model of AD. Gene delivery of apoE2 may prevent or reduce brain Abeta burden and the subsequent development of neuritic plaques.     

Fragmented QRS on a 12-lead ECG: a predictor of mortality and cardiac events in patients with coronary artery disease.

BACKGROUND: Fragmented QRS (fQRS) on a 12-lead electrocardiogram (ECG) is associated with myocardial scar in patients with coronary artery disease (CAD). OBJECTIVE: We postulated that fQRS is a predictor of cardiac events and mortality in patients who have known CAD or who are being evaluated for CAD. METHODS: The cardiac events (myocardial infarction, need for revascularization, or cardiac death) and all-cause mortality were retrospectively reviewed in 998 patients (mean age 65.5 +/- 11.9 years, male 967) who underwent nuclear stress test. The fQRS on a 12-lead ECG included various RSR' patterns (> or =1 R' prime or notching of S wave or R wave) without typical bundle branch block in 2 contiguous leads corresponding to a major coronary artery territory. RESULTS: All-cause mortality (93 [34.1%] vs 188 [25.9%]) and cardiac event rate (135 [49.5%] vs 200 [27.6%]) were higher in the fQRS group compared with the non-fQRS group during a mean follow-up of 57 +/- 23 months. A Kaplan-Meier survival analysis revealed significantly lower event-free survival for cardiac events (P <.001) and all-cause mortality (P = .02). Multivariate Cox regression analysis revealed that significant fQRS was an independent significant predictor for cardiac events but not for all-cause mortality. The Kaplan-Meier survival analysis showed no significant difference between fQRS and Q waves groups for cardiac events (P = .48) and all-cause mortality (P = .08). CONCLUSION: The fQRS is an independent predictor of cardiac events in patients with CAD. It is associated with significantly lower event-free survival for a cardiac event on long-term follow-up.     

Chronic pain. Sources of late-life pain and risk factors for disability

The prevalence of pain peaks in middle age and decreases thereafter, according to most epidemiologic studies of complaints of pain. However, this apparent decrease in pain in older adults may be a statistical artifact. Eighty to 85% of persons experience a significant health problem that predisposes them to pain at some time after age 65. With aging, patients experience less frequent head, abdominal, and chest pain and more frequent joint pain. Women are more likely to report musculoskeletal pain and multiple pain sites than men, but there are no gender differences for reports of chest and abdominal pain. Many patients with chronic pain have clinically significant depressive symptoms and low self-reported quality-of-life scores.     

Is 30-Day Mortality after Admission for Heart Failure an Appropriate Metric for Quality?

Background

The Centers for Medicare and Medicaid Services (CMS) model for publicly reporting national 30-day-risk-adjusted mortality rates for patients admitted with heart failure fails to include clinical variables known to impact total mortality or take into consideration the culture of end-of-life care. We sought to determine if those variables were related to the 30-day mortality of heart failure patients at Geisinger Medical Center.

Development of OMP based indirect ELISA to gauge the antibody titers in bovines against Pasteurella multocida

Pasteurella multocida (P. multocida) is an important pathogen of various domestic animals. The outer membrane proteins (OMPs) play a major role in pathogenesis and immunogenicity of P. multocida. The aim of the study was to develop indirect enzyme linked immuno sorbant assay (ELISA) based on OMPs to ascertain the antibody titers in animals post-infection or to gauge the potency of vaccine. The OMPs were extracted and purified from P. multocida P:52 (vaccine strain) and P. multocida B:2 isolated from natural outbreak of Haemorrhagic septicaemia (HS) and analyzed on SDS PAGE and through western blot. The OMPs profile of the vaccine strain and the isolate from the natural outbreak of HS were found to be similar. Optimization of various components viz. coating antigens, anti-species conjugate, etc. were carried out against both anti-P. multocida hyper immune and pre immune serum. Validation of OMP based indirect ELISA assay to measure immune response against P. multocida in bovine revealed 91% diagnostic sensitivity (DSN) and about 100% diagnostic specificity (DSP) at 25% cut off. OMP based indirect ELISA was found to be more specific, but less sensitive as compared to WCL based assay.Key Words: Diagnostic sensitivity, Diagnostic specificity, Indirect ELISA, Outer membrane proteins, Pasteurella multocida     

Does adjuvant nutritional support diminish steroid dependency in Crohn disease?

BACKGROUND: Nutritional therapy plays an important role in the management of Crohn disease, particularly during the acute phase. Nutritional supplementation may also prevent relapses during the quiescent phase of Crohn disease, though this aspect has not been widely explored. METHODS: Thirty-three patients with Crohn disease in remission were studied. All had steroid-dependent disease. Patients were randomized to receive either elemental diet (n = 19, EO28 Extra) or polymeric diet (Forticips, n = 14). The supplement was given orally in addition to normal food in an amount to provide 35%-50% of pre-trial total calorie intake. Prednisolone was withdrawn gradually. Patients were followed up for 12 months. Failure was defined as increase in CDAI by 100 points from baseline to >200, inability to withdraw chronic steroid therapy completely, need for surgery or steroid therapy. RESULTS: The nutritional supplement was successful in 14 (43%) patients who remained in remission for 12 months with complete withdrawal of steroids. The response to elemental diet (42%) was similar to that of polymeric diet (43%). Nutrition supplement failed in 13 (39%). Six (18%) patients were intolerant to enteral feeding because of smell and taste problems. Per-protocol analysis of data indicated that the success rate of nutrition supplement in steroid-dependent patients was 52% (14 out of 27 patients). No disease or patient-related factors helped predict the response to nutrition supplement. CONCLUSION: Nutritional supplementation with either an elemental or polymeric diet may provide a safe and effective alternative to chronic steroid therapy in patients with steroid-dependent Crohn disease.     

Cells with Fc gamma receptors from normal donors suppress granulocytic macrophage colony formation

We investigated the role of normal human marrow cells with Fc receptors for IgG (Fc gamma+) on autologous granulocyte-macrophage colony (GM- CFC) formation. It was found that Fc gamma+ normal human marrow cells, both with (E+) or without receptors for sheep erythrocytes suppressed GM-CFC at as low a concentration as 0.25 X 10(5) cells/ml of culture. A similar effect was observed with E- Fc gamma+ but not E+ Fc gamma+ peripheral blood cells. Suppression by Fc gamma+ cells did not require mitogen activation and was not inactivated by irradiation (2000 R). This report presents a new in vitro regulatory mechanism for GM-CFC growth in normal donors.     

Treatment of Partial Thickness Rotator Cuff Tears in Overhead Athletes

Purpose of Review

To review the etiology, classification, presentation, evaluation, treatment strategy, and outcomes in overhead athletes with partial thickness rotator cuff tears.

Recent Findings

Despite advances in surgical repair techniques, return to play following surgical repair of partial rotator cuff tears remains modest at best.

Summary

Overhead athletes may be particularly prone to rotator cuff pathology due to the supraphysiological strains within the tendon during the throwing motion, as well as mechanical stress with contact between the undersurface of the rotator cuff and the glenoid. The true prevalence of partial tears may be underestimated given the high incidence of asymptomatic tears. Both dynamic ultrasound and enhanced contrast MRI have improved our understanding of this pathology. For most overhead athletes, nonoperative management is the most common course. Despite advances in imaging, diagnosis, and surgical techniques, our ability to return these patients to their elite level is modest at best when nonoperative management fails and surgical treatment is performed. If a surgical route is needed, debridement alone is the most frequent procedure given concerns of over constraint and poor return to play with surgical repair of the partial thickness rotator cuff tear.

     

Paramedic-Initiated Home Care Referrals and Use of Home Care and Emergency Medical Services

Objective: We examined the association between paramedic-initiated home care referrals and utilization of home care, 9-1-1, and Emergency Department (ED) services. Methods: This was a retrospective cohort study of individuals who received a paramedic-initiated home care referral after a 9-1-1 call between January 1, 2011 and December 31, 2012 in Toronto, Ontario, Canada. Home care, 9-1-1, and ED utilization were compared in the 6 months before and after home care referral. Nonparametric longitudinal regression was performed to assess changes in hours of home care service use and zero-inflated Poisson regression was performed to assess changes in the number of 9-1-1 calls and ambulance transports to ED. Results: During the 24-month study period, 2,382 individuals received a paramedic-initiated home care referral. After excluding individuals who died, were hospitalized, or were admitted to a nursing home, the final study cohort was 1,851. The proportion of the study population receiving home care services increased from 18.2% to 42.5% after referral, representing 450 additional people receiving services. In longitudinal regression analysis, there was an increase of 17.4 hours in total services per person in the six months after referral (95% CI: 1.7–33.1, p = 0.03). The mean number of 9-1-1 calls per person was 1.44 (SD 9.58) before home care referral and 1.20 (SD 7.04) after home care referral in the overall study cohort. This represented a 10% reduction in 9-1-1 calls (95% CI: 7–13%, p < 0.001) in Poisson regression analysis. The mean number of ambulance transports to ED per person was 0.91 (SD 8.90) before home care referral and 0.79 (SD 6.27) after home care referral, representing a 7% reduction (95% CI: 3–11%, p < 0.001) in Poisson regression analysis. When only the participants with complete paramedic and home care records were included in the analysis, the reductions in 9-1-1 calls and ambulance transports to ED were attenuated but remained statistically significant. Conclusions: Paramedic-initiated home care referrals in Toronto were associated with improved access to and use of home care services and may have been associated with reduced 9-1-1 calls and ambulance transports to ED.     

Biology‐Driven Gene‐Gene Interaction Analysis of Age‐Related Cataract in the eMERGE Network

Bioinformatics approaches to examine gene‐gene models provide a means to discover interactions between multiple genes that underlie complex disease. Extensive computational demands and adjusting for multiple testing make uncovering genetic interactions a challenge. Here, we address these issues using our knowledge‐driven filtering method, Biofilter, to identify putative single nucleotide polymorphism (SNP) interaction models for cataract susceptibility, thereby reducing the number of models for analysis. Models were evaluated in 3,377 European Americans (1,185 controls, 2,192 cases) from the Marshfield Clinic, a study site of the Electronic Medical Records and Genomics (eMERGE) Network, using logistic regression. All statistically significant models from the Marshfield Clinic were then evaluated in an independent dataset of 4,311 individuals (742 controls, 3,569 cases), using independent samples from additional study sites in the eMERGE Network: Mayo Clinic, Group Health/University of Washington, Vanderbilt University Medical Center, and Geisinger Health System. Eighty‐three SNP‐SNP models replicated in the independent dataset at likelihood ratio test P < 0.05. Among the most significant replicating models was rs12597188 (intron of CDH1)–rs11564445 (intron of CTNNB1). These genes are known to be involved in processes that include: cell‐to‐cell adhesion signaling, cell‐cell junction organization, and cell‐cell communication. Further Biofilter analysis of all replicating models revealed a number of common functions among the genes harboring the 83 replicating SNP‐SNP models, which included signal transduction and PI3K‐Akt signaling pathway. These findings demonstrate the utility of Biofilter as a biology‐driven method, applicable for any genome‐wide association study dataset.