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Cement directed kyphoplasty reduces cement leakage as compared with vertebroplasty: results of a controlled, randomized trial

Tue, 05/12/2015 - 10:32pm

STUDY DESIGN: A novel randomized, controlled, unblinded clinical trial comparing 2 procedural interventions for painful osteoporotic vertebral compression fractures.

OBJECTIVE: The primary study objective was to evaluate cement leakage for a cement directed kyphoplasty system (CDKS) with anteriorly biased cement flow and vertebroplasty. The secondary study objective was to compare adjacent level fracture rates and vertebral body height for these 2 intervention methods.

SUMMARY OF BACKGROUND DATA: Cement leakage remains a significant clinical problem associated with vertebroplasty and kyphoplasty procedures. Uncontrolled cement flow in the posterior direction can result in leakage into the vertebral veins or spinal canal, leading to potentially serious clinical complications.

METHODS: Seventy-seven patients with painful osteoporotic vertebral compression fractures were enrolled. Patients were randomized 2:1 for treatment with CDKS (49 patients, 65 levels) or vertebroplasty (28 patients, 39 levels). Cement leakage was evaluated from radiographs and computed tomographic scans. Three- and 12-month follow-ups included additional radiographs and computed tomographic scans to assess changes in vertebral body height and the incidence of new fractures.

RESULTS: Treatment with CDKS significantly reduced the number of levels with leaks and the total number of leaks per level, as compared with vertebroplasty (P = 0.0132 and P = 0.0012, respectively). Significantly, fewer lateral cortical and spinal canal leaks (posterior leaks) occurred in the CDKS group (P = 0.0050, P = 0.02260, respectively). Three adjacent level fractures occurred in the vertebroplasty group, as compared with 2 in the CDKS group. Vertebral body height maintenance was equivalent.

CONCLUSION: Cement directed kyphoplasty effectively reduces posterior cement leakage, reducing the risk of leakage related complications.

LEVEL OF EVIDENCE: 2.

Multipronged CD4(+) T-cell effector and memory responses cooperate to provide potent immunity against respiratory virus

Tue, 05/12/2015 - 10:32pm

Over the last decade, the known spectrum of CD4(+) T-cell effector subsets has become much broader, and it has become clear that there are multiple dimensions by which subsets with a particular cytokine commitment can be further defined, including their stage of differentiation, their location, and, most importantly, their ability to carry out discrete functions. Here, we focus on our studies that highlight the synergy among discrete subsets, especially those defined by helper and cytotoxic function, in mediating viral protection, and on distinctions between CD4(+) T-cell effectors located in spleen, draining lymph node, and in tissue sites of infection. What emerges is a surprising multiplicity of CD4(+) T-cell functions that indicate a large arsenal of mechanisms by which CD4(+) T cells act to combat viruses.

Amyotrophic lateral sclerosis: Problems and prospects

Tue, 05/12/2015 - 10:32pm

Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the approximately 10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies.

Primary endpoints of the biventricular pacing after cardiac surgery trial

Tue, 05/12/2015 - 10:32pm

BACKGROUND: This study sought to determine whether optimized biventricular pacing increases cardiac index in patients at risk of left ventricular dysfunction after cardiopulmonary bypass. Procedures included coronary artery bypass, aortic or mitral surgery and combinations. This trial was approved by the Columbia University Institutional Review Board and was conducted under an Investigational Device Exemption.

METHODS: Screening of 6,346 patients yielded 47 endpoints. With informed consent, 61 patients were randomized to pacing or control groups. Atrioventricular and interventricular delays were optimized 1 (phase I), 2 (phase II), and 12 to 24 hours (phase III) after bypass in all patients. Cardiac index was measured by thermal dilution in triplicate. A 2-sample t test assessed differences between groups and subgroups.

RESULTS: Cardiac index was 12% higher (2.83+/-0.16 [standard error of the mean] vs 2.52+/-0.13 liters/minute/square meter) in the paced group, less than predicted and not statistically significant (p = 0.14). However, when aortic and aortic-mitral surgery groups were combined, cardiac index increased 29% in the paced group (2.90+/-0.19, n = 14) versus controls (2.24+/-0.15, n = 11) (p = 0.0138). Using a linear mixed effects model, t-test revealed that mean arterial pressure increased with pacing versus no pacing at all optimization points (phase I 79.2+/-1.7 vs 74.5+/-1.6 mm Hg, p = 0.008; phase II 75.9+/-1.5 vs 73.6+/-1.8, p = 0.006; phase III 81.9+/-2.8 vs 79.5+/-2.7, p = 0.002).

CONCLUSIONS: Cardiac index did not increase significantly overall but increased 29% after aortic valve surgery. Mean arterial pressure increased with pacing at 3 time points. Additional studies are needed to distinguish rate from resynchronization effects, emphasize atrioventricular delay optimization, and examine clinical benefits of temporary postoperative pacing. All rights reserved.

Evolution of faculty affairs and faculty development offices in U.S. medical schools: a 10-year follow-up survey

Tue, 05/12/2015 - 10:32pm

PURPOSE: To determine how U.S. MD-granting medical schools manage, fund, and evaluate faculty affairs/development functions and to determine the evolution of these offices between 2000 and 2010.

METHOD: In December 2010, the authors invited faculty affairs designees at 131 U.S. MD-granting medical schools to complete a questionnaire developed by the Association of American Medical Colleges Group on Faculty Affairs, based on a 2000 survey. Schools were asked about core functions, budget, staffing, and performance metrics. The authors analyzed the data using descriptive statistics.

RESULTS: A total of 111 schools (84.7%) responded. Fifty percent of the offices were established since 2000. Seventy-eight percent reported their top core function as administrative support for appointments, promotions, and tenure, as in 2000. Faculty policies, appointments, databases, governance support, grievance proceedings, management issues, and annual trend analyses continued as major functions. All 11 core functions identified in 2000 remain predominantly provided by central offices of faculty affairs, except support of major leadership searches. Web site communication emerged as a new core function. Similar to 2000, several other offices were responsible for some faculty development functions. Office size and budget correlated positively with size of the faculty and age of the office (P < .05 for all). Thirty-five schools (31.5%) reported formally evaluating their faculty affairs office.

CONCLUSIONS: The number of faculty affairs offices and their responsibilities have substantially increased since 2000. Most major core functions have not changed. These offices are now an established part of the central administration of most medical schools.

Apoptosis-associated speck-like protein containing a caspase recruitment domain inflammasomes mediate IL-1beta response and host resistance to Trypanosoma cruzi infection

Tue, 05/12/2015 - 10:32pm

The innate immune response to Trypanosoma cruzi infection comprises several pattern recognition receptors (PRRs), including TLR-2, -4, -7, and -9, as well as the cytosolic receptor Nod1. However, there are additional PRRs that account for the host immune responses to T. cruzi. In this context, the nucleotide-binding oligomerization domain-like receptors (NLRs) that activate the inflammasomes are candidate receptors that deserve renewed investigation. Following pathogen infection, NLRs form large molecular platforms, termed inflammasomes, which activate caspase-1 and induce the production of active IL-1beta and IL-18. In this study, we evaluated the involvement of inflammasomes in T. cruzi infection and demonstrated that apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) inflammasomes, including NLR family, pyrin domain-containing 3 (NLRP3), but not NLR family, caspase recruitment domain-containing 4 or NLR family, pyrin domain-containing 6, are required for triggering the activation of caspase-1 and the secretion of IL-1beta. The mechanism by which T. cruzi mediates the activation of the ASC/NLRP3 pathway involves K(+) efflux, lysosomal acidification, reactive oxygen species generation, and lysosomal damage. We also demonstrate that despite normal IFN-gamma production in the heart, ASC(-)/(-) and caspase-1(-)/(-) infected mice exhibit a higher incidence of mortality, cardiac parasitism, and heart inflammation. These data suggest that ASC inflammasomes are critical determinants of host resistance to infection with T. cruzi.

Uncoupling protein 2 impacts endothelial phenotype via p53-mediated control of mitochondrial dynamics

Tue, 05/12/2015 - 10:32pm

RATIONALE: Mitochondria, although required for cellular ATP production, are also known to have other important functions that may include modulating cellular responses to environmental stimuli. However, the mechanisms whereby mitochondria impact cellular phenotype are not yet clear.

OBJECTIVE: To determine how mitochondria impact endothelial cell function.

METHODS AND RESULTS: We report here that stimuli for endothelial cell proliferation evoke strong upregulation of mitochondrial uncoupling protein 2 (UCP2). Analysis in silico indicated increased UCP2 expression is common in highly proliferative cell types, including cancer cells. Upregulation of UCP2 was critical for controlling mitochondrial membrane potential (Deltapsi) and superoxide production. In the absence of UCP2, endothelial growth stimulation provoked mitochondrial network fragmentation and premature senescence via a mechanism involving superoxide-mediated p53 activation. Mitochondrial network fragmentation was both necessary and sufficient for the impact of UCP2 on endothelial cell phenotype.

CONCLUSIONS: These data identify a novel mechanism whereby mitochondria preserve normal network integrity and impact cell phenotype via dynamic regulation of UCP2.

Cochlear implant electrode failure secondary to silicone touch-up during device manufacturing

Tue, 05/12/2015 - 10:32pm

STUDY DESIGN: Retrospective case report.

SETTING: Tertiary referral cochlear implant center.

PATIENT: A 21-year-old woman was implanted with Advanced Bionics HiFocus Clarion device without complication. Five years later, the patient presented with dizziness, fluctuating implant performance, and facial pain.

INTERVENTION: Surgical exploration revealed a torn electrode silicon casing in conjunction with scar contraction bending the electrode against bony facial nerve canal at the facial recess. Suspension of the electrode such that the damaged portion was not in contact with mastoid cavity led to temporary resolution of symptoms. Explantation and reimplantation procedures were carried out 2 months later.

RESULTS: Postexplantation device analysis by the manufacturer demonstrated silicone touch-up at the site of failure. Six years since reimplantation, the patient has remained symptom-free. It is very likely that the touch-up silicon weakened the electrode and, in conjunction with chronic scar contraction, led to the tear on the silicon casing.

CONCLUSION: Isolated cochlear implant electrode failure is a rare but possible long-term complication in older generation devices. The author reports 1 case of implant device failure partly because of silicon touch-up that was applied at the location of electrode failure during its manufacturing process.

Expression of inhibitory markers is increased on effector memory T cells during hepatitis C virus/HIV coinfection as compared to hepatitis C virus or HIV monoinfection

Tue, 05/12/2015 - 10:32pm

OBJECTIVE: Hepatitis C virus (HCV)/HIV coinfection is associated with rapid progression of hepatic fibrosis and liver disease. T-cell response has been implicated in the pathophysiological outcome of the disease.

DESIGN: This study sought to evaluate the role of memory T-cell exhaustion in enhancing immune dysfunction during coinfection.

METHODS: Sixty-four patients were included in the study; HCV monoinfected (n = 21), HIV monoinfected (n = 23), HCV/HIV coinfected (n = 20), and healthy controls (n = 20). Peripheral blood mononuclear cells (PBMCs) were isolated; immunophenotyped and functional assays were performed.

RESULTS: A significant increase in the naive T cells and central memory T cells and a marked reduction in effector memory T cells (TEM) were observed with coinfection as compared to monoinfection. Inhibitory markers programmed death 1 (PD-1) and T-cell immunoglobulin and mucin domain containing molecule 3 (TIM3) were highly upregulated on TEM in coinfection and functionally, these TEM cells displayed lowered proliferation. Increased expression of PD-1 and TIM3 correlated with decreased levels of CD8+CD107a+ TEM cells in coinfection. Pro-inflammatory cytokines interferon-gamma and interleukin-2 (IL-2) secretion by TEM cells were also reduced during chronic viral infection. Secretion of IL-10, a human cytokine synthesis inhibitory factor, was significantly upregulated in CD4 TEM with HCV/HIV coinfection in comparison to HCV monoinfection.

CONCLUSION: TEM cells play an important role during viral infection and enhanced expression of inhibitory markers is associated with decreased proliferation and cytotoxicity and increased IL-10 production, which was pronounced in HCV/HIV coinfection. Thus, decreased TEM functionality contributes to diminished host immune responses during HCV/HIV coinfection as compared to HCV or HIV monoinfection.

Drosophila Myc integrates multiple signaling pathways to regulate intestinal stem cell proliferation during midgut regeneration

Tue, 05/12/2015 - 10:32pm

Intestinal stem cells (ISCs) in the Drosophila adult midgut are essential for maintaining tissue homeostasis, and their proliferation and differentiation speed up in order to meet the demand for replenishing the lost cells in response to injury. Several signaling pathways including JAK-STAT, EGFR and Hippo (Hpo) pathways have been implicated in damage-induced ISC proliferation, but the mechanisms that integrate these pathways have remained elusive. Here, we demonstrate that the Drosophila homolog of the oncoprotein Myc (dMyc) functions downstream of these signaling pathways to mediate their effects on ISC proliferation. dMyc expression in precursor cells is stimulated in response to tissue damage, and dMyc is essential for accelerated ISC proliferation and midgut regeneration. We show that tissue damage caused by dextran sulfate sodium feeding stimulates dMyc expression via the Hpo pathway, whereas bleomycin feeding activates dMyc through the JAK-STAT and EGFR pathways. We provide evidence that dMyc expression is transcriptionally upregulated by multiple signaling pathways, which is required for optimal ISC proliferation in response to tissue damage. We have also obtained evidence that tissue damage can upregulate dMyc expression post-transcriptionally. Finally, we show that a basal level of dMyc expression is required for ISC maintenance, proliferation and lineage differentiation during normal tissue homeostasis.

Relationship of left ventricular hypertrophy and diastolic function with cardiovascular and renal outcomes in African Americans with hypertensive chronic kidney disease

Tue, 05/12/2015 - 10:32pm

African Americans with hypertension are at high risk for adverse outcomes from cardiovascular and renal disease. Patients with stage 3 or greater chronic kidney disease have a high prevalence of left ventricular (LV) hypertrophy and diastolic dysfunction. Our goal was to study prospectively the relationships of LV mass and diastolic function with subsequent cardiovascular and renal outcomes in the African American Study of Kidney Disease and Hypertension cohort study. Of 691 patients enrolled in the cohort, 578 had interpretable echocardiograms and complete relevant clinical data. Exposures were LV hypertrophy and diastolic parameters. Outcomes were cardiovascular events requiring hospitalization or causing death; a renal composite outcome of doubling of serum creatinine or end-stage renal disease (censoring death); and heart failure. We found strong independent relationships between LV hypertrophy and subsequent cardiovascular (hazard ratio, 1.16; 95% confidence interval, 1.05-1.27) events, but not renal outcomes. After adjustment for LV mass and clinical variables, lower systolic tissue Doppler velocities and diastolic parameters reflecting a less compliant LV (shorter deceleration time and abnormal E/A ratio) were significantly (P < 0.05) associated with future heart failure events. This is the first study to show a strong relationship among LV hypertrophy, diastolic parameters, and adverse cardiac outcomes in African Americans with hypertension and chronic kidney disease. These echocardiographic risk factors may help identify high-risk patients with chronic kidney disease for aggressive therapeutic intervention.

Nucleosome dynamics as modular systems that integrate DNA damage and repair

Tue, 05/12/2015 - 10:32pm

By some estimates, a eukaryotic cell must repair up to 10,000 DNA lesions per cell cycle to counteract endogenous sources of DNA damage. Exposure to environmental toxins, UV sources, or other radiations only increases this enormous number. Failure to repair such lesions can lead to a deleterious mutation rate, genomic instability, or cell death. The timely and efficient repair of eukaryotic DNA damage is further complicated by the realization that DNA lesions must be detected and repaired in the context of chromatin with its complex organization within the nucleus. Numerous studies have shown that chromatin packaging can inhibit nearly all repair pathways, and recent work has defined specific mechanisms that facilitate DNA repair within the chromatin context. In this review, we provide a broad overview of chromatin regulatory mechanisms, mainly at the nucleosomal level, and then focus on recent work that elucidates the role of chromatin structure in regulating the timely and efficient repair of DNA double-strand breaks (DSBs).

Whole-patient measure of safety: using administrative data to assess the probability of highly undesirable events during hospitalization

Tue, 05/12/2015 - 10:32pm

Hospitals often have limited ability to obtain primary clinical data from electronic health records to use in assessing quality and safety. We outline a new model that uses administrative data to gauge the safety of care at the hospital level. The model is based on a set of highly undesirable events (HUEs) defined using administrative data and can be customized to address the priorities and needs of different users. Patients with HUEs were identified using discharge abstracts from July 1, 2008 through June 30, 2010. Diagnoses were classified as HUEs based on the associated present-on-admission status. The 2-year study population comprised more than 6.5 million discharges from 161 hospitals. The proportion of hospitalizations including at least one HUE during the 24-month study period varied greatly among hospitals, with a mean of 7.74% (SD 2.3%) and a range of 13.32% (max, 15.31%; min, 1.99%). The whole-patient measure of safety provides a global measure to use in assessing hospitals with the patient's entire care experience in mind. As administrative and clinical datasets become more consistent, it becomes possible to use administrative data to compare the rates of HUEs across organizations and to identify opportunities for improvement.

Different kenyon cell populations drive learned approach and avoidance in Drosophila

Tue, 05/12/2015 - 10:32pm

In Drosophila, anatomically discrete dopamine neurons that innervate distinct zones of the mushroom body (MB) assign opposing valence to odors during olfactory learning. Subsets of MB neurons have temporally unique roles in memory processing, but valence-related organization has not been demonstrated. We functionally subdivided the alphabeta neurons, revealing a value-specific role for the approximately 160 alphabeta core (alphabetac) neurons. Blocking neurotransmission from alphabeta surface (alphabetas) neurons revealed a requirement during retrieval of aversive and appetitive memory, whereas blocking alphabetac only impaired appetitive memory. The alphabetac were also required to express memory in a differential aversive paradigm demonstrating a role in relative valuation and approach behavior. Strikingly, both reinforcing dopamine neurons and efferent pathways differentially innervate alphabetac and alphabetas in the MB lobes. We propose that conditioned approach requires pooling synaptic outputs from across the alphabeta ensemble but only from the alphabetas for conditioned aversion.

Shocking revelations and saccharin sweetness in the study of Drosophila olfactory memory

Tue, 05/12/2015 - 10:32pm

It is now almost forty years since the first description of learning in the fruit fly Drosophila melanogaster. Various incarnations of the classic mutagenesis approach envisaged in the early days have provided around one hundred learning defective mutant fly strains. Recent technological advances permit temporal control of neural function in the behaving fly. These approaches have radically changed experiments in the field and have provided a neural circuit perspective of memory formation, consolidation and retrieval. Combining neural perturbations with more classical mutant intervention allows investigators to interrogate the molecular and cellular processes of memory within the defined neural circuits. Here, we summarize some of the progress made in the last ten years that indicates a remarkable conservation of the neural mechanisms of memory formation between flies and mammals. We emphasize that considering an ethologically-relevant viewpoint might provide additional experimental power in studies of Drosophila memory.

Delineating breast ductal carcinoma using combined dye-enhanced wide-field polarization imaging and optical coherence tomography

Tue, 05/12/2015 - 10:32pm

Intra-operative delineation of breast cancer is a challenging problem. We used dye-enhanced wide-field polarization imaging for rapid demarcation of en face cancer margins and optical coherence tomography (OCT) for cross-sectional evaluation. Ductal carcinoma specimens were stained with methylene blue. Wide-field reflectance images were acquired at 440 and 640 nm. Wide-field fluorescence images were excited at 640 nm and registered between 660 nm and 750 nm. OCT images were acquired using a 1310 nm swept-source system. The results were validated against histopathology. Both imaging modalities provided diagnostic information on cancer margins. Combined OCT and wide-field polarization imaging shows promise for intra-operative detection of ductal breast carcinoma.

Sodium acetate as a replacement for sodium bicarbonate in medical toxicology: a review

Tue, 05/12/2015 - 10:32pm

Sodium bicarbonate is central to the treatment of many poisonings. When it was placed on the FDA drug shortage list in 2012, alternative treatment strategies to specific poisonings were considered. Many hospital pharmacies, poison centers, and medical toxicologists proposed sodium acetate as an adequate alternative, despite a paucity of data to support its use in medical toxicology. The intention of this review is to educate the clinician on the use of sodium acetate and to advise them on the potential adverse events when given in excess. We conducted a literature search focused on the pharmacology of sodium acetate, its use as a buffer in pathologic acidemia and dialysis baths, and potential adverse events associated with excess sodium acetate infusion. It appears safe to replace sodium bicarbonate infusion with sodium acetate on an equimolar basis. The metabolism of acetate, however, is more complex than bicarbonate. Future prospective studies will be needed to confirm the efficacy of sodium acetate in the treatment of the poisoned patient.