Showing papers by "University of Medicine and Dentistry of New Jersey published in 2016"

DNA methylation age is associated with mortality in a longitudinal Danish twin study.

Abstract: An epigenetic profile defining the DNA methylation age (DNAm age) of an individual has been suggested to be a biomarker of aging, and thus possibly providing a tool for assessment of health and mortality. In this study, we estimated the DNAm age of 378 Danish twins, age 30-82 years, and furthermore included a 10-year longitudinal study of the 86 oldest-old twins (mean age of 86.1 at follow-up), which subsequently were followed for mortality for 8 years. We found that the DNAm age is highly correlated with chronological age across all age groups (r = 0.97), but that the rate of change of DNAm age decreases with age. The results may in part be explained by selective mortality of those with a high DNAm age. This hypothesis was supported by a classical survival analysis showing a 35% (4-77%) increased mortality risk for each 5-year increase in the DNAm age vs. chronological age. Furthermore, the intrapair twin analysis revealed a more-than-double mortality risk for the DNAm oldest twin compared to the co-twin and a 'dose-response pattern' with the odds of dying first increasing 3.2 (1.05-10.1) times per 5-year DNAm age difference within twin pairs, thus showing a stronger association of DNAm age with mortality in the oldest-old when controlling for familial factors. In conclusion, our results support that DNAm age qualifies as a biomarker of aging.

Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.

Abstract: The fungal pathogen Candida glabrata readily acquires resistance to multiple types of antifungal drugs. Here, Healey et al. show that C. glabrata clinical isolates often carry mutations in a gene involved in DNA mismatch repair, and this is associated with increased propensity to develop antifungal resistance.

Supply and Demand for Radiation Oncology in the United States: Updated Projections for 2015 to 2025

Abstract: Purpose Prior studies have forecasted demand for radiation therapy to grow 10 times faster than the supply between 2010 and 2020. We updated these projections for 2015 to 2025 to determine whether this imbalance persists and to assess the accuracy of prior projections. Methods and Materials The demand for radiation therapy between 2015 and 2025 was estimated by combining current radiation utilization rates determined by the Surveillance, Epidemiology, and End Results data with population projections provided by the US Census Bureau. The supply of radiation oncologists was forecast by using workforce demographics and full-time equivalent (FTE) status provided by the American Society for Radiation Oncology (ASTRO), current resident class sizes, and expected survival per life tables from the US Centers for Disease Control. Results Between 2015 and 2025, the annual total number of patients receiving radiation therapy during their initial treatment course is expected to increase by 19%, from 490,000 to 580,000. Assuming a graduating resident class size of 200, the number of FTE physicians is expected to increase by 27%, from 3903 to 4965. In comparison with prior projections, the new projected demand for radiation therapy in 2020 dropped by 24,000 cases (a 4% relative decline). This decrease is attributable to an overall reduction in the use of radiation to treat cancer, from 28% of all newly diagnosed cancers in the prior projections down to 26% for the new projections. By contrast, the new projected supply of radiation oncologists in 2020 increased by 275 FTEs in comparison with the prior projection for 2020 (a 7% relative increase), attributable to rising residency class sizes. Conclusion The supply of radiation oncologists is expected to grow more quickly than the demand for radiation therapy from 2015 to 2025. Further research is needed to determine whether this is an appropriate correction or will result in excess capacity.

Treatment of adult obesity with bariatric surgery.

Abstract: In 2013, approximately 179,000 bariatric surgery procedures were performed in the United States, including the laparoscopic sleeve gastrectomy (42.1%), Roux-en-Y gastric bypass (34.2%), and laparoscopic adjustable gastric banding (14.0%). Choice of procedure depends on the medical conditions of the patient, patient preference, and expertise of the surgeon. On average, weight loss of 60% to 70% of excess body weight is achieved in the short term, and up to 50% at 10 years. Remission of type 2 diabetes mellitus occurs in 60% to 80% of patients two years after surgery and persists in about 30% of patients 15 years after Roux-en-Y gastric bypass. Other obesity-related comorbidities are greatly reduced, and health-related quality of life improves. The Roux-en-Y procedure carries an increased risk of malabsorption sequelae, which can be minimized with nutritional supplementation and surveillance. Overall, these procedures have a mortality risk of less than 0.5%. Cohort studies show that bariatric surgery reduces all-cause mortality by 30% to 50% at seven to 15 years postsurgery compared with patients with obesity who did not have surgery. Dietary changes, such as consuming protein first at every meal, and regular physical activity are critical for patient success after bariatric surgery. The family physician is well positioned to counsel patients about bariatric surgical options, the risks and benefits of surgery, and to provide long-term support and medical management postsurgery.

eEF2K/eEF2 Pathway Controls the Excitation/Inhibition Balance and Susceptibility to Epileptic Seizures

Abstract: Alterations in the balance of inhibitory and excitatory synaptic transmission have been implicated in the pathogenesis of neurological disorders such as epilepsy. Eukaryotic elongation factor 2 kinase (eEF2K) is a highly regulated, ubiquitous kinase involved in the control of protein translation. Here, we show that eEF2K activity negatively regulates GABAergic synaptic transmission. Indeed, loss of eEF2K increases GABAergic synaptic transmission by upregulating the presynaptic protein Synapsin 2b and α5-containing GABAA receptors and thus interferes with the excitation/inhibition balance. This cellular phenotype is accompanied by an increased resistance to epilepsy and an impairment of only a specific hippocampal-dependent fear conditioning. From a clinical perspective, our results identify eEF2K as a potential novel target for antiepileptic drugs, since pharmacological and genetic inhibition of eEF2K can revert the epileptic phenotype in a mouse model of human epilepsy.

Multicenter validation of American Association for the Surgery of Trauma grading system for acute colonic diverticulitis and its use for emergency general surgery quality improvement program.

Abstract: Background The American Association for the Surgery of Trauma (AAST) has developed a new grading system for uniform description of anatomic severity of emergency general surgery (EGS) diseases, ranging from Grade I (mild) to Grade V (severe). The purpose of this study was to determine the relationship of AAST grades for acute colonic diverticulitis with patient outcomes. A secondary purpose was to propose an EGS quality improvement program using risk-adjusted center outcomes, similar to National Surgical Quality Improvement Program and Trauma Quality Improvement Program methodologies. Methods This was a retrospective study of 1,105 patients (one death) from 13 centers. At each center, two reviewers (blinded to each other's assignments) assigned AAST grades. Interrater reliability was measured using κ coefficient. Relationship between AAST grade and clinical events (complications, intensive care unit use, surgical intervention, and 30-day readmission) as well as length of stay was measured using regression analyses to control for age, comorbidities, and physiologic status at the time of admission. Final model was also used to calculate observed-to-expected (O-E) ratios for adverse outcomes (death, complications, readmissions) for each center. Results Median age was 54 years, 52% were males, 43% were minorities, and 22% required a surgical intervention. Almost two thirds had Grade I or II disease. There was a high level of agreement for grades between reviewers (κ = 0.81). Adverse events increased from 13% for Grade I, to 18% for Grade II, 28% for Grade III, 44% for Grade IV, and 50% for Grade V. Regression analysis showed that higher disease grades were independently associated with all clinical events and length of stay, after adjusting for age, comorbidities, and physiology. O-E ratios showed statistically insignificant variations in risk of death, complications, or readmissions. Conclusion AAST grades for acute colonic diverticulitis are independently associated with clinical outcomes and resource use. EGS quality improvement program methodology that incorporates AAST grade, age, comorbidities, and physiologic status may be used for measuring quality of EGS care. High-quality EGS registries are essential for developing meaningful quality metrics. Level of evidence Prognostic study, level V.

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS): Implications for Clinical Trials

Abstract: Importance Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. Objective To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). Design, Setting, and Participants A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion ( Exposure Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. Main Outcomes and Measures Unified Huntington’s Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. Results Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P P P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [−0.05 to 0.11]), cognitive (−0.54 [−0.67 to −0.40] vs 0.22 [0.12 to 0.32]), and functional (−0.08 [−0.09 to −0.06] vs −0.01 [−0.02 to 0]) measures compared with those without expansion ( P Conclusions and Relevance Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Effect on Clinical Outcome and Growth Factor Synthesis With Adjunctive Use of Pulsed Electromagnetic Fields for Fifth Metatarsal Nonunion Fracture: A Double-Blind Randomized Study.

Abstract: Background:Electromagnetic bone growth stimulators have been found to biologically enhance the bone healing environment, with upregulation of numerous growth factors. The purpose of the study was t...

Mechanisms of HIV Neuropathogenesis: Role of Cellular Communication Systems.

Abstract: Background One of the major complications of Human Immunodeficiency Virus (HIV) infection is the development of HIV-Associated Neurocognitive Disorders (HANDs) in approximately 50-60% of HIV infected individuals. Despite undetectable viral loads in the periphery owing to anti-retroviral therapy, neuroinflammation and neurocognitive impairment are still prevalent in HIV infected individuals. Several studies indicate that the central nervous system (CNS) abnormalities observed in HIV infected individuals are not a direct effect of viral replication in the CNS, rather these neurological abnormalities are associated with amplification of HIV specific signals by unknown mechanisms. We propose that some of these mechanisms of damage amplification are mediated by gap junction channels, pannexin and connexin hemichannels, tunneling nanotubes and microvesicles/exosomes. Objective Our laboratory and others have demonstrated that HIV infection targets cell to cell communication by altering all these communication systems resulting in enhanced bystander apoptosis of uninfected cells, inflammation and viral infection. Here we discuss the role of these communication systems in HIV neuropathogenesis. Conclusion In the current manuscript, we have described the mechanisms by which HIV "hijacks" these host cellular communication systems, leading to exacerbation of HIV neuropathogenesis, and to simultaneously promote the survival of HIV infected cells, resulting in the establishment of viral reservoirs.

TRPM7 kinase activity regulates murine mast cell degranulation

Abstract: Key points The Mg2+ and Ca2+ conducting transient receptor potential melastatin 7 (TRPM7) channel–enzyme (chanzyme) has been implicated in immune cell function. Mice heterozygous for a TRPM7 kinase deletion are hyperallergic, while mice with a single point mutation at amino acid 1648, silencing kinase activity, are not. As mast cell mediators trigger allergic reactions, we here determine the function of TRPM7 in mast cell degranulation and histamine release. Our data establish that TRPM7 kinase activity regulates mast cell degranulation and release of histamine independently of TRPM7 channel function. Our findings suggest a regulatory role of TRPM7 kinase activity on intracellular Ca2+ and extracellular Mg2+ sensitivity of mast cell degranulation. Abstract Transient receptor potential melastatin 7 (TRPM7) is a divalent ion channel with a C-terminally located α-kinase. Mice heterozygous for a TRPM7 kinase deletion (TRPM7+/∆K) are hypomagnesaemic and hyperallergic. In contrast, mice carrying a single point mutation at amino acid 1648, which silences TRPM7 kinase activity (TRPM7KR), are not hyperallergic and are resistant to systemic magnesium (Mg2+) deprivation. Since allergic reactions are triggered by mast cell-mediated histamine release, we investigated the function of TRPM7 on mast cell degranulation and histamine release using wild-type (TRPM7+/+), TRPM7+/∆K and TRPM7KR mice. We found that degranulation and histamine release proceeded independently of TRPM7 channel function. Furthermore, extracellular Mg2+ assured unperturbed IgE-DNP-dependent exocytosis, independently of TRPM7. However, impairment of TRPM7 kinase function suppressed IgE-DNP-dependent exocytosis, slowed the cellular degranulation rate, and diminished the sensitivity to intracellular calcium (Ca2+) in G protein-induced exocytosis. In addition, G protein-coupled receptor (GPCR) stimulation revealed strong suppression of histamine release, whereas removal of extracellular Mg2+ caused the phenotype to revert. We conclude that the TRPM7 kinase activity regulates murine mast cell degranulation by changing its sensitivity to intracellular Ca2+ and affecting granular mobility and/or histamine contents.

Post-traumatic Stress Disorder Symptoms and Mental Health over Time among Low-Income Women at Increased Risk of HIV in the U.S

Abstract: Women living in poverty suffer more post-traumatic stress disorder (PTSD) symptoms than do members of the general population; however we know little about factors associated with changes in their PTSD symptoms over time. Using data from HPTN 064, a cohort of women from low-income, high-HIV-prevalence communities across six eastern states (n=1,860), we assessed the prevalence of and changes in PTSD symptoms over 12 months and the effect of potential predictors on symptom acquisition and remission (via the Primary Care-PTSD symptoms scale). Forty-three percent screened positive for PTSD symptoms. Those reporting food insecurity, ongoing abuse, depressive symptoms, or binge drinking were more likely to acquire PTSD symptoms. Those with ongoing abuse or depressive symptoms were less likely to experience PTSD symptom remission. Findings suggest a need to integrate programs to reduce abuse, depression, and economic hardship with those that address sexual health risks among women living in low-income, high-HIV-prevalence neighborhoods.

Pannexin1 Channels Are Required for Chemokine-Mediated Migration of CD4 + T Lymphocytes: Role in Inflammation and Experimental Autoimmune Encephalomyelitis

Abstract: Pannexin1 (Panx1) channels are large high conductance channels found in all vertebrates that can be activated under several physiological and pathological conditions. Our published data indicate that HIV infection results in the extended opening of Panx1 channels (5-60 min), allowing for the secretion of ATP through the channel pore with subsequent activation of purinergic receptors, which facilitates HIV entry and replication. In this article, we demonstrate that chemokines, which bind CCR5 and CXCR4, especially SDF-1α/CXCL12, result in a transient opening (peak at 5 min) of Panx1 channels found on CD4(+) T lymphocytes, which induces ATP secretion, focal adhesion kinase phosphorylation, cell polarization, and subsequent migration. Increased migration of immune cells is key for the pathogenesis of several inflammatory diseases including multiple sclerosis (MS). In this study, we show that genetic deletion of Panx1 reduces the number of the CD4(+) T lymphocytes migrating into the spinal cord of mice subjected to experimental autoimmune encephalomyelitis, an animal model of MS. Our results indicate that opening of Panx1 channels in response to chemokines is required for CD4(+) T lymphocyte migration, and we propose that targeting Panx1 channels could provide new potential therapeutic approaches to decrease the devastating effects of MS and other inflammatory diseases.

Acute experimental changes in mood state regulate immune function in relation to central opioid neurotransmission: a model of human CNS-peripheral inflammatory interaction.

Abstract: Although evidence shows depressed moods enhance risk for somatic diseases, molecular mechanisms underlying enhanced somatic susceptibility are ill-defined. Knowledge of these molecular mechanisms will inform development of treatment and prevention strategies across comorbid depressive and somatic illnesses. Existing evidence suggests that interleukin-18 (IL-18; an IL-1 family cytokine) is elevated in depression and implicated in pathophysiology underlying comorbid medical illnesses. We previously identified strong associations between baseline IL-18 and μ-opioid receptor availability in major depressive disorder (MDD) volunteers. Combined with the evidence in animal models, we hypothesized that experimental mood induction would change IL-18, the extent proportional to opioid neurotransmitter release. Using the Velten technique in a [11C]carfentanil positron emission tomography neuroimaging study, we examined the impact of experimentally induced mood (sad, neutral) on plasma IL-18 and relationships with concurrent changes in the central opioid neurotransmission in 28 volunteers (healthy, MDD). Results showed mood induction impacted IL-18 (F2,25=12.2, P<0.001), sadness increasing IL-18 (T27=2.6, P=0.01) and neutral mood reducing IL-18 (T27=−4.1, P<0.001). In depressed volunteers, changes in IL-18 were more pronounced (F2,25=3.6, P=0.03) and linearly proportional to sadness-induced μ-opioid activation (left ventral pallidum, bilateral anterior cingulate cortices, right hypothalamus and bilateral amygdala). These data demonstrate that dynamic changes of a pro-inflammatory IL-1 superfamily cytokine, IL-18, and its relationship to μ-opioid neurotransmission in response to experimentally induced sadness. Further testing is warranted to delineate the role of neuroimmune interactions involving IL-18 in enhancing susceptibility to medical illness (that is, diabetes, heart disease and persistent pain states) in depressed individuals.

Congress of Neurological Surgeons Systematic Review and Evidence-Based Guideline on Pretreatment Ophthalmology Evaluation in Patients With Suspected Nonfunctioning Pituitary Adenomas.

Abstract: Background Nonfunctioning pituitary adenomas (NFPAs) are the most frequent pituitary tumors. Visual symptoms from NFPAs are common and include visual field defects, loss of central vision, and motility problems resulting in diplopia. Objective To create evidence-based guidelines in an attempt to formulate guidance for preoperative ophthalmologic evaluation of NFPA patients. Methods An extensive literature search was performed. Only clinical articles describing preoperative ophthalmologic evaluation of adult patients with NFPA were included. To ascertain the class of evidence for the posttreatment follow-up, the authors used the Clinical Assessment evidence-based classification. Results Six studies met the inclusion criteria with respect to the questions regarding the preoperative ophthalmologic evaluation of NFPA patients. Based on the studies located through the search, the authors formulated evidence-based recommendations as they pertain to the necessity of ophthalmologic evaluation before surgical treatment. Conclusion Preoperative ophthalmologic evaluation is recommended. Such evaluation can provide prognostic factors for recovery and, when paired with postoperative evaluation, documents postoperative change. In addition to formal ophthalmologic examination, tests of value include automated static perimetry and optical coherence tomography. Older patients and patients with longer duration (>4 months) of vision loss should be counseled regarding the reduced chance of postoperative vision improvement. The full guidelines document for this chapter can be located at https://www.cns.org/guidelines/guidelines-management-patients-non-functioning-pituitary-adenomas/Chapter_4. Abbreviations NFPA, nonfunctioning pituitary adenomaOCT, optical coherence tomography.

Intraoperative corneal thickness change and clinical outcomes after corneal collagen crosslinking: Standard crosslinking versus hypotonic riboflavin.

Abstract: Purpose To determine intraoperative changes in corneal thickness and outcomes of corneal collagen crosslinking (CXL) using 2 intraoperative regimens: riboflavin–dextran or hypotonic riboflavin. Setting Cornea and refractive surgery practice, Teaneck, New Jersey, USA. Design Prospective randomized case series. Methods Eyes with keratoconus or corneal ectasia were treated. All eyes received preloading with riboflavin 0.1% in 20% dextran. During ultraviolet-A (UVA) exposure, patients were randomly assigned to 1 of 2 study arms; that is, riboflavin–dextran or hypotonic riboflavin. Intraoperative pachymetry was measured before and after the corneal epithelium was removed, after initial riboflavin loading, and after UVA light exposure. Patients were evaluated for maximum keratometry (K), uncorrected distance visual acuity (UDVA), corrected distance visual acuity, corneal thickness, and endothelial cell count (ECC). Results Forty-eight eyes were treated. After removal of the epithelium and riboflavin loading, the mean pachymetry was 430 μm and 432 μm in the standard group and hypotonic group, respectively. Immediately after 30-minute UVA administration, the mean pachymetry was 302 μm and 342 μm, respectively. There was no statistically significant difference in the postoperative maximum K change, UDVA, corneal thickness, or ECC between the 2 groups. Conclusions The cornea thinned substantially during the CXL procedure. The use of hypotonic riboflavin rather than riboflavin–dextran during UVA administration decreased the amount of corneal thinning during the procedure by 30%, from 128 μm to 90 μm. However, there were no significant differences in clinical efficacy or changes in ECC or function between groups postoperatively. In general, corneal thinning during CXL did not seem to compromise the safety of the endothelium. Financial Disclosures Dr. Hersh is a consultant to Avedro, Inc. Dr. Rosenblat has no financial or proprietary interest in any material or method mentioned.

Does Autophagy Mediate Cardiac Myocyte Death During Stress

Abstract: Although autophagy generally promotes survival of cardiac myocytes, it can also promote cardiac myocyte death under some conditions. Here, we describe how activation of autophagy leads to death of cardiac myocytes, introduce autosis as a novel and unique form of cell death by autophagy, and discuss the functional significance of autophagic cell death in cardiac myocytes. Autophagy is an evolutionally conserved mechanism for the degradation of cellular components and organelles by lysosomes. Because autophagy is capable of eliminating large protein aggregates and even damaged organelles, it is a unique component of cellular quality control mechanisms. Autophagy also plays an important role in the maintenance of cellular energetics by recycling amino acids and fatty acids for ATP production. One can speculate that these properties of autophagy are particularly advantageous in terminally differentiated cardiac myocytes because protein aggregates and damaged intracellular organelles are not diluted through cell division in these cells and cardiac myocytes have especially high energetic demands. Consistent with these functions, a large number of studies have supported the notion that autophagy is protective in the heart at baseline and in response to stress.1 However, strong evidence also exists that the activation of autophagy in some situations induces cell death. For example, cardiac myocyte death is attenuated by interventions that inhibit activation of autophagy in some models of ischemia/reperfusion,2 pressure overload,3 doxorubicin-induced cardiomyopathy,4 and excessive mitophagy in response to activation of Parkin.5 Nevertheless, the cell-death–promoting effects of autophagy in the heart remains controversial,6,7 in part, because of technical issues (see below) and because of the general belief that autophagy is solely an adaptive mechanism. Here, we discuss the induction of cardiac myocyte death by autophagy in the heart in particular pathological conditions. Autophagic cell death has been described as massive cytoplasmic vacuolization …

Borrelia burgdorferi induces a type I interferon response during early stages of disseminated infection in mice

Abstract: Lyme borrelia genotypes differ in their capacity to cause disseminated disease. Gene array analysis was employed to profile the host transcriptome induced by Borrelia burgdorferi strains with different capacities for causing disseminated disease in the blood of C3H/HeJ mice during early infection. B. burgdorferi B515, a clinical isolate that causes disseminated infection in mice, differentially regulated 236 transcripts (P < 0.05 by ANOVA, with fold change of at least 2). The 216 significantly induced transcripts included interferon (IFN)-responsive genes and genes involved in immunity and inflammation. In contrast, B. burgdorferi B331, a clinical isolate that causes transient skin infection but does not disseminate in C3H/HeJ mice, stimulated changes in only a few genes (1 induced, 4 repressed). Transcriptional regulation of type I IFN and IFN-related genes was measured by quantitative RT-PCR in mouse skin biopsies collected from the site of infection 24 h after inoculation with B. burgdorferi. The mean values for transcripts of Ifnb, Cxcl10, Gbp1, Ifit1, Ifit3, Irf7, Mx1, and Stat2 were found to be significantly increased in B. burgdorferi strain B515-infected mice relative to the control group. In contrast, transcription of these genes was not significantly changed in response to B. burgdorferi strain B331 or B31-4, a mutant that is unable to disseminate. These results establish a positive association between the disseminating capacity of B. burgdorferi and early type I IFN induction in a murine model of Lyme disease.

Initial treatment of complete rotator cuff tear and transition to surgical treatment: systematic review of the evidence.

Abstract: Background rotator cuff tear affects many people. Natural history, and evidence for non-operative treatment remains limited. Our objective is to assess evidence available for the efficacy and morbidity of commonly used systemic medications, physiotherapy, and injections alongside evaluating any negative long-term effects. Methods a systematic search was performed of PubMed, Cochrane, EMBASE and CINAHL dates (1 January 1960 - 1 December 2014), search terms: 'rotator cuff tear', 'natural history', 'atraumatic', 'injection', 'physiotherapy' or 'physical therapy', 'injection', 'corticosteroid', 'PRP', 'MSC', risk of conservative treatment', and 'surgical indication'. Results eleven studies were included. The mean Coleman Methodology Score modified for conservative therapy is 69.21 (range 88-44) (SD 12.31). This included 2 RCTs, 7 prospective, and 2 retrospective studies. Evidence suggests it is safe to monitor symptomatic rotator cuff tears, as tear size and symptoms are not correlated with pain, function, and/or ultimate outcome. Conclusions complete rotator cuff tears may be effectively treated with injections, exercise in the short and intermediate terms respectively. Negative effect of corticosteroids on rotator cuff tissue has not been demonstrated. Timing to end conservative treatment is unknown, but likely indicated when a patient demonstrates increased weakness and loss of function not recoverable by physiotherapy.

Human papillomavirus infection in the oral cavity of HIV patients is not reduced by initiating antiretroviral therapy.

Abstract: Objective: The incidence of human papillomavirus (HPV)-related oral malignancies is increasing among HIV-infected populations, and the prevalence of oral warts has reportedly increased among HIV patients receiving antiretroviral therapy (ART). We explored whether ART initiation among treatment-naive HIV-positive adults is followed by a change in oral HPV infection or the occurrence of oral warts.

Telomere length measurement by a novel Luminex-based assay: a blinded comparison to Southern blot

Abstract: Telomere length (TL) is a potential biomarker of aging and age-related disease risk. We recently published a novel Luminex-based method for high-throughput, low-cost TL measurement. Here we describe a blinded comparison of the Luminex method to Southern blot, the most precise TL measurement method. Luminex and Southern blot measurements for the same 50 DNA samples were taken in two independent laboratories; each sample was measured twice, several months apart. The inter-assay CV for Luminex ranged from 5.5 to 9.1 (depending on CV estimation method), and Southern blot CV from 1.0 to 1.7. Both measures were inversely associated with age. The correlation between the repeated measurements was 0.66 for Luminex and 0.97 for Southern blot. The correlation between Southern blot and Luminex was 0.65 in round 1 and 0.75 in round 2, and the relationship showed no evidence of non-linearity. Our results demonstrate that the Luminex assay is a valid and reproducible method for high-throughput TL measurement. The Luminex assay involves no DNA amplification, which may make Luminex an attractive alternative to PCR-based TL measurement.

Cervical Lymph Node Metastasis in Adenoid Cystic Carcinoma of the Larynx: A Collective International Review

Abstract: Adenoid cystic carcinoma (AdCC) of the head and neck is a well-recognized pathologic entity that rarely occurs in the larynx. Although the 5-year locoregional control rates are high, distant metastasis has a tendency to appear more than 5 years post treatment. Because AdCC of the larynx is uncommon, it is difficult to standardize a treatment protocol. One of the controversial points is the decision whether or not to perform an elective neck dissection on these patients. Because there is contradictory information about this issue, we have critically reviewed the literature from 1912 to 2015 on all reported cases of AdCC of the larynx in order to clarify this issue. During the most recent period of our review (1991–2015) with a more exact diagnosis of the tumor histology, 142 cases were observed of AdCC of the larynx, of which 91 patients had data pertaining to lymph node status. Eleven of the 91 patients (12.1%) had nodal metastasis and, based on this low proportion of patients, routine elective neck dissection is therefore not recommended.

Metformin pharmacogenomics: a genome-wide association study to identify genetic and epigenetic biomarkers involved in metformin anticancer response using human lymphoblastoid cell lines.

Abstract: Metformin is currently considered as a promising anticancer agent in addition to its anti-diabetic effect. To better individualize metformin therapy and explore novel molecular mechanisms in cancer treatment, we conducted a pharmacogenomic study using 266 lymphoblastoid cell lines (LCLs). Metformin cytotoxicity assay was performed using the MTS assay. Genome-wide association (GWA) analyses were performed in LCLs using 1.3 million SNPs, 485k DNA methylation probes, 54k mRNA expression probe sets, and metformin cytotoxicity (IC50s). Top candidate genes were functionally validated using siRNA screening, followed by MTS assay in breast cancer cell lines. Further study of one top candidate, STUB1, was performed to elucidate the mechanisms by which STUB1 might contribute to metformin action. GWA analyses in LCLs identified 198 mRNA expression probe sets, 12 SNP loci, and 5 DNA methylation loci associated with metformin IC50 with P-values <10−4 or <10−5. Integrated SNP/methylation loci-expression-IC50 analyses found 3 SNP loci or 5 DNA methylation loci associated with metformin IC50 through trans-regulation of expression of 11 or 26 genes with P-value <10−4. Functional validation of top 61 candidate genes in 4 IPA networks indicated down regulation of 14 genes significantly altered metformin sensitivity in two breast cancer cell lines. Mechanistic studies revealed that the E3 ubiquitin ligase, STUB1, could influence metformin response by facilitating proteasome-mediated degradation of cyclin A. GWAS using a genomic data-enriched LCL model system, together with functional and mechanistic studies using cancer cell lines, help us to identify novel genetic and epigenetic biomarkers involved in metformin anticancer response.

Awareness of Subjective Fatigue After Moderate to Severe Traumatic Brain Injury.

Abstract: OBJECTIVE: As measurements of subjective fatigue after traumatic brain injury (TBI) rely on self-assessment, deficits in self-awareness after TBI may distort subjective fatigue reports. This study investigates awareness of subjective fatigue after TBI using self- and informant reports. PARTICIPANTS: Fourteen adults with moderate to severe TBI and 7 healthy controls (HCs). MEASURES: Modified Fatigue Impact Scale (MFIS) and battery of cognitive and emotional tests. Informants completed an "other-report," rating their perception of participant's fatigue. Subjective fatigue awareness was defined as discrepancy between self- and other-MFIS scores. RESULTS: Adults with TBI showed greater discrepancies between self- and other-MFIS scores than did HCs. Negative relations were found between fatigue awareness and symptoms of depression, but there were no relationships between fatigue awareness and cognitive performance. CONCLUSIONS: Results indicate that adults with TBI have poorer awareness of subjective fatigue than HCs. Correlations between subjective fatigue awareness and depression support existing literature implicating strong emotional components in the experience of subjective fatigue postinjury. FINDINGS suggest cautious interpretation of subjective fatigue, as responses may not reflect fatigue symptoms exclusively. Language: en

Prostate cancer characteristics in the World Trade Center cohort, 2002-2013.

Abstract: An increased incidence of prostate cancer was reported in three cohorts of World Trade Center (WTC) respondents. It is uncertain whether this increase is because of WTC-related exposures or enhanced surveillance. Prostate cancer cases (2002-2013) were obtained from the WTC Health Program. Age, race, and Gleason score distribution were compared with New York State Cancer Registry cases from the same time period. Multivariate models were adjusted for age and race. Analyses of clinical characteristics of prostate cancer cases within the cohort were also carried out, adjusting for age, race, and WTC exposure categories. WTC respondents had a prostate cancer age-standardized rate ratio of 1.65 [95% confidence interval (CI): 1.37-1.93] compared with New York State; age-specific ratios were highest for ages 30-49 (2.28; 95% CI: 1.51-3.43), 70-74 (2.05; 95% CI: 1.03-4.10), and 80-84 years (5.65; 95% CI: 1.41-22.58). High WTC exposure was associated with advanced clinical stage (5.58; 95% CI: 1.05-29.76; Ptrend=0.03). WTC respondents continue to have a higher prostate cancer rate compared with New York State as a whole. Respondents with a higher WTC exposure level may have had more advanced clinical stage of prostate cancer.

Patterns and Correlates of Baseline Thiazide-Type Diuretic Prescription in the Systolic Blood Pressure Intervention Trial

Abstract: Thiazides and thiazide-type diuretics are recommended as first-line agents for the treatment of hypertension, but contemporary information on their use in clinical practice is lacking. We examined patterns and correlates of thiazide prescription in a cross-sectional analysis of baseline data from participants enrolled in the Systolic Blood Pressure Intervention Trial (SPRINT). We examined baseline prescription of thiazides in 7582 participants receiving at least 1 antihypertensive medication by subgroup, and used log-binomial regression to calculate adjusted prevalence ratios for thiazide prescription (versus no thiazide). Forty-three percent of all participants were prescribed a thiazide at baseline, but among participants prescribed a single agent, the proportion was only 16%. The prevalence of thiazide prescription differed significantly by demographic factors, with younger participants, women, and blacks all having higher adjusted prevalence of thiazide prescription than other corresponding subgroups. Participants in the lowest category of kidney function (estimated glomerular filtration rate <30 mL/min per 1.73 m2) were half as likely to be prescribed a thiazide as participants with preserved kidney function. In conclusion, among persons with hypertension and heightened cardiovascular risk, we found that thiazide prescription varied significantly by demographics and kidney disease status, despite limited evidence about relative differences in effectiveness.

A fully human antibody to gp41 selectively eliminates HIV-infected cells that transmigrated across a model human blood brain barrier.

Abstract: Objective Many HIV patients on combined antiretroviral therapy exhibit HIV-associated neurocognitive disorders because the brain becomes a viral reservoir. There is a need for therapeutics that can enter the central nervous system (CNS) and eradicate the virus. Design Radiolabeled human mAb 2556 to HIV gp41 selectively kills HIV-infected cells in vivo and in vitro. Here we tested the ability of 213Bi-2556 to cross a tissue culture model of the human blood brain barrier and kill HIV-infected peripheral blood mononuclear cells (PBMCs) and monocytes on the CNS side of the barrier. Methods 2556 mAb isoelectric point was determined with isoelectric focusing. The ability of radiolabeled 2556 to penetrate through the barrier was studied by adding it to the upper chamber of the barriers and its penetration into the CNS side was followed for 5 h. To assess the ability of Bi-2556 to kill the HIV-infected cells on the CNS side of barrier, the HIV-infected and uninfected PBMCs and monocytes were allowed to transmigrate across the barriers overnight followed by application of Bi-2556 or control mAb Bi-1418 to the top of the barrier. Killing of cells was measured by TUNEL and Trypan blue assays. The barriers were examined by confocal microscopy for overt damage. Results The isoelectric point of Bi-2556 was 9.6 enabling its penetration through the barrier by transcytosis. Bi-2556 killed significantly more transmigrated HIV-infected cells in comparison to Bi-1418 and uninfected cells. No overt damage to barriers was observed. Conclusion We demonstrated that Bi-2556 mAb crossed an in-vitro human blood brain barrier and specifically killed transmigrated HIV-infected PBMCs and monocytes without overt damage to the barrier.

Ultrasound Evaluation of the Urethra and Bladder Neck Before and After Transurethral Bulking.

Abstract: Objectives The aims of the study were to describe ultrasound findings in women with stress urinary incontinence (SUI) after transurethral injection of Coaptite, to describe symptoms 3 months after injection, and to determine whether there was an association between degree of improvement and sonographic findings. Methods This is a prospective cohort study of women with SUI undergoing transurethral Coaptite injection. Subjects completed the Urinary Distress Inventory and Incontinence Severity Index preinjection and 3 months postinjection. Translabial ultrasound was performed immediately after and 3 months postinjection. Two- and three-dimensional images were captured to measure the dimensions and location of Coaptite in relation to the bladder neck as well as degree of coaptation. Change in volume of injection over time was calculated using these measurements. Results Twenty subjects were enrolled in the study. At 3 months, 45% of subjects had 90% or greater improvement, 45% had 50% to 75% improvement, and 10% had less than 30% improvement. Mean distance of Coaptite from the bladder neck at 3 months was not statistically different from the distance immediately after injection. There was a 40.9% to 45.8% mean reduction in volume at 3 months as well as a 39.5% reduction in coaptation. Degree of improvement was associated with mean change in volume over time: those with the least improvement had the greatest reduction in volume. Volume of initial injection, percent coaptation, and number of vials used to perform the injection were not associated with patient symptoms. Conclusions In this series, 90% of patients who underwent Coaptite injection for SUI reported 50% or greater improvement. The volume of Coaptite decreased by 40% over time, and the degree of shrinkage correlated with clinical outcomes.