eScholarship@UMMS

Syndicate content
Recent documents in eScholarship@UMMS
Updated: 1 hour 17 min ago

A systematic review of pharmacological pain management in multiple sclerosis

Sun, 10/25/2015 - 7:56pm

BACKGROUND: Both chronic and acute pain have been cited as the most common symptoms amongst patients with multiple sclerosis (MS), with recent prevalence estimates as high as 83 %. The evidence for spasticity and trigeminal neuralgia pharmacological treatments in MS has been systematically reviewed, but no equivalent reviews have been published concerning MS pain unrelated to these two conditions.

OBJECTIVE: Our objective was to systematically review pain management strategies for the reduction of non-spastic and non-trigeminal neuralgic pain in MS patients.

DATA SOURCES: Experimental studies published after 1965 were chosen for review by searching electronic databases (e.g. PubMed, Cumulative Index to Nursing and Allied Health Literature, Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and clinicaltrials.gov) and bibliographies/citations of previously published reviews.

STUDY SELECTION: Studies were included if all participants were adults clinically diagnosed with MS, study sample was not restricted to participants with spasticity or trigeminal neuralgia, and participant-reported pain was a primary or secondary outcome measured with a validated tool.

STUDY APPRAISAL AND SYNTHESIS METHODS: Records were screened and methodological qualities of included studies were assessed independently by two reviewers under the supervision of another reviewer using the principles recommended in the Cochrane Handbook for Systematic Review of Interventions and the levels of evidence espoused by the American Academy of Neurology.

RESULTS: Fifteen studies met the inclusion and exclusion criteria for review; interventions included antidepressants, anticonvulsants, dextromethorphan/quinidine, cannabinoids, and opioids/opioid antagonists. The pooled effect size for anticonvulsants (4 studies, 78 participants) was -1.88 (95 % CI: -3.13 to -0.64). The pooled effect size for cannabinoids (3 studies, 565 participants) was 0.08 (95 % CI: -0.74 to 0.89). Overall, only four trials reported Class 1 evidence. For these trials, dizziness was the most commonly reported adverse event, followed by nausea and somnolence.

LIMITATIONS: The relatively small number of trials in MS patients with chronic pain precludes specific recommendations for treatment strategies. The review did not reveal any studies of drug combinations.

CONCLUSIONS: More trials with rigorous design and reporting are needed to determine effective treatments for specific pain types presenting in people living with MS.

Characterization and optimization of the glucan particle-based vaccine platform

Sun, 10/25/2015 - 7:56pm

Glucan particles (GPs) are hollow porous Saccharomyces cerevisiae cell walls that are treated so that they are composed primarily of beta-1,3-d-glucans. Our previous studies showed that GPs can serve as an effective vaccine platform. Here, we characterize CD4(+) T-cell and antibody responses in immunized mice as a function of antigen (ovalbumin) encapsulation, antigen dose, particle numbers, time, immunization schedule, and trapping methods. Although we found that GPs served as an effective adjuvant when admixed with free antigens for IgG1 antibody production, stronger CD4(+) T-cell and IgG2c antibody responses were stimulated when antigens were encapsulated inside GPs, suggesting that the GP platform acts as both an adjuvant and a delivery system. Vigorous T-cell and antibody responses were stimulated even at submicrogram antigen doses, as long as the number of GPs was kept at 5 x 10(7) particles per immunization. One prime and one boost were sufficient to elicit robust immune responses. In addition, strong antigen-specific antibody and T-cell responses prevailed up to 20 months following the last immunization, including those of gamma interferon (IFN-gamma), interleukin 17A (IL-17A), and dual IFN-gamma/IL-17A-secreting CD4(+) T cells. Finally, robust immune responses were observed using generally recognized as safe (GRAS) materials (alginate and calcium, with or without chitosan) to trap antigens within GPs. Thus, these studies demonstrate that antigens encapsulated into GPs make an effective vaccine platform that combines adjuvanticity and antigen delivery to elicit strong durable immune responses at relatively low antigen doses using translationally relevant formulations.

QTc-prolongation in posterior circulation stroke

Sun, 10/25/2015 - 7:56pm

BACKGROUND AND PURPOSE: To evaluate the relationship between infarct location and QTc-prolongation in patients with posterior circulation strokes.

METHODS: Admission electrocardiograms (ECG) of 131 patients among a prospective sample of 407 consecutive adult patients in the New England Medical Center Posterior Circulation Registry were retrospectively analyzed. The QT interval (ms) was measured and corrected using Bazett's formula (QTcBazett) as well as linear regression functions (QTcLinear). QTcBazett > 440 ms and QTcLinear > /= 450 ms for men ( > /=460 ms for women) were considered prolonged. Multivariable linear and logistic regression analyses were used to identify independent predictors of the QTc.

RESULTS: Overall, 34% of patients had a prolonged QTcBazett and 7% had a prolonged QTcLinear noted on the admission ECG. There was a significant association between temporal lobe infarction and QTcBazett and QTcLinear (p < 0.001 for both) in multivariable linear regression analyses adjusting for demographics, ECG parameters, and preadmission medication use. In multivariable logistic regression analysis, temporal lobe infarction emerged as an independent predictor of prolonged QTcBazett (p = 0.009) and QTcLinear (p = 0.008), respectively. Sensitivity analyses excluding patients with transient ischemic attack yielded similar results. Exploratory analyses indicated that patients with temporal lobe infarction had worse functional 30-day outcomes in multivariable logistic regression (p = 0.022). However, there was no significant association between QTc and 30-day functional outcome.

CONCLUSIONS: QTc-prolongation is common after posterior circulation stroke and associated with temporal lobe infarction. Prospective studies are needed to confirm these preliminary findings and to examine potential long-term consequences.

Investigating the effect of characteristic x-rays in cadmium zinc telluride detectors under breast computerized tomography operating conditions

Sun, 10/25/2015 - 7:56pm

A number of research groups have been investigating the use of dedicated breast computerized tomography (CT). Preliminary results have been encouraging, suggesting an improved visualization of masses on breast CT as compared to conventional mammography. Nonetheless, there are many challenges to overcome before breast CT can become a routine clinical reality. One potential improvement over current breast CT prototypes would be the use of photon counting detectors with cadmium zinc telluride (CZT) (or CdTe) semiconductor material. These detectors can operate at room temperature and provide high detection efficiency and the capability of multi-energy imaging; however, one factor in particular that limits image quality is the emission of characteristic x-rays. In this study, the degradative effects of characteristic x-rays are examined when using a CZT detector under breast CT operating conditions. Monte Carlo simulation software was used to evaluate the effect of characteristic x-rays and the detector element size on spatial and spectral resolution for a CZT detector used under breast CT operating conditions. In particular, lower kVp spectra and thinner CZT thicknesses were studied than that typically used with CZT based conventional CT detectors. In addition, the effect of characteristic x-rays on the accuracy of material decomposition in spectral CT imaging was explored. It was observed that when imaging with 50-60 kVp spectra, the x-ray transmission through CZT was very low for all detector thicknesses studied (0.5-3.0 mm), thus retaining dose efficiency. As expected, characteristic x-ray escape from the detector element of x-ray interaction increased with decreasing detector element size, approaching a 50% escape fraction for a 100 mum size detector element. The detector point spread function was observed to have only minor degradation with detector element size greater than 200 mum and lower kV settings. Characteristic x-rays produced increasing distortion in the spectral response with decreasing detector element size. If not corrected for, this caused a large bias in estimating tissue density parameters for material decomposition. It was also observed that degradation of the spectral response due to characteristic x-rays caused worsening precision in the estimation of tissue density parameters. It was observed that characteristic x-rays do cause some degradation in the spatial and spectral resolution of thin CZT detectors operating under breast CT conditions. These degradations should be manageable with careful selection of the detector element size. Even with the observed spectral distortion from characteristic x-rays, it is still possible to correctly estimate tissue parameters for material decomposition using spectral CT if accurate modeling is used.

DNA vaccine prime followed by boost with live attenuated virus significantly improves antigen-specific T cell responses against human cytomegalovirus

Sun, 10/25/2015 - 7:56pm

As a leading cause of congenital infection and a major threat to immunocompromised individuals, human cytomegalovirus (HCMV) is a major global public health concern. Effective HCMV vaccines would need to induce potent and balanced humoral and cellular immune responses. In this pilot study, immunogenicity studies were conducted in mice to examine HCMV antigen-specific antibody and T cell responses when a heterologous prime-boost immunization strategy was tested. DNA vaccines expressing either targets of protective antibody responses (gB and gM/gN) or well characterized T cell immunogens (pp65, pp150, and IE1) were used as the priming immunization while the live attenuated HCMV vaccine Towne strain was used as the boost, which may act like an inactivated vaccine due to the inability of HCMV to replicate in a mouse host. Our data indicate that while DNA vaccines were effective in priming HCMV-specific antibody responses, the final titers of gB- or gM-specific antibodies were not much different from those elicited by using multiple immunizations of HCMV alone. In contrast, DNA priming significantly enhanced T cell responses against gB, pp65, and IE1 as measured by IFN-gamma. However, HCMV alone was not effective in eliciting strong T cell immune responses when used in a mouse host. Our data indicate that the complexity of antigen composition from a large virus, such as HCMV, may affect the profile of immune responses when viral vaccines are used as a boost.

Apoptosis induced by the fungal pathogen gliotoxin requires a triple phosphorylation of Bim by JNK

Sun, 10/25/2015 - 7:56pm

We previously reported that gliotoxin (GT), the major virulence factor of the mold Aspergillus fumigatus causing invasive aspergillosis (IA) in immunocompromised patients, induces apoptosis in a Bak-dependent manner. The signaling pathway leading to Bak activation and subsequent mitochondrial outer membrane permeabilization (MOMP) is elusive. Here, we show that GT and the supernatant of A. fumigatus (but not its GT-defective mutant) activate the JNK pathway and require a co-operative JNK-mediated BimEL phosphorylation at three sites (S100, T112 and S114) to induce apoptosis in mouse fibroblasts, human bronchial and mouse alveolar epithelial cells. Cells (i) treated with the JNK inhibitor SP600125, (ii) deleted or knocked down for JNK1/2 or Bim or (iii) carrying the BimEL triple phosphomutant S100A/T112A/S114A instead of wild-type BimEL are similarly resistant to GT-induced apoptosis. Triple-phosphorylated BimEL is more stable, redistributes from a cytoskeletal to a membrane fraction, better interacts with Bcl-2 and Bcl-xL and more effectively activates Bak than the unphosphorylated mutant. These data indicate that JNK-mediated BimEL phosphorylation at S100, T112 and S114 constitutes a novel regulatory mechanism to activate Bim in response to apoptotic stimuli.

Evolving concepts of gliogenesis: a look way back and ahead to the next 25 years

Sun, 10/25/2015 - 7:56pm

Glial cells are present in all organisms with a CNS and, with increasing brain complexity, glial cells have undergone substantive increases in cell number, diversity, and functions. Invertebrates, such as Drosophila, possess glial subtypes with similarity to mammalian astrocytes in their basic morphology and function, representing fertile ground for unraveling fundamental aspects of glial biology. Although glial subtypes in simple organisms may be relatively homogenous, emerging evidence suggests the possibility that mammalian astrocytes might be highly diversified to match the needs of local neuronal subtypes. In this Perspective, we review classic and new roles identified for astrocytes and oligodendrocytes by recent studies. We propose that delineating genetic and developmental programs across species will be essential to understand the core functions of glia that allow enhanced neuronal function and to achieve new insights into glial roles in higher-order brain function and neurological disease.

Heart rate is a prognostic risk factor for myocardial infarction: a post hoc analysis in the PERFORM (Prevention of cerebrovascular and cardiovascular Events of ischemic origin with teRutroban in patients with a history oF ischemic strOke or tRansient isc

Sun, 10/25/2015 - 7:56pm

BACKGROUND: Elevated resting heart rate is known to be detrimental to morbidity and mortality in cardiovascular disease, though its effect in patients with ischemic stroke is unclear. We analyzed the effect of baseline resting heart rate on myocardial infarction (MI) in patients with a recent noncardioembolic cerebral ischemic event participating in PERFORM.

METHODS: We compared fatal or nonfatal MI using adjusted Cox proportional hazards models for PERFORM patients with baseline heart rate < 70 bpm (n=8178) or > /=70 bpm (n=10,802). In addition, heart rate was analyzed as a continuous variable. Other cerebrovascular and cardiovascular outcomes were also explored.

RESULTS: Heart rate > /=70 bpm was associated with increased relative risk for fatal or nonfatal MI (HR 1.32, 95% CI 1.03-1.69, P=0.029). For every 5-bpm increase in heart rate, there was an increase in relative risk for fatal and nonfatal MI (11.3%, P=0.0002). Heart rate > /=70 bpm was also associated with increased relative risk for a composite of fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (excluding hemorrhagic death) (P < 0001); vascular death (P < 0001); all-cause mortality (P < 0001); and fatal or nonfatal stroke (P=0.04). For every 5-bpm increase in heart rate, there were increases in relative risk for fatal or nonfatal ischemic stroke, fatal or nonfatal MI, or other vascular death (4.7%, P < 0.0001), vascular death (11.0%, P < 0.0001), all-cause mortality (8.0%, P < 0.0001), and fatal and nonfatal stroke (2.4%, P=0.057).

CONCLUSION: Elevated heart rate > /=70 bpm places patients with a noncardioembolic cerebral ischemic event at increased risk for MI.

Cutting edge: TLR signaling licenses IRAK1 for rapid activation of the NLRP3 inflammasome

Sun, 10/25/2015 - 7:55pm

Activation of the NLRP3 inflammasome by diverse stimuli requires a priming signal from TLRs and an activation signal from purinergic receptors or pore-forming toxins. In this study, we demonstrate, through detailed analysis of NLRP3 activation in macrophages deficient in key downstream TLR signaling molecules, that MyD88 is required for an immediate early phase, whereas Toll/IL-1R domain-containing adapter inducing IFN-beta is required for a subsequent intermediate phase of posttranslational NLRP3 activation. Both IL-1R-associated kinase (IRAK) 1 and IRAK4 are critical for rapid activation of NLRP3 through the MyD88 pathway, but only IRAK1 is partially required in the Toll/IL-1R domain-containing adapter inducing IFN-beta pathway. IRAK1 and IRAK4 are also required for rapid activation of NLRP3 by Listeria monocytogenes, as deletion of IRAK1 or IRAK4 led to defective inflammasome activation. These findings define the pathways that lead to rapid NLRP3 activation and identify IRAK1 as a critical mediator of a transcription-independent,inflammasome-dependent early warning response to pathogenic infection.

Assessing the need for improved access to rheumatology care: a survey of Massachusetts community health center medical directors

Sun, 10/25/2015 - 7:55pm

OBJECTIVE: Access to rheumatology care can expedite diagnosis and treatment of rheumatic diseases and reduce disparities. We surveyed community health center (CHC) medical directors to evaluate rheumatology care in underserved areas and potential strategies for improvement.

METHODS: We identified 77 Massachusetts CHCs that provide adult medical services and sent a 40-item survey to their physician medical directors. Survey questions assessed the centers' prevalence of rheumatic diseases, prescribing practices of immunosuppressive medications, and possible interventions to improve care. We compared CHC characteristics and rheumatology-specific items and then stratified our data by the response to whether improved access to rheumatology care was needed. Qualitative data were analyzed thematically.

RESULTS: Thirty-six CHC physician medical directors returned surveys (47% response rate). Fifty-five percent indicated a need for better access to rheumatology care. Eighty-six percent of CHC physicians would not start a patient with rheumatoid arthritis on a disease-modifying antirheumatic drug; 94% would not start a patient with systemic lupus erythematosus on an immunosuppressant. When we compared CHCs that reported needing better access to rheumatology care to those that did not, the former described a significantly greater percentage of patients with private insurance or Medicaid who required outside rheumatology referrals (P < 0.05). Language differences and insurance status were highlighted as barriers to obtaining rheumatology care. Sixteen directors (57%) ranked the patient navigator-a layperson to assist with care coordination-as their first-choice intervention.

CONCLUSIONS: Community health center medical directors expressed a need for better access to rheumatology services. A patient navigator for rheumatic diseases was proposed to help improve care and reduce health disparities.

Genomic analysis identifies targets of convergent positive selection in drug-resistant Mycobacterium tuberculosis

Sun, 10/25/2015 - 7:55pm

M. tuberculosis is evolving antibiotic resistance, threatening attempts at tuberculosis epidemic control. Mechanisms of resistance, including genetic changes favored by selection in resistant isolates, are incompletely understood. Using 116 newly sequenced and 7 previously sequenced M. tuberculosis whole genomes, we identified genome-wide signatures of positive selection specific to the 47 drug-resistant strains. By searching for convergent evolution--the independent fixation of mutations in the same nucleotide position or gene--we recovered 100% of a set of known resistance markers. We also found evidence of positive selection in an additional 39 genomic regions in resistant isolates. These regions encode components in cell wall biosynthesis, transcriptional regulation and DNA repair pathways. Mutations in these regions could directly confer resistance or compensate for fitness costs associated with resistance. Functional genetic analysis of mutations in one gene, ponA1, demonstrated an in vitro growth advantage in the presence of the drug rifampicin.

Cost-effectiveness of helicopter versus ground emergency medical services for trauma scene transport in the United States

Sun, 10/25/2015 - 7:55pm

STUDY OBJECTIVE: We determine the minimum mortality reduction that helicopter emergency medical services (EMS) should provide relative to ground EMS for the scene transport of trauma victims to offset higher costs, inherent transport risks, and inevitable overtriage of patients with minor injury.

METHODS: We developed a decision-analytic model to compare the costs and outcomes of helicopter versus ground EMS transport to a trauma center from a societal perspective during a patient's lifetime. We determined the mortality reduction needed to make helicopter transport cost less than $100,000 and $50,000 per quality-adjusted life-year gained compared with ground EMS. Model inputs were derived from the National Study on the Costs and Outcomes of Trauma, National Trauma Data Bank, Medicare reimbursements, and literature. We assessed robustness with probabilistic sensitivity analyses.

RESULTS: Helicopter EMS must provide a minimum of a 15% relative risk reduction in mortality (1.3 lives saved/100 patients with the mean characteristics of the National Study on the Costs and Outcomes of Trauma cohort) to cost less than $100,000 per quality-adjusted life-year gained and a reduction of at least 30% (3.3 lives saved/100 patients) to cost less than $50,000 per quality-adjusted life-year. Helicopter EMS becomes more cost-effective with significant reductions in patients with minor injury who are triaged to air transport or if long-term disability outcomes are improved.

CONCLUSION: Helicopter EMS needs to provide at least a 15% mortality reduction or a measurable improvement in long-term disability to compare favorably with other interventions considered cost-effective. Given current evidence, it is not clear that helicopter EMS achieves this mortality or disability reduction. Reducing overtriage of patients with minor injury to helicopter EMS would improve its cost-effectiveness. Inc. All rights reserved.

Identification of strain-specific B-cell epitopes in Trypanosoma cruzi using genome-scale epitope prediction and high-throughput immunoscreening with peptide arrays

Sun, 10/25/2015 - 7:55pm

BACKGROUND: The factors influencing variation in the clinical forms of Chagas disease have not been elucidated; however, it is likely that the genetics of both the host and the parasite are involved. Several studies have attempted to correlate the T. cruzi strains involved in infection with the clinical forms of the disease by using hemoculture and/or PCR-based genotyping of parasites from infected human tissues. However, both techniques have limitations that hamper the analysis of large numbers of samples. The goal of this work was to identify conserved and polymorphic linear B-cell epitopes of T. cruzi that could be used for serodiagnosis and serotyping of Chagas disease using ELISA.

METHODOLOGY: By performing B-cell epitope prediction on proteins derived from pair of alleles of the hybrid CL Brener genome, we have identified conserved and polymorphic epitopes in the two CL Brener haplotypes. The rationale underlying this strategy is that, because CL Brener is a recent hybrid between the TcII and TcIII DTUs (discrete typing units), it is likely that polymorphic epitopes in pairs of alleles could also be polymorphic in the parental genotypes. We excluded sequences that are also present in the Leishmania major, L. infantum, L. braziliensis and T. brucei genomes to minimize the chance of cross-reactivity. A peptide array containing 150 peptides was covalently linked to a cellulose membrane, and the reactivity of the peptides was tested using sera from C57BL/6 mice chronically infected with the Colombiana (TcI) and CL Brener (TcVI) clones and Y (TcII) strain.

FINDINGS AND CONCLUSIONS: A total of 36 peptides were considered reactive, and the cross-reactivity among the strains is in agreement with the evolutionary origin of the different T. cruzi DTUs. Four peptides were tested against a panel of chagasic patients using ELISA. A conserved peptide showed 95.8% sensitivity, 88.5% specificity, and 92.7% accuracy for the identification of T. cruzi in patients infected with different strains of the parasite. Therefore, this peptide, in association with other T. cruzi antigens, may improve Chagas disease serodiagnosis. Together, three polymorphic epitopes were able to discriminate between the three parasite strains used in this study and are thus potential targets for Chagas disease serotyping.

Oncofetal protein IMP3: a new diagnostic biomarker for laryngeal carcinoma

Sun, 10/25/2015 - 7:55pm

An accurate diagnosis of laryngeal squamous cell carcinoma (LSCC) is essential for patient management. The diagnosis of LSCC, especially in superficial biopsies, can present a diagnostic challenge for pathologists. The ability to diagnose LSCC would be greatly improved by the detection of a tumor-associated antigen. IMP3 is an oncofetal protein associated with aggressive and advanced tumors and is specifically expressed in malignant tumors but not found in benign tissues. The aim of this study was to determine the expression and diagnostic value of IMP3 in LSCC to determine whether it can serve as a diagnostic biomarker. A total of 238 cases (laryngectomy, n = 121; biopsy, n = 117) consisting of 11 laryngeal carcinoma in situ/severe dysplasia and 227 invasive LSCC were examined by immunohistochemistry for IMP3 expression. IMP3 showed strong cytoplasmic staining in 217 (92%) of 238 LSCCs regardless of histologic grade. In addition, 58 (89%) of 65 small biopsies ( < /=5 mm in greatest dimension) containing a minute amount of carcinoma were positive for IMP3. In contrast to malignant tumors, IMP3 expression was not found in any of the adjacent benign squamous epithelium (0/118 cases; 0%), mild or moderate dysplasia (0/139 cases; 0%), or pseudoepitheliomatous hyperplasia (0/99 cases; 0%). In summary, we are the first to describe that IMP3 is a highly sensitive and specific biomarker for LSCC. The expression of IMP3 in LSCC can be used as a positive biomarker to increase the level of confidence in establishing a definitive diagnosis of a malignancy in laryngeal biopsy.

Evaluation of an institution-wide guideline for hyperglycemic emergencies at a tertiary academic medical center

Sun, 10/25/2015 - 7:55pm

BACKGROUND: No previous studies exist examining implementation of an institution-wide guideline and order set for hyperglycemic emergencies (diabetic ketoacidosis [DKA] and hyperosmolar hyperglycemic state [HHS]).

OBJECTIVE: Evaluate the impact of an institutional guideline and order set for hyperglycemic emergencies.

METHODS: This retrospective descriptive study evaluated patients with a diagnosis of DKA or HHS. Two time periods were evaluated: phase 1 (PRE) assessed practice preguideline implementation, and phase 2 (POST) assessed practice postguideline and order set introduction.

RESULTS: A total of 172 patients (91 PRE and 81 POST) were included in the analysis. There was no difference in the mean hospital length of stay (LOS) in the PRE versus POST groups (5.2 +/- 4 vs 5.9 +/- 8.6 days, P = .49). The mean intensive care unit (ICU) LOS was shorter in the POST group (64.8 +/- 19 vs 37.1 +/- 74.8 hours, P < .01). The POST group had an increase in frequency of assessments for clearance of urinary ketones (18 vs 33.3%, P = .03) and beta-hydroxybutyrate (16 vs 37%, P < .01). Frequency of point-of-care glucose testing (12.5 +/- 4.6 vs 15.1 +/- 4.7, P < .01) and time to anion gap closure (13 +/- 9 vs 9.3 +/- 7.4 hours, P < .01) improved in the POST group. There was no difference in the number of patients experiencing hypoglycemia or hypokalemia between both groups.

CONCLUSIONS: Implementation of an institutional guideline and order set for hyperglycemic emergencies decreased ICU LOS and time to anion gap closure, with no difference in rates of hypoglycemia.

Systolic left ventricular function according to left ventricular concentricity and dilatation in hypertensive patients: the Losartan Intervention For Endpoint reduction in hypertension study

Sun, 10/25/2015 - 7:55pm

BACKGROUND: Left ventricular hypertrophy [LVH, high left ventricular mass (LVM)] is traditionally classified as concentric or eccentric based on left ventricular relative wall thickness. We evaluated left ventricular systolic function in a new four-group LVH classification based on left ventricular dilatation [high left ventricular end-diastolic volume (EDV) index and concentricity (LVM/EDV)] in hypertensive patients.

METHODS AND RESULTS: Nine hundred thirty-nine participants in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) echocardiography substudy had measurable LVM at enrolment. Patients with LVH (LVM/body surface area > /=116 g/m in men and > /=96 g/m in women) were divided into four groups; 'eccentric nondilated' (normal LVM/EDV and EDV), 'eccentric dilated' (increased EDV, normal LVM/EDV), 'concentric nondilated' (increased LVM/EDV with normal EDV), and 'concentric dilated' (increased LVM/EDV and EDV) and compared to patients with normal LVM. At baseline, 12% had eccentric nondilated, 20% eccentric dilated, 29% concentric nondilated, and 14% concentric dilated LVH, with normal LVM in 25%. Compared with the concentric nondilated LVH group, those with concentric dilated LVH had significantly lower pulse pressure/stroke index and ejection fraction; higher LVM index, stroke volume, cardiac output, left ventricular midwall shortening, left atrial volume and isovolumic relaxation time; and more had segmental wall motion abnormalities (all P < 0.05). Similar differences existed between patients with eccentric dilated and those with eccentric nondilated LVH (all P < 0.05). Compared with patients with normal LVM, the eccentric nondilated had higher LV stroke volume, pulse pressure/stroke index, Cornell voltage product and SBP, and lower heart rate and fewer were African-American (all P < 0.05).

CONCLUSION: The new four-group classification of LVH identifies dilated subgroups with reduced left ventricular function among patients currently classified with eccentric or concentric LVH.

Regional implementation of a pediatric cardiology chest pain guideline using SCAMPs methodology

Sun, 10/25/2015 - 7:55pm

BACKGROUND AND OBJECTIVES: Chest pain is a complaint for which children are frequently evaluated. Cardiac causes are rarely found despite expenditure of considerable time and resources. We describe validation throughout New England of a clinical guideline for cost-effective evaluation of pediatric patients first seen by a cardiologist for chest pain using a unique methodology termed the Standardized Clinical Assessment and Management Plans (SCAMPs).

METHODS: A total of 1016 ambulatory patients, ages 7 to 21 years initially seen for chest pain at Boston Children's Hospital (BCH) or the New England Congenital Cardiology Association (NECCA) practices, were evaluated by using a SCAMPs chest pain guideline. Findings were analyzed for diagnostic elements, patterns of care, and compliance with the guideline. Results from the NECCA practices were compared with those of Boston Children's Hospital, a regional core academic center.

RESULTS: Two patients had chest pain due to a cardiac etiology, 1 with pericarditis and 1 with an anomalous coronary artery origin. Testing performed outside of guideline recommendations demonstrated only incidental findings. Patients returning for persistent symptoms did not have cardiac disease. The pattern of care for the NECCA practices and BCH differed minimally.

CONCLUSIONS: By using SCAMPs methodology, we have demonstrated that chest pain in children is rarely caused by heart disease and can be evaluated in the ambulatory setting efficiently and effectively using minimal resources. The methodology can be implemented regionally across a wide range of clinical practice settings and its approach can overcome a number of barriers that often limit clinical practice guideline implementation.

Cross reactivity of serum antibody responses elicited by DNA vaccines expressing HA antigens from H1N1 subtype influenza vaccines in the past 30 years

Sun, 10/25/2015 - 7:55pm

In the past three decades, ten H1 subtype influenza vaccines have been recommended for global seasonal flu vaccination. Some of them were used only for one year before being replaced by another H1 flu vaccine while others may be used for up to seven years. While the selection of a new seasonal flu vaccine was based on the escape of a new emerging virus that was not effectively protected by the existing flu formulation, there is limited information on the magnitude and breadth of cross reactivity among H1 subtype virus circulation over a long period. In the current study, HA-expressing DNA vaccines were constructed to express individual HA antigens from H1 subtype vaccines used in the past 30 y. Rabbits naive to HA antibody responses were immunized with these HA DNA vaccines and the cross reactivity of these sera against HA antigen and related H1 viruses in the same period was studied. Our data indicate that the level of cross reactivity was different for different viral isolates and the key mutations responsible for the cross reactivity may involve only a limited number of residues. Our results provide useful information for the development of improved seasonal vaccines than can achieve broad protection against viruses within the same H1 subtype.

Cyclic-di-GMP and cyclic-di-AMP activate the NLRP3 inflammasome

Sun, 10/25/2015 - 7:55pm

The cyclic dinucleotides 3'-5'diadenylate (c-diAMP) and 3'-5' diguanylate (c-diGMP) are important bacterial second messengers that have recently been shown to stimulate the secretion of type I Interferons (IFN-Is) through the c-diGMP-binding protein MPYS/STING. Here, we show that physiologically relevant levels of cyclic dinucleotides also stimulate a robust secretion of IL-1beta through the NLRP3 inflammasome. Intriguingly, this response is independent of MPYS/STING. Consistent with most NLRP3 inflammasome activators, the response to c-diGMP is dependent on the mobilization of potassium and calcium ions. However, in contrast to other NLRP3 inflammasome activators, this response is not associated with significant changes in mitochondrial potential or the generation of mitochondrial reactive oxygen species. Thus, cyclic dinucleotides activate the NLRP3 inflammasome through a unique pathway that could have evolved to detect pervasive bacterial pathogen-associated molecular patterns associated with intracellular infections.