Citations

Previous studies have shown that human immunodeficiency virus (HIV) protease cleaves procaspase 8 to a fragment, termed Casp8p41, that lacks caspase activity but nonetheless contributes to T cell apoptosis. Herein, we show that Casp8p41 contains a domain that interacts with the BH3-binding groove of pro-apoptotic Bak to cause Bak oligomerization, Bak-mediated membrane permeabilization, and cell death. Levels of active Bak are higher in HIV-infected T cells that express Casp8p41. Conversely, targeted mutations in the Bak-interacting domain diminish Bak binding and Casp8p41-mediated cell death. Similar mutations in procaspase 8 impair the ability of HIV to kill infected T cells. These observations support a novel paradigm in which HIV converts a normal cellular constituent into a direct activator that functions like a BH3-only protein.

Abstract Background/Objectives The risk of chronic kidney disease ( CKD ) in patients who regularly drink soda is controversial. The objective of this meta‐analysis was to evaluate the associations between consumption of sugar‐sweetened and artificially sweetened soda and CKD . Methods A literature search was performed using MEDLINE , EMBASE and the C ochrane D atabase of S ystematic R eviews from inception until 30 J une 2014. Studies that reported odds ratios or hazard ratios comparing the risk of CKD in patients consuming significant amounts of either sugar‐sweetened or artificially sweetened soda versus those who did not consume soda were included. Pooled risk ratios ( RR ) and 95% confidence intervals ( CI ) were calculated using a random‐effects, generic inverse variance method. Results Five studies were included in our analysis of the association between consumption of sugar‐sweetened soda and CKD . The pooled RR of CKD in patients consuming sugar‐sweetened soda was 1.58 (95% CI 1.00–2.49). Four studies were selected to assess the association between consumption of artificially sweetened soda and CKD . The pooled RR of CKD in patients consuming artificially sweetened soda was 1.33 (95% CI 0.82–2.15). Conclusions Our study demonstrates statistically significant increased risks of CKD in patients consuming sugar‐sweetened soda, but not in patients consuming artificially sweetened soda. This finding suggests that sugar‐sweetened soda consumption is associated with CKD and may impact clinical management and primary prevention of CKD in high‐risk patients.

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.

Objective The present study was performed to identify factors that lead to a favorable outcome of postpalatoplasty velopharyngeal incompetence using the double-opposing Z-palatoplasty. Design A retrospective analysis was performed on 23 consecutive nonsyndromic patients who underwent secondary surgical management of velopharyngeal incompetence using a double-opposing Z-palatoplasty technique following primary, non-Furlow palatoplasty for overt cleft palate. Main Outcome Measures All subjects were evaluated preoperatively using a perceptual speech assessment scale, nasendoscopy, and videofluoroscopy. Inclusion criteria consisted of a velopharyngeal gap of 9 mm or less on phonation. Patients were followed with perceptual speech assessment for at least 1 year following secondary surgery. Results The perceptual speech assessment score for all patients decreased from 6.48 ± 2.26 (mean ± standard deviation; range, 3 to 11) to 1.90 ± 1.51 (range, 0 to 6) at 6 months or more postoperatively ( P < .0001). Of the 21 patients with follow-up data 1 year or more post–op, 16 (76%) achieved velopharyngeal competence and five (24%) had borderline competence. Preoperative assessment factors associated with compromised outcome included a large velopharyngeal gap of 7 to 9 mm, poor lateral wall motion of 40% or less, and an elevated perceptual speech assessment score. Conclusion Double-opposing Z-palatoplasty is a surgical technique that can be used successfully to correct velopharyngeal incompetence in selected secondary palatoplasty patients. This technique permits correction of velopharyngeal incompetence and restoration of the velopharyngeal mechanism irrespective of prior intravelar veloplasty and without accompanying loss in the nasal airway. Preoperative assessment can better identify those patients who are less likely to achieve velopharyngeal competence following double-opposing Z-palatoplasty alone.

ABSTRACTMolecular transduction of biological signals is understood primarily in terms of the cooperative structural transitions of protein macromolecules, providing a mechanism through which discrete local structure perturbations affect global macromolecular properties. The recognition that proteins lacking tertiary stability, commonly referred to as intrinsically disordered proteins (IDPs), mediate key signaling pathways suggests that protein structures without cooperative intramolecular interactions may also have the ability to couple local and global structure changes. Presented here are results from experiments that measured and tested the ability of disordered proteins to couple local changes in structure to global changes in structure. Using the intrinsically disordered N‐terminal region of the p53 protein as an experimental model, a set of proline (PRO) and alanine (ALA) to glycine (GLY) substitution variants were designed to modulate backbone conformational propensities without introducing non‐native intramolecular interactions. The hydrodynamic radius (Rh) was used to monitor changes in global structure. Circular dichroism spectroscopy showed that the GLY substitutions decreased polyproline II (PPII) propensities relative to the wild type, as expected, and fluorescence methods indicated that substitution‐induced changes in Rh were not associated with folding. The experiments showed that changes in local PPII structure cause changes in Rh that are variable and that depend on the intrinsic chain propensities of PRO and ALA residues, demonstrating a mechanism for coupling local and global structure changes. Molecular simulations that model our results were used to extend the analysis to other proteins and illustrate the generality of the observed PRO and alanine effects on the structures of IDPs. Proteins 2014; 82:3373–3384. © 2014 Wiley Periodicals, Inc.

AbstractBackgroundA valid biomarker is ‘an indicator of normal biologic or pathogenic processes, or pharmacological responses to a therapeutic intervention’. There is no validated biomarker for irritable bowel syndrome (IBS). The aim of the study was to assess ability of three quantitative traits to identify treatable processes to discriminate between IBS‐diarrhea (IBS‐D) patients, IBS‐constipation (IBS‐C) patients and healthy volunteers (HV).MethodsIn 30 HV, 30 IBS‐C patients and 64 IBS‐D patients, we characterized bowel symptoms and quantitated pathophysiological mechanisms: bile acid (BA) synthesis (serum C4 and FGF19), fecal BA and fat, colonic transit (CT), and intestinal permeability (IP). We used multiple logistic regression and receiver‐operating characteristic (ROCAUC) to appraise three factors (fecal BA, CT, and IP) individually and in combination to identify discriminant targets for treatment in IBS.Key ResultsThere were significant associations between the three subgroups and symptoms reflecting bowel function and the quantitative traits. There were significant associations between fecal BA and CT at 48 h (r = 0.43; p < 0.001) and between fecal BA and IP (r = 0.23; p = 0.015). Individually, fecal BA and CT48 (but not IP) were significant independent predictors for distinguishing HV from IBS. In combination, they discriminated HV from IBS‐D patients (ROCAUC 0.70), HV from IBS‐C patients (ROCAUC 0.73), and IBS‐C patients from IBS‐D patients (ROCAUC 0.86). Colonic transit and fecal BA excretion together discriminate between healthy volunteers and IBS‐C patients or IBS‐D patients, or between the IBS subgroups with 75–90% specificity at 60% sensitivity.Conclusions & InferencesColonic transit and fecal BA individually and together constitute useful biomarkers to identify treatable mechanisms in IBS and to differentiate subgroups of IBS.

BackgroundDevice infection is associated with increased mortality in patients receiving cardiovascular implantable electronic device (CIED) therapy. However, long‐term mortality associated with CIED infections has not been systematically analyzed in larger studies. This study sought to determine the long‐term mortality associated with CIED infection in a large cohort of Medicare beneficiaries.MethodsWe used a retrospective study design to analyze 3‐year mortality in 200,219 Medicare fee‐for‐service patients admitted for CIED generator implantation, replacement, or revision between January 1, 2007 and December 31, 2007. Multivariate analysis adjusting for age, sex, race, and 28 comorbidities was performed to determine the relative risk (RR) of death in the 12 quarters following CIED infection.ResultsPatients with CIED infection, compared to device recipients without infection, had increased mortality that persisted for at least 3 years after the admission quarter for all device types: pacemakers (PMs: 53.8% vs 33%; P < 0.001), implantable cardioverter defibrillator (ICD: 47.7% vs 31.6%; P < 0.001), and cardiac resynchronization therapy‐defibrillator (CRT‐D: 50.8% vs 36.5%; P < 0.001). After adjusting for patient demographics and comorbidities, significantly increased RR of death following CIED infection persisted for at least 3 years following PM infection, and for at least 2 years with single‐ and dual‐chamber ICD infection.ConclusionsCIED recipients who develop device infection have increased, device‐dependent, long‐term mortality even after successful treatment of infection. The etiology of this persistent increased risk of death associated with CIED infection is unknown and merits further investigation.

Occipital neuralgia is a debilitating disorder first described in 1821 as recurrent headaches localized in the occipital region. Other symptoms that have been associated with this condition include paroxysmal burning and aching pain in the distribution of the greater, lesser, or third occipital nerves. Several etiologies have been identified in the cause of occipital neuralgia and include, but are not limited to, trauma, fibrositis, myositis, fracture of the atlas, and compression of the C‐2 nerve root, C1‐2 arthrosis syndrome, atlantoaxial lateral mass osteoarthritis, hypertrophic cervical pachymeningitis, cervical cord tumor, Chiari malformation, and neurosyphilis. The management of occipital neuralgia can include conservative approaches and/or surgical interventions. Occipital neuralgia is a multifactorial problem where multiple anatomic areas/structures may be involved with this pathology. A review of these etiologies may provide guidance in better understanding occipital neuralgia. Clin. Anat. 28:101–108, 2015. © 2014 Wiley Periodicals, Inc.

Background. Little is known on the prevalence of peripheral artery disease (PAD) in developing countries.Study design. Population-based study in Atahualpa. InPhase I, the Edinburgh claudication questionnaire (ECQ) was used for detection of suspected symptomatic PAD; persons with a negative ECQ but a pulse pressure ≥65 mmHg were suspected of asymptomatic PAD. InPhase II, the ankle-brachial index will be used to test reliability of screening instruments and to determine PAD prevalence. InPhase III, participants will be followed up to estimate the relevance of PAD as a predictor of vascular outcomes.Results. DuringPhase I, 665 Atahualpa residents aged ≥40 years were enrolled (mean age: 59.5 ± 12.6 years, 58% women). A poor cardiovascular health status was noticed in 464 (70%) persons of which 27 (4%) had a stroke and 14 (2%) had ischemic heart disease. Forty-four subjects (7%) had suspected symptomatic PAD and 170 (26%) had suspected asymptomatic PAD. Individuals with suspected PAD were older, more often women, and had a worse cardiovascular profile than those with nonsuspected PAD.Conclusions. Prevalence of suspected PAD in this underserved population is high. Subsequent phases of this study will determine whether prompt detection of PAD is useful to reduce the incidence of catastrophic vascular diseases in the region.