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Emerging therapies for Angelman syndrome, a severe neurodevelopmental disorder, are focused on restoring UBE3A gene expression in the brain. Further therapeutic opportunities may arise from a better understanding of how UBE3A gene products—both long and short isoforms of the ubiquitin ligase E3A (UBE3A)—function in neurons. Great strides have been made recently toward identifying ubiquitin substrates of UBE3A in vitro and in heterologous expression systems. From this work, a particularly close relationship between UBE3A and subunits of the 19S regulatory particle of the proteasome has become evident. We propose that further research cognizant of isoform-specific UBE3A functional roles will be instrumental in elucidating key UBE3A/substrate relationships within distinct neuronal compartments, lending to the discovery of novel therapeutic targets and valuable clinical biomarkers for the treatment of Angelman syndrome. • UBE3A substrates hold promise for the treatment of Angelman syndrome (AS). • Neuronal context is key to understanding AS-relevant UBE3A/substrate relationships. • Subcellular localization of UBE3A isoforms may influence substrate interactions. • Disruption of UBE3A/proteasome interactions could broadly impact brain function. [ABSTRACT FROM AUTHOR]

Background & Aims: We studied the reliability of the previously described Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and validated it with an independent cohort of investigators. Methods: We created a new library of 57 videos of flexible sigmoidoscopy and stratified them based on disease severity. Twenty-five investigators were each randomly assigned to assess 28 videos (which included 4 duplicates to assess intraobserver reliability). Investigators were blinded to clinical details except for 2 of 4 duplicated videos (to assess the impact of knowledge of symptoms on assessment). Three descriptors (“vascular pattern”, “bleeding”, and “erosions and ulcers”) comprising the UCEIS were scored with a visual analogue scale (VAS) to assess overall severity. Intrainvestigator and interinvestigator agreement was characterized by κ statistical analysis; reliability ratios were used to compare VAS and UCEIS scores. Results: There was a high level of correlation between UCEIS scores and overall assessment of severity (correlation coefficient, 0.93). Internal consistency (Cronbach α analysis) was 0.86. Intrainvestigator and interinvestigator reliability ratios for UCEIS scores were 0.96 and 0.88, respectively. Intrainvestigator agreement in determination of the UCEIS score was good (κ = 0.72), with individual descriptors ranging from a κ of 0.47 (for bleeding) to 0.87 (for vascular pattern). Interinvestigator agreement in determination of UCEIS scores was moderate (κ = 0.50), with descriptors ranging from a κ of 0.48 (for bleeding) to 0.54 (for vascular pattern). Intrainvestigator variability in determining UCEIS scores did not change appreciably when a video was presented with clinical details. Conclusions: The UCEIS and its components show satisfactory intrainvestigator and interinvestigator reliability. Among investigators, the UCEIS accounted for a median of 86% of the variability in evaluation of overall severity on the VAS when assessing the endoscopic severity of UC and was unaffected by knowledge of clinical details. [Copyright &y& Elsevier]

Abstract: Despite strong scientific data indicating associations among sugar-sweetened beverages (SSB) and numerous adverse health outcomes, little is known about culturally specific beliefs and potential individual-level behavioral strategies to reduce SSB intake. The primary objective of this formative study targeting adults residing in rural southwest Virginia was to apply the Theory of Planned Behavior to investigate culturally specific attitudes, subjective norms, and perceived behavioral control constructs related to the consumption of SSB, water, and artificially sweetened beverages. Using a homogenous sampling strategy, eight focus groups were conducted with 54 adult participants who exceeded recommendations of <1 cup of SSB/day. An experienced moderator and co-moderator utilized a semi-structured script, grounded in the Theory of Planned Behavior, to execute the focus group. All focus groups were audiotaped and transcribed verbatim. Three researchers independently coded meaning units to the major themes and subsequently met to gain consensus in coding. Important beverage-specific themes emerged for attitudes, subjective norms, perceived behavioral control, and intentions. Across all beverages, the most notable themes included taste (n=161 meaning units), availability/convenience (n=95 meaning units), habit/addiction (n=57 meaning units), and cost (n=28 meaning units). Health consequences associated with beverages and water-quality issues also surfaced, as well as normative beliefs, including the influence of doctors and peers. The identified themes and subthemes provide critical insight into understanding culturally relevant context and beliefs associated with beverage consumption behaviors and helps inform the development and evaluation of future intervention efforts targeting SSB consumption in the health disparate region of southwest Virginia. [Copyright &y& Elsevier]

Background and Aims: It is not clear what induction dose of mesalamine is optimal for treating patients with mildly and moderately active ulcerative colitis (UC). This study was conducted to determine the efficacy and safety of mesalamine 4.8 g/day compared with 2.4 g/day for the treatment of moderately active UC. Methods: A multicenter, randomized, double-blind, 6-week, active-control study (ASCEND III) was conducted to assess the noninferiority of delayed-release mesalamine 4.8 g/day (Asacol HD, 800-mg tablet; Procter & Gamble, Pharmaceuticals, Inc, Mason, Ohio) with 2.4 g/day (Asacol, 400-mg tablet; Procter & Gamble Pharmaceuticals, Inc) in 772 patients with moderately active UC. The primary endpoint was treatment success (overall improvement) at week 6, defined as improvement in the Physician''s Global Assessment (based on clinical assessments of rectal bleeding, stool frequency, and sigmoidoscopy), with no worsening in any individual clinical assessment. Results: The primary objective of noninferiority was met. Seventy percent (273 of 389) of patients who received 4.8 g/day of mesalamine achieved treatment success at week 6, compared with 66% (251 of 383) of patients receiving 2.4 g/day (95% confidence interval for 2.4 g/day minus 4.8 g/day, −11.2 to 1.9). In addition, 43% of patients who received 4.8 g/day mesalamine achieved clinical remission at week 6 compared with 35% of patients who received 2.4 g/day (P = .04). A therapeutic advantage for the 4.8 g/day dose was observed among patients previously treated with corticosteroids, oral mesalamines, rectal therapies, or multiple UC medications. Both regimens were well-tolerated with similar adverse events. Conclusions: Delayed-release mesalamine 4.8 g/day (800-mg tablet) is efficacious and well-tolerated in patients with moderately active UC. [Copyright &y& Elsevier]

Summary: Objective: Some patients suffer from recurrent or chronic rhinosinusitis (CRS) because of previously unrecognized immunodeficiency disease. The purpose of the study was to evaluate the incidence of CRS in children with different types of primary humoral deficiency. Study design: Among 842 cases of primary immunodeficiency diseases diagnosed in the Department of Immunology of the Children''s Memorial Institute in Warsaw from 1980 up to February 2006 antibody deficiencies occurred most frequently—in 50.4%. In this group the retrospective study of patients’ history suggesting CRS prior to intravenous gamma-globulin substitution therapy was performed. Results: CRS was observed most frequently in the group of patients with agammaglobulinemia less often in patients with dysgammaglobulinemia, and other antibody deficiencies. Conclusions: The occurrence of frequent bacterial infections, complicating common colds, should alert the physician to the possibility of immunodeficiency. Immunological testing should be an integral part of evaluation of patients with refractory CRS. [Copyright &y& Elsevier]

Summary: Objectives: PRAME (Preferentially Expressed Antigen in Melanoma) is a tumor-associated antigen recognized by immunocytes, and it induces cytotoxic T cell-mediated responses in melanoma. PRAME expression in tumors interferes with retinoic acid receptor (RAR) signaling thus promoting tumor progression. Here, we study PRAME expression in head and neck squamous cell carcinoma (HNSCC) to determine its potential clinical significance. Materials and methods: PRAME expression in HNSCC was evaluated by immunohistochemistry in tissue microarrays of primary tumors (n =53), metastatic lymph nodes (n =8) and normal oral mucosa (n =11). Biopsies of dysplastic oral lesions (n =12) were also examined. PRAME expression levels in tissues were correlated with markers of poor prognosis in HNSCC. PRAME mRNA in HNSCC cell lines and in normal immortalized human keratinocytes (HaCaT cell line) was measured by qRT-PCR, and the protein expression by flow cytometry and western blots. Results: PRAME was expressed in HNSCC cell lines and HNSCC lesions. PRAME expression in dysplastic mucosa was variable. No or only weak expression was found in normal cells or tissues. PRAME expression levels significantly correlated with the tumor grade, size, nodal involvement and the clinical status of HNSCC patients. Conclusions: Elevated PRAME expression associates with clinicopathologic markers of poor outcome in HNSCC and might identify potential candidates with pre-cancerous lesions for chemoprevention with retinoids. [Copyright &y& Elsevier]

Objectives: We sought to determine whether matrix metalloproteinase (MMP) inhibitor, PG-116800, reduced left ventricular (LV) remodeling after myocardial infarction (MI). Background: PG-116800 is an oral MMP inhibitor with significant antiremodeling effects in animal models of MI and ischemic heart failure. Methods: In an international, randomized, double-blind, placebo-controlled study, 253 patients with first ST-segment elevation MI and ejection fraction between 15% and 40% were enrolled 48± 24 h after MI and treated with placebo or PG-116800 for 90 days. Major efficacy end points were changes in LV volumes as determined by serial echocardiography, and clinical and safety outcomes were also collected. Results: In total, 203 patients (80%) completed 90 days of treatment and had evaluable baseline and 90-day echocardiograms. The proportion of patients with anterior MI (78% vs. 81%) and primary percutaneous coronary intervention (90% vs. 91%) along with baseline LV ejection fraction (35.5% vs. 36.8%) did not differ between PG-116800-treated and placebo-treated patients. There was no difference in the change in LV end-diastolic volume index from days 0 to 90 with PG-116800 versus placebo (5.09 ± 1.45 ml/m2 vs. 5.48 ± 1.41 ml/m2, p = 0.42). Changes in LV diastolic volume, LV systolic volume, LV ejection fraction, sphericity index, plus rates of death or reinfarction were not significantly improved with PG-116800. PG-116800 was well tolerated; however, there was increased incidence of arthralgia and joint stiffness without significant increase in overall musculoskeletal adverse events (21% vs. 15%, p = 0.33). Conclusions: Matrix metalloproteinase inhibition with PG-116800 failed to reduce LV remodeling or improve clinical outcomes after MI. [Copyright &y& Elsevier]

Recent studies have shown that a short lingual frenulum is a potential risk factor for obstructive sleep apnea syndrome (OSAS) in children. A short frenulum leads to abnormal orofacial development and may consequently contribute to sleep-disordered breathing by narrowing the upper airways and increasing the risk of upper-airway collapsibility. The aim of this study was to assess the impact of a short lingual frenulum on the risk of OSAS in children. Children from pre-, primary, secondary, and high school, aged 3–17 years, were included in the study. Parents/guardians were asked to fill in the Pediatric Sleep Questionnaire (PSQ), and then, children at risk of OSAS were enrolled in the study group. A control group was established randomly from patients with negative PSQ results. A physical examination, including measurements of head-forward posture (HFP) and length of the free tongue, inter-incisor distance and subjective high-arched palate evaluation was performed in children from both groups. A total of 1,500 PSQ questionnaires were distributed, and less than half (713) were returned correctly filled in. In the second part of the study, 135 children were evaluated: 67 in the study group and 68 in the control group. The mean ages were 9.4 ± 3.0 and 9.5 ± 3.1 years, respectively. Children in the study group had significantly shorter lingual frenula, higher HFP measures, and had a higher prevalence of a high-arched palate. Based on statistical analysis, a short lingual frenulum (OR 5.02 [1.58–15.94]). The study identified a relationship between a short lingual frenulum and the risk of OSAS in children. Detecting and addressing ankyloglossia in children is necessary before it leads to orofacial changes, malocclusion, and consequently, sleep apnea. Furthermore, OSAS was associated with higher HFP, but no relationship was found between the two parameters. [ABSTRACT FROM AUTHOR]