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Alternative polyadenylation (APA) is conserved in all eukaryotic cells. Selective use of polyadenylation sites appears to be a highly regulated process and contributes to human pathogenesis. In this article we report that the yeast RPB2 gene is alternatively polyadenylated, producing two mRNAs with different lengths of 3'UTR. In normally growing wild-type cells, polyadenylation preferentially uses the promoter-proximal poly(A) site. After UV damage transcription of RPB2 is initially inhibited. As transcription recovers, the promoter-distal poly(A) site is preferentially used instead, producing more of a longer form of RPB2 mRNA. We show that the relative increase in the long RPB2 mRNA is not caused by increased mRNA stability, supporting the preferential usage of the distal poly(A) site during transcription recovery. We demonstrate that the 3'UTR of RPB2 is sufficient for this UV-induced regulation of APA. We present evidence that while transcription initiation rates do not seem to influence selection of the poly(A) sites of RPB2, the rate of transcription elongation is an important determinant.

PURPOSE: To determine the mean and range of location-averaged breast skin thickness using high-resolution dedicated breast CT for use in Monte Carlo-based estimation of normalized glandular dose coefficients.

METHODS: This study retrospectively analyzed image data from a clinical study investigating dedicated breast CT. An algorithm similar to that described by Huang et al. ["The effect of skin thickness determined using breast CT on mammographic dosimetry," Med. Phys. 35(4), 1199-1206 (2008)] was used to determine the skin thickness in 137 dedicated breast CT volumes from 136 women. The location-averaged mean breast skin thickness for each breast was estimated and the study population mean and range were determined. Pathology results were available for 132 women, and were used to investigate if the distribution of location-averaged mean breast skin thickness varied with pathology. The effect of surface fitting to account for breast curvature was also studied.

RESULTS: The study mean (+/- interbreast SD) for breast skin thickness was 1.44 +/- 0.25 mm (range: 0.87-2.34 mm), which was in excellent agreement with Huang et al. Based on pathology, pair-wise statistical analysis (Mann-Whitney test) indicated that at the 0.05 significance level, there were no significant difference in the location-averaged mean breast skin thickness distributions between the groups: benign vs malignant (p = 0.223), benign vs hyperplasia (p = 0.651), hyperplasia vs malignant (p = 0.229), and malignant vs nonmalignant (p = 0.172).

CONCLUSIONS: Considering this study used a different clinical prototype system, and the study participants were from a different geographical location, the observed agreement between the two studies suggests that the choice of 1.45 mm thick skin layer comprising the epidermis and the dermis for breast dosimetry is appropriate. While some benign and malignant conditions could cause skin thickening, in this study cohort the location-averaged mean breast skin thickness distributions did not differ significantly with pathology. The study also underscored the importance of considering breast curvature in estimating breast skin thickness.

The promotion of membrane fusion by most paramyxoviruses requires an interaction between the viral attachment and fusion (F) proteins to enable receptor binding by the former to trigger the activation of the latter for fusion. Numerous studies demonstrate that the F-interactive sites on the Newcastle disease virus (NDV) hemagglutinin-neuraminidase (HN) and measles virus (MV) hemagglutinin (H) proteins reside entirely within the stalk regions of those proteins. Indeed, stalk residues of NDV HN and MV H that likely mediate the F interaction have been identified. However, despite extensive efforts, the F-interactive site(s) on the Nipah virus (NiV) G attachment glycoprotein has not been identified. In this study, we have introduced individual N-linked glycosylation sites at several positions spaced at intervals along the stalk of the NiV G protein. Five of the seven introduced sites are utilized as established by a retardation of electrophoretic mobility. Despite surface expression, ephrinB2 binding, and oligomerization comparable to those of the wild-type protein, four of the five added N-glycans completely eliminate the ability of the G protein to complement the homologous F protein in the promotion of fusion. The most membrane-proximal added N-glycan reduces fusion by 80%. However, unlike similar NDV HN and MV H mutants, the NiV G glycosylation stalk mutants retain the ability to bind F, indicating that the fusion deficiency of these mutants is not due to prevention of the G-F interaction. These findings suggest that the G-F interaction is not mediated entirely by the stalk domain of G and may be more complex than that of HN/H-F.

BACKGROUND: Models are needed for implementing weight management interventions for adolescents through readily accessible venues. This study evaluated the feasibility and efficacy of a school nurse-delivered intervention in improving diet and activity and reducing body mass index (BMI) among overweight and obese adolescents.

METHODS: Six high schools were randomized to either a 6-session school nurse-delivered counseling intervention utilizing cognitive-behavioral techniques or nurse contact with provision of information. Eighty-four overweight or obese adolescents in grades 9 through 11 completed behavioral and physiological assessments at baseline and 2- and 6-month follow-ups.

RESULTS: At 2 months, intervention participants ate breakfast on more days/week (difference = 1.01 days; 95% CI: 0.11, 1.92), and had a lower intake of total sugar (difference = -45.79 g; 95% CI: -88.34, -3.24) and added sugar (difference = -51.35 g; 95% CI: -92.45, -10.26) compared to control participants. At 6 months, they were more likely to drink soda ≤ one time/day (OR 4.10; 95% CI: 1.19, 16.93) and eat at fast food restaurants ≤ one time/week (OR 4.62; 95% CI: 1.10, 23.76) compared to control participants. There were no significant differences in BMI, activity, or caloric intake.

CONCLUSION: A brief school nurse-delivered intervention was feasible, acceptable, and improved selected obesogenic behaviors, but not BMI.

Copyright 2013, American School Health Association.

INTRODUCTION: Sodium hypochlorite is the active ingredient in bleach, a ubiquitous household disinfectant, and has known toxicities depending on route of exposure and amount. Acute kidney injury due to sodium hypochlorite exposure has never been reported. Patients that did develop nephrotoxicity following bleach exposure did so due to development of other risk factors for kidney injury such as volume depletion or sepsis.

DISCUSSION: We report a patient who presented with black urine after parenteral self-administration of a large quantity of bleach. We review the clinical presentation, laboratory and biopsy findings, and outcome as well as discuss possible mechanisms of sodium hypochlorite toxicity and management strategies.

INTRODUCTION: Intraoperative cholangiogram (IOC) can define biliary ductal anatomy. Routine IOC has been proposed previously. However, current surgeon IOC utilization practice patterns and outcomes are unclear.

METHODS: Nationwide Inpatient Sample 2004-2009 was queried for patients with acute biliary disease undergoing cholecystectomy (CCY). Analyses only included surgeons performing >/=10 CCY/year. We dichotomized surgeons into a routine IOC group vs. selective. Outcomes included bile duct injury, complications, mortality, length of stay, and cost.

RESULTS: Of the nonweighted patients, 111,815 underwent CCY. A total of 4,740 actual surgeon yearly volumes were examined. On average, each surgeon performed 23.6 CCYs and 7.9 IOCs annually, using IOC in 33 % of cases. The routine IOC group used IOC for 96 % of cases, whereas selective IOC group used IOC approximately 25 % of the time. Routine IOC surgeons had no difference in mortality (0.4 %) or rate of bile duct injury (0.25 vs. 0.26 %), but higher overall complications (7.3 vs. 6.8 %, p = 0.04). Patients of routine IOC surgeons received more additional procedures and incurred higher costs.

CONCLUSION: Routine IOC does not decrease the rate of bile duct injury, but is associated with significant added cost. Surgeons' routine use of IOC is correlated with increased rates of postsurgical procedures, and is associated with increased overall complications. These data suggest routine IOC may not improve outcomes.

Recognition of microbial nucleic acids is one strategy by which mammalian hosts respond to infectious agents. Intracellular DNA that is introduced into cells during infection elicits potent inflammatory responses by triggering the induction of antiviral type I IFNs and the maturation and secretion of inflammatory cytokines, such as TNF-alpha, IL-1beta, and IL-18. In addition, if nucleases, such as DNase II or DNase III (Trex1), fail to clear self-DNA, accumulated DNA gains access to intracellular compartments where it drives inflammatory responses leading to autoimmune disease. In this review, we discuss a rapidly evolving view of how cytosolic DNA-sensing machineries coordinate antimicrobial immunity and, if unchecked, lead to autoimmune disease.

Postoperative nausea and vomiting (PONV) is a common complaint after plastic and reconstructive surgery. Transdermal scopolamine is a commonly used agent for prevention of PONV. Anisocoria from transdermal scopolamine use is an adverse effect that has not been reported in the plastic surgery literature. We present a series of 3 craniofacial patients in which ipsilateral mydriasis occurred and spontaneously resolved after removal of the scopolamine patch. Given the various causes and potentially grave implications of unilateral mydriasis, we discourage the use of transdermal scopolamine in craniofacial surgery, and especially in orbital surgery. However, if transdermal scopolamine is decided to be used for PONV prophylaxis, we recommend educating the patient, the operating room staff, and the surgical team regarding this potential adverse effect and to avoid finger-to-eye contamination after patch manipulation.

This special issue discusses the ethical issues providers face in collaborative primary care settings. It is organized in three sections: (a) Common Themes, (b) Context-Specific Quandaries, and (c) Research and Training. It provides case examples to illustrate ethical dilemmas, describe professional ethical standards pertinent to the case, identifies gaps in available guidance and how guidelines might be elucidated in state statues (without going into detail about specific states), offers feasible recommendations to BHCs for deciding an ethical course when extant guidance was lacking, and then demonstrates and applies the recommendations to achieve an ethical resolution to the case example.

Integrated primary care is particularly valuable to rural communities. Behavioral health care is often in short supply, and small or close-knit communities can intensify the stigma of seeking specialty mental health in rural settings. These and other barriers result in reduced access to needed behavioral health care. Nonetheless, rural practice of integrated primary care presents unique challenges to practitioners of multiple disciplines, including issues of competence, confidentiality, and dual relationships. This article provides an illustrative vignette to describe ethical issues in the rural practice of integrated primary care. It will review discipline-specific guidance in approaching these challenges and will offer recommendations for addressing disparities in the approaches of various disciplines engaged in the practice of integrated primary care.

BACKGROUND: Two-dimensional speckle tracking imaging (STI) has recently been applied to the study of left atrial (LA) reservoir function. We utilized STI to analyze LA function in diastolic dysfunction (DD), hypothesizing that LA strain abnormality is part of the pathogenesis of diastolic dysfunction.

METHODS: We applied STI to 50 patients with Grade 1-2 DD, comparing these results to 100 normal controls. Complete Doppler analysis of filling was made using peak E, peak A and tissue Doppler e' velocities; E/e' was used as a surrogate for LA pressure and LA stiffness index was calculated.

RESULTS: In analysis of covariance, adjusting for age and gender, compared with controls, DD patients had higher E/e', greater LA volume and greater LA stiffness, but lower E/A ratio and global LA strain. LA strain appears to be inversely related to LA volume, but not to other indices of LV diastolic function. In subgroup analysis, LA strain was significantly lower, and stiffness significantly higher in DD, even after correction for differences in LA volume and E/A ratio. Analysis of ROC curves suggests that abnormal LA strain is a better marker for diastolic dysfunction than LA enlargement.

CONCLUSION: LA strain by STI is significantly reduced in early diastolic dysfunction and is related to higher LA stiffness and LA size. Reduction in LA strain is partially independent of LA volume; accordingly we hypothesize that reduced atrial strain indicates impaired atrial distensibility.

Systolic pulmonary and hepatic vein flow reversals can typically be seen with severe atrioventricular (AV) valve regurgitation and during atrial fibrillation (AF). We report the case of a 67-year-old woman who presented with recent-onset exertional dyspnea. Her pacemaker was near end-of-life and reverted to a VVI mode from the preset DDDR mode. Electrocardiography demonstrated retrograde 1:1 ventriculoatrial (VA) conduction and spectral Doppler analysis revealed prominent systolic pulmonary and hepatic vein flow reversals. Symptoms, electrocardiogram (ECG) findings, and the spectral Doppler abnormalities resolved completely following a generator replacement and resumption of DDDR pacing.

Atg6 (beclin 1 in mammals) is a core component of the Vps34 complex that is required for autophagy. Beclin 1 (Becn1) functions as a tumor suppressor, and Becn1(+/-) tumors in mice possess elevated cell stress and p62 levels, altered NF-kappaB signaling and genome instability. The tumor suppressor function of Becn1 has been attributed to its role in autophagy, and the potential functions of Atg6/Becn1 in other vesicle trafficking pathways for tumor development have not been considered. Here, we generate Atg6 mutant Drosophila and demonstrate that Atg6 is essential for autophagy, endocytosis and protein secretion. By contrast, the core autophagy gene Atg1 is required for autophagy and protein secretion, but it is not required for endocytosis. Unlike null mutants of other core autophagy genes, all Atg6 mutant animals possess blood cell masses. Atg6 mutants have enlarged lymph glands (the hematopoietic organ in Drosophila), possess elevated blood cell numbers, and the formation of melanotic blood cell masses in these mutants is not suppressed by mutations in either p62 or NFkappaB genes. Thus, like mammals, altered Atg6 function in flies causes hematopoietic abnormalities and lethality, and our data indicate that this is due to defects in multiple membrane trafficking processes.

PURPOSE OF REVIEW: The review focuses on the latest techniques that are evolving in the management of small bowel bleeding.

RECENT FINDINGS: Video capsule endoscopy has the highest yield of diagnosis when it is performed within 48 h of the bleeding event (78 versus 48%). The pooled detection rate of double balloon endoscopy was noted to be 68.1% for obscure gastrointestinal bleeding according to a systematic review of 66 studies in the last 10 years. Also a recent review, which focused on analysis of 68 studies found that the procedural characteristics were comparable for double balloon, single balloon and spiral enteroscopy though the procedure time was fastest for the spiral enteroscopy group. Medical therapy for vascular lesions is in its infancy but shows promise.

SUMMARY: Advanced diagnostic and therapeutic endoscopic techniques are changing the paradigm of care for patients with small bowel bleeding.

Alpha-1 antitrypsin Deficiency (AATD) has been an attractive target for the development of gene therapy because it is a common single gene disorder, for which there would appear to be significant benefit to be gained for lung disease patients by augmentation of plasma levels of wild-type (M) alpha-1 antitrypsin (AAT). While a significant proportion of patients also have liver disease, which is unlikely to be benefitted by augmentation, the potential to treat or prevent lung disease by replacement of plasma levels to at least 11 microMolar (571 mcg/ml) is the basis upon which several protein replacement therapies have been licensed for human use. Further enhancing the likelihood of success of gene therapy is the fact that the AAT coding sequence is relatively short and the protein appears to function primarily in the plasma and extracellular space. This means that AAT production from any cell or tissue capable of secreting it could be useful therapeutically for augmentation. Based on these considerations, attempts have been made to develop AAT therapies using nonviral gene transfer, gammaretrovirus, recombinant adenovirus (rAd), and recombinant adeno-associated virus (rAAV) vectors. These have resulted in three phase I clinical trials (one of cationic liposome, one of rAAV2, and one of rAAV1) and one phase II clinical trial (with rAAV1). The results of the latter trial, while promising, demonstrated levels were only 3 to 5% of the target range. This indicates the need to further increase the dose of the vector and/or to increase the levels to within the therapeutic range.

BACKGROUND: Here we apply objective, reliable methods of dysmorphology diagnosis to a patient with Johanson-Blizzard syndrome (MIM #243800). Using an extensive normative database, we computed standardized scores on a graded continuum for operational definitions of nasal alar hypoplasia, a commonly observed feature of this condition.

CASE: Most of these measurements in this case were greater than 2 standard deviations below the mean, adjusted for age, gender, and ethnicity.

CONCLUSION: This report provides a worked example of quantitative anthropometric assessment in the context of a case report, using tools that may find general application in clinical genetics.

Because there is increasing demand for critical care providers in the United States, many medical ICUs for adults have begun to integrate nurse practitioners and physician assistants into their medical teams. Studies suggest that such advanced practice providers (APPs), when appropriately trained in acute care, can be highly effective in helping to deliver high-quality medical critical care and can be important elements of teams with multiple providers, including those with medical house staff. One aspect of building an integrated team is a practice model that features appropriate coding and billing of services by all providers. Therefore, it is important to understand an APP's scope of practice, when they are qualified for reimbursement, and how they may appropriately coordinate coding and billing with other team providers. In particular, understanding when and how to appropriately code for critical care services (Current Procedural Terminology [CPT] code 99291, critical care, evaluation and management of the critically ill or critically injured patient, first 30-74 min; CPT code 99292, critical care, each additional 30 min) and procedures is vital for creating a sustainable program. Because APPs will likely play a growing role in medical critical care units in the future, more studies are needed to compare different practice models and to determine the best way to deploy this talent in specific ICU settings.