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PURPOSE: To test the hypothesis that subjects with a known malignancy at the time of acute pulmonary embolism (PE) have different clinical characteristics and predictors of 30-day all-cause mortality when compared with subjects with no known malignancy.

MATERIALS AND METHODS: A retrospective (August 2003 to March 2010) cohort of 1596 consecutive positive (for acute PE) computed tomography pulmonary angiograms (CTPAs) performed at a single, large, urban teaching hospital was separated into those from subjects with (n=835) and those from subjects without (n=761) a known malignancy. Clinical characteristics were compared between groups, and a logistic regression model determined predictors of 30-day all-cause mortality for each group.

RESULTS: Subjects with malignancy were older (60.8+/-13.9 vs. 54.5+/-18.8 y, P1.0) had a higher risk of 30-day death only among subjects with no known malignancy at the time of the CTPA (odds ratio=4.08, 95% confidence interval: 1.67-9.96).

CONCLUSIONS: Among subjects who present with acute PE, those with a malignancy had different clinical characteristics and predictors of mortality when compared with the cohort of subjects with no known malignancy. A computed tomography-derived right to left ventricular diameter ratio predicts 30-day all-cause mortality only for those subjects who do not have a malignancy.

Comment on: Progenitor cell mobilizing treatments prevent experimental transplant arteriosclerosis. [J Surg Res. 2012]

PURPOSE: Ureteroneocystostomy (UCN) is the most widely used urinary reconstruction technique during kidney transplantation. Disadvantages of this technique include a high incidence of hematuria and reflux, plus the potential for obstruction resulting from distal ureteral fibrosis. Pyeloureterostomy (PU) avoids these complications but increases the technical complexity.

METHODS: Between January 1990 and December 2005, 1066 adults patients underwent kidney transplantations; 768 patients (72.1%) had urinary reconstruction by PU and 298 (27.9%) underwent UNC.

RESULTS: Patients in the PU group underwent simultaneous ipsilateral native nephrectomy. The operative time was longer in the PU group compared with the UNC group: 210 +/- 36 min versus 182 +/- 24 min (P < 0.001). Overall surgical complications in the PU group were comparable to those in the UNC group (9.5% versus 12.3%). The urinary complication rate was also comparable in both groups: 3.2% (25 of 768) in the PU group and 5% (15 of 298) in the UNC group. However, urinary obstruction comprised 60% of urinary complications in the UNC group, compared with 32% in the PU group (P < 0.01). We treated most urinary complications non-operatively. However, 24% of patients (six of 25) in the PU group needed operative intervention or revision for ureteral reconstruction, compared with 46.6% (seven of 15) in the UNC group (P < 0.01).

CONCLUSIONS: Pyeloureterostomy is a safe and effective method for urinary tract reconstruction in renal transplantation. Pyeloureterostomy should be part of every transplant surgeon's armamentarium.

CONTEXT: Built environment-focused interventions and policies are recommended as sustainable approaches for promoting physical activity. Physical activity has not traditionally been considered in land use and transportation decision making. Effective collaboration with non-public health partners requires knowledge of their perceived barriers to such consideration.

OBJECTIVE: This analysis sought to (a) establish prevalence estimates of selected barriers to the consideration of physical activity in community design and layout decisions and (b) describe how barrier reporting by public health officials differs from other municipal officials among a wide range of job functions and departments in a geographically diverse sample.

DESIGN: A Web-based survey was conducted among municipal officials in 94 cities and towns with populations of at least 50 000 residents in 8 states.

PARTICIPANTS: A total of 453 municipal officials from public health, planning, transportation/public works, community and economic development, parks and recreation, city management, and municipal legislatures in 83 cities and towns responded to the survey.

MAIN OUTCOME MEASURES: Five barriers to consideration of physical activity in community design and layout were assessed.

RESULTS: The most common barriers included lack of political will (23.5%), limited staff (20.4%), and lack of collaboration across municipal departments (16.2%). Fewer participants reported opposition from the business community or residents as barriers. Public health department personnel were more likely to report the barriers of limited staff and lack of collaboration across municipal departments than other professionals. They were also more likely to report lack of political will than city managers or mayors and municipal legislators.

CONCLUSIONS: Barriers to increasing consideration of physical activity in decision making about community design and layout are encouragingly low. Implications for public health practice include the need to strategically increase political will despite public health staffing constraints and perceived lack of collaboration with relevant departments such as planning and public works/transportation.

Electrical activity regulates the manner in which neurons mature and form connections to each other. However, it remains unclear whether increased single-cell activity is sufficient to alter the development of synaptic connectivity of that neuron or whether a global increase in circuit activity is necessary.

To address this question, we genetically increased neuronal excitability of in vivo individual adult-born neurons in the mouse dentate gyrus via expression of a voltage-gated bacterial sodium channel. We observed that increasing the excitability of new neurons in an otherwise unperturbed circuit leads to changes in both their input and axonal synapses.

Furthermore, the activity-dependent transcription factor Npas4 is necessary for the changes in the input synapses of these neurons, but it is not involved in changes to their axonal synapses. Our results reveal that an increase in cell-intrinsic activity during maturation is sufficient to alter the synaptic connectivity of a neuron with the hippocampal circuit and that Npas4 is required for activity-dependent changes in input synapses.

BACKGROUND AND PURPOSE: Recanalization strategies mediated by intra-arterial fibrinolytic therapy in combination with mechanical clot disruption may be a more effective treatment approach than either therapy used alone. There are few preclinical animal models to evaluate these strategies. Here we report on a model to simultaneously evaluate both of these treatment approaches.

METHODS: Allogeneic clot was injected through the 6 F guide catheter after creating >50% luminal stenosis of the common carotid arteries of New Zealand White rabbits. The stenosis was released after 1 h, allowing sufficient time for clot-vessel wall interaction. Occlusion was confirmed and each vessel was assigned to receive either balloon angioplasty alone, intra-arterial tissue plasminogen activator (tPA, Alteplase, Genentech, San Francisco, California, USA), tPA delivery through prototype balloon infusion wire (NIT Therapeutics, Pittsburgh, Pennsylvania, USA), partial stent deployment or partial stent deployment with locally delivered tPA. The negative control received no treatment.

RESULTS: In vivo revascularization Thrombolysis in Cerebral Infarction (TICI) score revealed that the balloon infusion wire achieved a stable and higher revascularization score of TICI 2B, with a lower dose of tPA in comparison with other treatment strategies. All treatment strategies resulted in endothelial denudation and exposure of the internal elastic lamina.

CONCLUSIONS: The proposed animal model permits reliable and consistent thromboembolic occlusion of the target vasculature and allows for an assessment of both pharmacologic and mechanical revascularization strategies for acute ischemic stroke.

INTRODUCTION: Smoking is the most preventable cause of death. Although effective, Web-assisted tobacco interventions are underutilized and recruitment is challenging. Understanding who participates in Web-assisted tobacco interventions may help in improving recruitment.

OBJECTIVES: To understand characteristics of smokers participating in a Web-assisted tobacco intervention (Decide2Quit.org).

METHODS: In addition to the typical Google advertisements, we expanded Decide2Quit.org recruitment to include referrals from medical and dental providers. We assessed how the expanded recruitment of smokers changed the users' characteristics, including comparison with a population-based sample of smokers from the national Behavioral Risk Factors Surveillance Survey (BRFSS). Using a negative binomial regression, we compared demographic and smoking characteristics by recruitment source, in particular readiness to quit and association with subsequent Decide2Quit.org use.

RESULTS: The Decide2Quit.org cohort included 605 smokers; the 2010 BRFSS dataset included 69,992. Compared to BRFSS smokers, a higher proportion of Decide2Quit.org smokers were female (65.2% vs 45.7%, P=.001), over age 35 (80.8% vs 67.0%, P=.001), and had some college or were college graduates (65.7% vs 45.9%, P=.001). Demographic and smoking characteristics varied by recruitment; for example, a lower proportion of medical- (22.1%) and dental-referred (18.9%) smokers had set a quit date or had already quit than Google smokers (40.1%, P

CONCLUSIONS: Recruitment from clinical practices complimented Google recruitment attracting smokers less motivated to quit and less experienced with Web-assisted tobacco interventions.

TRIAL REGISTRATION: Clinicaltrials.gov NCT00797628; http://clinicaltrials.gov/ct2/show/NCT00797628 (Archived by WebCite at http://www.webcitation.org/6F3tqz0b3).

A balanced immune response requires combating infectious assaults while striving to maintain quiescence towards the self. One of the central players in this process is the pleiotropic cytokine transforming growth factor-beta (TGF-beta), whose deficiency results in spontaneous systemic autoimmunity in mice. The dominant function of TGF-beta is to regulate the peripheral immune homeostasis, particularly in the microbe-rich and antigen-rich environment of the gut. To maintain intestinal integrity, the epithelial cells, myeloid cells and lymphocytes that inhabit the gut secrete TGF-beta, which acts in both paracrine and autocrine fashions to activate its signal transducers, the SMAD transcription factors. The SMAD pathway regulates the production of IgA by B cells, maintains the protective mucosal barrier and promotes the balanced differentiation of CD4(+) T cells into inflammatory T helper type 17 cells and suppressive FOXP3(+) T regulatory cells. While encounters with pathogenic microbes activate SMAD proteins to evoke a protective inflammatory immune response, SMAD activation and synergism with immunoregulatory factors such as the vitamin A metabolite retinoic acid enforce immunosuppression toward commensal microbes and innocuous food antigens. Such complementary context-dependent functions of TGF-beta are achieved by the co-operation of SMAD proteins with distinct dominant transcription activators and accessory chromatin modifiers. This review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-beta in the gut that are dictacted by fluid orchestrations of SMADs and their myriad partners.

Recombinant adeno-associated viruses (rAAVs) have been tested in humans and other large mammals without adverse events. However, one study of mucopolysaccharidosis VII correction in mice showed repeated integration of rAAV in cells from hepatocellular carcinoma (HCC) in the Dlk1-Dio3 locus, suggesting possible insertional mutagenesis. In contrast, another study found no association of rAAV integration with HCC, raising questions about the generality of associations between liver transformation and integration at Dlk1-Dio3. Here we report that in rAAV-treated ornithine transcarbamylase (Otc)-deficient mice, four examples of integration sites in Dlk1-Dio3 could be detected in specimens from liver nodule/tumors, confirming previous studies of rAAV integration in the Dlk1-Dio3 locus in the setting of another murine model of metabolic disease. In one case, the integrated vector was verified to be present at about one copy per cell, consistent with clonal expansion. Another verified integration site in liver nodule/tumor tissue near the Tax1bp1 gene was also detected at about one copy per cell. The Dlk1-Dio3 region has also been implicated in human HCC and so warrants careful monitoring in ongoing human clinical trials with rAAV vectors.

Insulin signalling is uniquely required for storing energy as fat in humans. While de novo synthesis of fatty acids and triacylglycerol occurs mostly in liver, adipose tissue is the primary site for triacylglycerol storage. Insulin signalling mechanisms in adipose tissue that stimulate hydrolysis of circulating triacylglycerol, uptake of the released fatty acids and their conversion to triacylglycerol are poorly understood. New findings include (1) activation of DNA-dependent protein kinase to stimulate upstream stimulatory factor (USF)1/USF2 heterodimers, enhancing the lipogenic transcription factor sterol regulatory element binding protein 1c (SREBP1c); (2) stimulation of fatty acid synthase through AMP kinase modulation; (3) mobilisation of lipid droplet proteins to promote retention of triacylglycerol; and (4) upregulation of a novel carbohydrate response element binding protein beta isoform that potently stimulates transcription of lipogenic enzymes. Additionally, insulin signalling through mammalian target of rapamycin to activate transcription and processing of SREBP1c described in liver may apply to adipose tissue. Paradoxically, insulin resistance in obesity and type 2 diabetes is associated with increased triacylglycerol synthesis in liver, while it is decreased in adipose tissue. This and other mysteries about insulin signalling and insulin resistance in adipose tissue make this topic especially fertile for future research.

Chlorhexidine is increasingly being used not only as an antiseptic to prevent hospital infections and an adjuvant in oral hygiene but also as a preservative in personal care products. As exposure to the agent becomes more widespread, reports of adverse reactions to it are increasing. Complications range from mild irritant contact dermatitis to life-threatening anaphylaxis. Allergic contact dermatitis in some cases precedes anaphylaxis. It is imperative that physicians be aware of the many possible sources of contact with this antiseptic and be alert to recognize the potentially debilitating and catastrophic reactions that may occur because of chlorhexidine sensitization.

Recombinant adeno-associated virus (rAAV) vectors are great tools for gene transfer due to their ability to mediate long-term gene expression. rAAVs have been used successfully as gene transfer vehicles in multiple animal models of CNS disorders, and several clinical trials are currently underway. rAAV vectors have been used at various stages of development with no apparent toxicity. There are multiple ways of delivering AAV vectors to the mouse CNS, depending on the stage of development. In neonates, intravascular injections into the facial vein are often used. In adults, direct injections into target regions of the brain are achieved with great spatiotemporal control through stereotaxic surgeries. Recently, discoveries of new AAV vectors with the ability to cross the blood brain barrier have made it possible to target the adult CNS by intravascular injections. Curr. Protoc. Microbiol. 29:14D.5.1-14D.5.18. (c) 2013 by John Wiley and Sons, Inc.

Liver-directed gene transfer and gene therapy are rapidly gaining attention primarily because the liver is centrally involved in a variety of metabolic functions that are affected in various inherited disorders. Recombinant adeno-associated virus (rAAV) is a popular gene delivery vehicle for gene therapy, and intravenous delivery of some rAAV serotypes results in very efficient transduction in the liver. rAAV-mediated gene transfer to the liver can be used to create somatic transgenic animals or disease models for studying the function of various genes and miRNAs. The liver is the target tissue for gene therapy of many inborn metabolic diseases and may also be exploited as a "biofactory" for production of coagulation factors, insulin, growth hormones, and other non-hepatic proteins. Hence, efficient delivery of transgenes and small RNAs to the liver by rAAV vectors has been of long-standing interest to research scientists and clinicians alike. This unit describes methods for delivery of rAAV vectors by several injection routes, followed by a range of analytical methods for assessing the expression, activity, and effects of the transgene and its product. Curr. Protoc. Microbiol. 29:14D.6.1-14D.6.32. (c) 2013 by John Wiley and Sons, Inc.

PURPOSE OF REVIEW: Gout is the most common type of inflammatory arthritis. This review summarizes the most recent studies on newer therapeutics, disease management strategies and treatment recommendations.

RECENT FINDINGS: There are several new therapeutic agents being investigated both for the management of the acute gout symptoms, targeting interleukin-1beta, as well as urate-lowering therapies including uricase and inhibitors of renal urate transporter proteins. Interventions led by pharmacists and nurses, which include patient education, lifestyle advice, monitoring and titration of urate-lowering medications have been implemented to improve gout management. Recently, the American College of Rheumatology has published guidelines for nonpharmacologic and pharmacologic therapeutic approaches for hyperuricemia and acute gouty arthritis.

SUMMARY: New therapeutic agents targeting the mechanism of inflammation (IL-1beta) are under investigation. In addition, new urate-lowering medications to be used alone or in combination with allopurinol are undergoing rigorous evaluation to use for patients not responding to or unable to take current therapies. There is also increasing interest in redesigning clinical care to improve patient education, self-management training and urate-lowering medication titration. Although we await results of these investigations, the American College of Rheumatology treatment guidelines provide a framework for clinicians in order to provide optimal gout care.

BACKGROUND AND OBJECTIVES: Increased systolic BP visit-to-visit variability (SBV) may be associated with higher overall mortality and cardiovascular events. However, few studies have examined these associations in patients with CKD, and the relation of SBV with CKD progression and ESRD has not been shown. This study analyzed the association of SBV with overall mortality, cardiovascular mortality, cardiovascular events, and renal events among individuals enrolled in the African American Study of Kidney Disease (AASK) trial.

DESIGN, SETTING, PARTICIPANTS, and MEASUREMENTS: This was a prospective observational study of 908 participants during the trial phase of the AASK study, with at least 1 year of BP measurements available and followed for 3-6.4 years. SBV was calculated as the SD of the systolic pressure from five visits occurring 3-12 months after randomization. The association of SBV with risk of overall mortality, cardiovascular mortality, a composite of fatal and nonfatal cardiovascular events, and a composite of renal events was assessed using proportional hazards regression and adjusting for multiple potential confounders.

RESULTS: Greater SBV was associated with higher overall mortality. The adjusted hazard ratio (95% confidence interval) was 2.82 (1.14-6.95) comparing the highest with lowest tertile of SBV. A similar comparison revealed that greater SBV was also associated with cardiovascular mortality (adjusted hazard ratio, 4.91; 1.12-21.50). SBV was associated with both the cardiovascular renal composite endpoints in unadjusted but not adjusted analyses.

CONCLUSIONS: In African Americans with CKD, SBV is strongly and independently associated with overall and cardiovascular mortality.

OBJECTIVE: The objective of this study is to develop an isotope dilution liquid chromatography tandem mass spectrometry assay to screen for hepatorenal tyrosinemia (HT) from newborn filter paper samples using pooled extracts to increase high throughput screening.

DESIGN AND METHODS: Succinylacetone (SUAC), the marker for HT, was extracted from dried blood spots with the formation of the hydrazone derivative of SUAC; up to eight sample extracts were pooled and the SUAC-derivative was analyzed by mass spectrometry methods with an injection-to-injection time of one minute. If any pooled sample extract screened positive, then the samples comprising the pooled sample were assayed individually.

RESULTS: Two newborn infants were identified with high levels of SUAC (7 and 23muM) and later confirmed to have HT. Three older children whose initial filter paper samples were taken at 195days to 614days of age with elevated SUAC (range 4.9-5muM) were identified; one of the three had clinical signs of HT and was placed on treatment (diagnosis of the other two are unavailable).

CONCLUSION: MS/MS analysis of pooled dried blood sample extracts permits sensitive, reduced instrumental analytical time and increase high throughput screening for HT. Elsevier Inc. All rights reserved.

Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase family, TYK2, and its downstream effector STAT1, in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently showed TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of interleukin (IL)-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the antiapoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway.

Gene duplication results in two identical paralogs that diverge through mutation, leading to loss or gain of interactions with other biomolecules. Here, we comprehensively characterize such network rewiring for C. elegans transcription factors (TFs) within and across four newly delineated molecular networks. Remarkably, we find that even highly similar TFs often have different interaction degrees and partners. In addition, we find that most TF families have a member that is highly connected in multiple networks. Further, different TF families have opposing correlations between network connectivity and phylogenetic age, suggesting that they are subject to different evolutionary pressures. Finally, TFs that have similar partners in one network generally do not in another, indicating a lack of pressure to retain cross-network similarity. Our multiparameter analyses provide unique insights into the evolutionary dynamics that shaped TF networks.

The SF1 helicase MOV10 is an antiviral factor that is incorporated into human immunodeficiency virus type 1 (HIV-1) virions. We now report that HIV-1 virions also incorporate UPF1, which belongs to the same SF1 helicase subfamily as MOV10 and functions in the nonsense-mediated decay (NMD) pathway. Unlike ectopic MOV10, the overexpression of UPF1 does not impair the infectivity of HIV-1 progeny virions. However, UPF1 becomes a potent inhibitor of HIV-1 progeny virion infectivity when residues required for its helicase activity are mutated. In contrast, equivalent mutations abolish the antiviral activity of MOV10. Importantly, cells depleted of endogenous UPF1, but not of another NMD core component, produce HIV-1 virions of substantially lower specific infectivity. The defect is at the level of reverse transcription, the same stage of the HIV-1 life cycle inhibited by ectopic MOV10. Thus, whereas ectopic MOV10 restricts HIV-1 replication, the related UPF1 helicase functions as a cofactor at an early post-entry step.

BACKGROUND: Health care providers do not routinely carry out brief counseling for tobacco cessation despite the evidence for its effectiveness. For this intervention to be routinely used, it must be brief, be convenient, require little investment of resources, require little specialized training, and be perceived as efficacious by providers. Technological advances hold much potential for addressing the barriers preventing the integration of brief interventions for tobacco cessation into the health care setting.

OBJECTIVE: This paper describes the development and initial evaluation of the Computer-Assisted Brief Intervention for Tobacco (CABIT) program, a web-based, multimedia tobacco intervention for use in opportunistic settings.

METHODS: The CABIT uses a self-administered, computerized assessment to produce personalized health care provider and patient reports, and cue a stage-matched video intervention. Respondents interested in changing their tobacco use are offered a faxed referral to a "best matched" tobacco treatment provider (ie, dynamic referral). During 2008, the CABIT program was evaluated in an emergency department, an employee assistance program, and a tobacco dependence program in New Jersey. Participants and health care providers completed semistructured interviews and satisfaction ratings of the assessment, reports, video intervention, and referrals using a 5-point scale.

RESULTS: Mean patient satisfaction scores (n = 67) for all domains ranged from 4.00 (Good) to 5.00 (Excellent; Mean = 4.48). Health care providers completed satisfaction forms for 39 patients. Of these 39 patients, 34 (87%) received tobacco resources and referrals they would not have received under standard care. Of the 45 participants offered a dynamic referral, 28 (62%) accepted.

CONCLUSIONS: The CABIT program provided a user-friendly, desirable service for tobacco users and their health care providers. Further development and clinical trial testing is warranted to establish its effectiveness in promoting treatment engagement and tobacco cessation.