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Recent documents in eScholarship@UMMS
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Preclinical investigations for thrombectomy devices--does it translate to humans

Thu, 05/15/2014 - 5:14pm

Currently, most preclinical models to validate thrombectomy technologies have not directly translated to the clinical arena. Herein, we review our strategy that combines in vitro and in vivo modeling to assess thrombectomy device safety and efficacy quantitatively.

Evaluation of a role functioning computer adaptive test (RF-CAT)

Thu, 05/15/2014 - 5:14pm

OBJECTIVES: To evaluate the validity and participants' acceptance of an online assessment of role function using computer adaptive test (RF-CAT).

METHODS: The RF-CAT and a set of established quality of life instruments were administered in a cross-sectional study in a panel sample (n = 444) recruited from the general population with over-selection of participants with selected self-report chronic conditions (n = 225). The efficiency, score accuracy, validity, and acceptability of the RF-CAT were evaluated and compared to existing measures.

RESULTS: The RF-CAT with a stopping rule of six items with content balancing used 25 of the available bank items and was completed on average in 66 s. RF-CAT and the legacy tools scores were highly correlated (.64-.84) and successfully discriminated across known groups. The RF-CAT produced a more precise assessment over a wider range than the SF-36 Role Physical scale. Patients' evaluations of the RF-CAT system were positive overall, with no differences in ratings observed between the CAT and static assessments.

CONCLUSIONS: The RF-CAT was feasible, more precise than the static SF-36 RP and equally acceptable to participants as legacy measures. In empirical tests of validity, the better performance of the CAT was not uniformly statistically significant. Further research exploring the relationship between gained precision and discriminant power of the CAT assessment is needed.

The spectrum of translational stroke research

Thu, 05/15/2014 - 5:14pm

Translational stroke research occurs at the interface between basic science and clinical research, and encompasses contributors with varied backgrounds and areas of expertise. The traditional approach to translational stroke research is to take novel discoveries of basic researchers about the mechanisms and consequences of ischemic brain injury and evaluate the potential of these discoveries to enhance clinical stroke diagnostics and therapeutics. Animal stroke modeling and imaging are key steps in this traditional bench-to-bedside paradigm for translational stroke research. Newer approaches to translational research include reverse and lateral translation. With these paradigms, basic researchers are stimulated to improve our understanding of the pathophysiological mechanisms that underlie a clinically observed phenomenon or treatment effect or improve upon an observed treatment effect by determining if drug modification can enhance a clinically beneficial effect. No matter how translational stroke research is conducted, this type of research is critical for the future and involves multidisciplinary teams that need to have productive and insightful ideas and communications.

Frequency and impact of intensive care unit complications on moderate-severe traumatic brain injury: early results of the Outcome Prognostication in Traumatic Brain Injury (OPTIMISM) Study

Thu, 05/15/2014 - 5:14pm

BACKGROUND: Known predictors of adverse outcomes in patients with moderate-severe TBI (msTBI) explain only a relatively small proportion of patient-related outcomes. The frequency and impact of intensive care unit complications (ICU-COMPL) on msTBI-associated outcomes are poorly understood.

METHODS: In 213 consecutive msTBI patients admitted to a Level I Trauma Center neuro trauma ICU, twenty-eight ICU-COMPL (21 medical and 7 neurological) were prospectively collected and adjudicated by group consensus, using pre-defined criteria. We determined frequencies, and explored associations of ICU-COMPL and hospital discharge outcomes using multivariable logistic regression.

RESULTS: The average age of the study sample was 53 years, and the median presenting Glasgow Coma Scale and Injury Severity Scores were 5 and 27, respectively. Hyperglycemia (79%), fever (62%), systemic inflammatory response syndrome (60%), and hypotension requiring vasopressors (42%) were the four most common medical ICU-COMPL. Herniation (39%), intracranial rebleed (39%), and brain edema requiring osmotherapy (37%) were the three most common neurological ICU-COMPL. After adjusting for admission variables, duration of ventilation, and ICU length-of-stay, patients with brain edema (OR 5.8; 95% CI 2, 16.7) had a significantly increased odds for dying during hospitalization whereas patients with hospital-acquired urinary tract infection (UTI) had a decreased odds (OR 0.05; 95% CI 0.005, 0.6). Sensitivity analysis revealed that UTI occurred later, suggesting a non-causal association with survival. Brain herniation (OR 15.7; 95% CI 2.6, 95.4) was associated with an unfavorable functional status (GOS 1-3).

CONCLUSION: ICU-COMPL are very common after msTBI, have a considerable impact on short-term outcomes, and should be considered in the prognostication of these high risk patients. Survival associations of time-dependent complications warrant cautious interpretation.

Reducing analytical variation between point-of-care and laboratory HbA1c testing

Thu, 05/15/2014 - 5:14pm

BACKGROUND: Point-of-care (POC) HbA1c testing allows for timely treatment changes, improved glycemic control, and patient and provider satisfaction. Substantial variation between POC and laboratory HbA1c results has been reported. At our university hospital diabetes clinic, we observed significant negative bias in HbA1c with the DCA Vantage (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) compared with the Tosoh G8 HPLC laboratory analyzer (Tosoh Bioscience, San Francisco, CA, USA). This led us to systematically analyze the bias with the goal of recalibrating the DCA to minimize bias.

METHODS: We analyzed 45 patient samples, with HbA1c ranging between 5% and 10.8%, concurrently on two DCA analyzers and on the Tosoh G8 machine. The bias for each sample was the difference between the value on the DCA and the Tosoh G8 analyzer. Based on regression equations derived from the data, a correction factor for each DCA analyzer was calculated. The analyzers were recalibrated and retested for bias.

RESULTS: At baseline, the mean bias (range) was -0.5229 (+0.1 to -1.3) for Analyzer 1 and -0.5348 (0.0 to -1.6) for Analyzer 2. After recalibration, the mean bias (range) was 0.000 (+0.6 to -0.6) and 0.0003 (+0.5 to -0.5) for Analyzers 1 and 2, respectively, and the systematic negative bias seen prior to the calibration was almost eliminated.

CONCLUSIONS: We recommend periodic recalibration of POC analyzers to eliminate systematic unidirectional bias and to harmonize results between the POC and central laboratory analyzers within a healthcare system. Calibration may need to be repeated with any change in the reagent lot. University School of Medicine.

The phylogeny of permanent prostate brachytherapy

Thu, 05/15/2014 - 5:14pm

Permanent prostate brachytherapy has been practiced for more than a century. This review examines the influence of earlier procedures on the modern transperineal ultrasound-directed technique. A literature review was conducted to examine the origin of current clinical practice. The dimensions of the modern brachytherapy seed, the prescription dose, and implant/teletherapy sequencing are vestigial features, which may be suboptimal in the current era of low-energy photon-emitting radionuclides and computerized dose calculations. Although the modern transperineal permanent prostate implant procedure has proven to be safe and effective, it should undergo continuous re-evaluation and evolution to ensure that its potential is maximized.

Coexisting intrarenal arteriovenous and caliceovenous fistulae after percutaneous nephrolithotomy: Case report and literature review

Thu, 05/15/2014 - 5:14pm

A 58-year-old man was re-admitted to the Urology service with delayed gross hematuria and unstable he-modynamics, following a percutaneous nephrolithotomy (PCNL) procedure performed for an obstructive solitary left lower calyceal stone. A selective left renal angiogram demonstrated an interpolar arteriovenous fistula (AVF), which was treated with successful coil embolization of a sub-segmental feeding branch. Sub-sequent nephrostogram confirmed a coexisting caliceovenous fistula, which was observed and healed spon-taneously. Iatrogenic coexisting intrarenal AVF and caliceovenous fistulae have never been reported and should be considered as a possible cause of delayed severe hematuria with unstable hemodynamics, and/or increase in baseline creatinine after PCNL.

Educating psychiatry residents in neuropsychiatry and neuroscience

Thu, 05/15/2014 - 5:14pm

Neuropsychiatry and psychiatric neuroscience should be part of the general psychiatry curriculum so that graduate psychiatrists will be able to allow their patients the benefit of neuroscientifically informed diagnosis and treatment. Current neurology and neuroscience educational requirements for US psychiatry training are reviewed. The draft milestone requirements for clinical neuroscience training as part of the US Accreditation Council for Graduate Medical Education's Next Accreditation System are also provided. Suggestions for the neuropsychiatric and neuroscience content of psychiatry residency training are made, along with a description of pedagogic methods and resources. Survey data are reviewed indicating agreement by programme directors with the importance of neuroscience training and an increase in the amount of time devoted to this area. Faculty staff development in neuropsychiatry and neuroscience literacy will be needed to provide high quality training in these areas.

Treating hypertension in patients with left ventricular dysfunction: hitting the fairway and avoiding the rough

Thu, 05/15/2014 - 5:14pm

Hypertension is a major risk factor in the development of heart failure (HF), yet current guidelines do not specify a target blood pressure (BP) for patients with established systolic or diastolic left ventricular (LV) dysfunction. While no randomized controlled trial (RCT) has been conducted to specify the optimal blood pressure in these patients, numerous trials have demonstrated the benefits of certain classes of medications and treatment strategies in patients with HF. Important factors to consider in treating hypertension in patients with HF include the type of HF (reduced vs. preserved ejection fraction), the etiology (ischemic vs. nonischemic), the severity of symptoms if any, the baseline blood pressure, as well as a wide variety of patient-specific factors. This paper reviews current evidence to address the question, "What should be the blood pressure goal in patients with asymptomatic and symptomatic left ventricular dysfunction?" We suggest a target blood pressure of 120-140/70-90 mm Hg in most cases, with lower pressures generally preferable if tolerated.

Improved image quality and detection of small cerebral infarctions with diffusion-tensor trace imaging

Thu, 05/15/2014 - 5:14pm

OBJECTIVE: The purpose of this study was to test a hypothesis that routinely performed diffusion-tensor trace imaging is of sufficient image quality and sensitivity for infarct detection to safely and routinely replace standard diffusion-weighted imaging (DWI) in the clinical setting.

MATERIALS AND METHODS: Both routine DWI and 15-direction diffusion-tensor imaging (DTI) with parallel acquisition technique were obtained on all brain MRI studies from a single 1.5-T MRI scanner at a tertiary care referral center over a 1-year period, permitting direct comparison of the two different diffusion studies on the same patients (2537 studies, 365 infarct-positive studies). A subset of images was assessed for image quality and quantitatively for ability to detect brain infarctions. The total set of positive studies was reviewed qualitatively for ability to detect small cerebral infarctions.

RESULTS: Fifteen-direction isotropic DWI (DTI trace images) with parallel acquisition technique resulted in consistently higher image quality with less distortion and higher image detail than routine DWI. Small infarcts were better seen, and in 12 cases, infarcts could only be seen on 15-direction isotropic diffusion-weighted images. The additional scanning time required for 15-direction isotropic DWI did not result in significantly increased motion-related reduction in image quality compared with standard DWI.

CONCLUSION: Diffusion-tensor trace images obtained with parallel acquisition technique are of improved image quality and improved sensitivity for detection of small cerebral infarctions relative to standard DWI. If such DTI data are acquired, routine DWI can be omitted.

Adipocyte lineages: tracing back the origins of fat

Thu, 05/15/2014 - 5:14pm

The obesity epidemic has intensified efforts to understand the mechanisms controlling adipose tissue development. Adipose tissue is generally classified as white adipose tissue (WAT), the major energy storing tissue, or brown adipose tissue (BAT), which mediates non-shivering thermogenesis. It is hypothesized that brite adipocytes (brown in white) may represent a third adipocyte class. The recent realization that brown fat exist in adult humans suggests increasing brown fat energy expenditure could be a therapeutic strategy to combat obesity. To understand adipose tissue development, several groups are tracing the origins of mature adipocytes back to their adult precursor and embryonic ancestors. From these studies emerged a model that brown adipocytes originate from a precursor shared with skeletal muscle that expresses Myf5-Cre, while all white adipocytes originate from a Myf5-negative precursors. While this provided a rational explanation to why BAT is more metabolically favorable than WAT, recent work indicates the situation is more complex because subsets of white adipocytes also arise from Myf5-Cre expressing precursors. Lineage tracing studies further suggest that the vasculature may provide a niche supporting both brown and white adipocyte progenitors; however, the identity of the adipocyte progenitor cell is under debate. Differences in origin between adipocytes could explain metabolic heterogeneity between depots and/or influence body fat patterning particularly in lipodystrophy disorders. Here, we discuss recent insights into adipose tissue origins highlighting lineage-tracing studies in mice, how variations in metabolism or signaling between lineages could affect body fat distribution, and the questions that remain unresolved. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

The normalcy of dormancy: common themes in microbial quiescence

Thu, 05/15/2014 - 5:14pm

All microorganisms are exposed to periodic stresses that inhibit growth. Many bacteria and fungi weather these periods by entering a hardy, nonreplicating state, often termed quiescence or dormancy. When this occurs during an infection, the resulting slowly growing pathogen is able to tolerate both immune insults and prolonged antibiotic exposure. While the stresses encountered in a free-living environment may differ from those imposed by host immunity, these growth-limiting conditions impose common pressures, and many of the corresponding microbial responses appear to be universal. In this review, we discuss the common features of these growth-limited states, which suggest new approaches for treating chronic infections such as tuberculosis.

Adipose tissue angiogenesis: impact on obesity and type-2 diabetes

Thu, 05/15/2014 - 5:14pm

The growth and function of tissues are critically dependent on their vascularization. Adipose tissue is capable of expanding many-fold during adulthood, therefore requiring the formation of new vasculature to supply growing and proliferating adipocytes. The expansion of the vasculature in adipose tissue occurs through angiogenesis, where new blood vessels develop from those pre-existing within the tissue. Inappropriate angiogenesis may underlie adipose tissue dysfunction in obesity, which in turn increases type-2 diabetes risk. In addition, genetic and developmental factors involved in vascular patterning may define the size and expandability of diverse adipose tissue depots, which are also associated with type-2 diabetes risk. Moreover, the adipose tissue vasculature appears to be the niche for pre-adipocyte precursors, and factors that affect angiogenesis may directly impact the generation of new adipocytes. Here we review recent advances on the basic mechanisms of angiogenesis, and on the role of angiogenesis in adipose tissue development and obesity. A substantial amount of data points to a deficit in adipose tissue angiogenesis as a contributing factor to insulin resistance and metabolic disease in obesity. These emerging findings support the concept of the adipose tissue vasculature as a source of new targets for metabolic disease therapies. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

Breastfeeding During Early Infancy is Associated with a Lower Incidence of Febrile Illnesses

Thu, 05/15/2014 - 5:14pm

Human breast milk is known to contain immunoprotective, antimicrobial, and anti-inflammatory agents. In a prospective clinical study of dengue virus infections during infancy, we examined the correlation between breastfeeding and the development of febrile illnesses in an infant population. We found that breastfeeding status and the frequency of breastfeeding during early infancy was associated with a lower incidence of febrile illnesses.

(De-) oiling inflammasomes

Thu, 05/15/2014 - 5:14pm

Activation of inflammasome signaling can produce harmful inflammation. In this issue of Immunity, Yan et al. (2013) suggest that omega-3 fatty acids commonly found in marine oils can suppress activation of NLRP3 and NLRP1b inflammasomes.

Breastfeeding During Early Infancy is Associated with Higher Weight-Based World Health Organization Anthropometry

Thu, 05/15/2014 - 5:14pm

The World Health Organization (WHO) Expert Committee on Physical Status: The Use and Interpretation of Anthropometry established reference anthropometric standards for the growth of healthy infants and children. As part of a prospective clinical study of dengue virus infections in infants, we measured the length and weight of healthy infants in San Pablo, Laguna, Philippines at two scheduled study visits. We examined the correlation between breastfeeding and WHO anthropometric z scores during early infancy in San Pablo, Laguna, Philippines. We found that breastfeeding status and the frequency of breastfeeding during early infancy positively correlated with weight-based WHO anthropometric z scores.

Nucleosome dynamics regulates DNA processing

Thu, 05/15/2014 - 5:14pm

The repair of DNA double-strand breaks (DSBs) is critical for the maintenance of genome integrity. The first step in DSB repair by homologous recombination is the processing of the ends by one of two resection pathways, executed by the Saccharomyces cerevisiae Exo1 and Sgs1-Dna2 machineries. Here we report in vitro and in vivo studies that characterize the impact of chromatin on each resection pathway. We find that efficient resection by the Sgs1-Dna2-dependent machinery requires a nucleosome-free gap adjacent to the DSB. Resection by Exo1 is blocked by nucleosomes, and processing activity can be partially restored by removal of the H2A-H2B dimers. Our study also supports a role for the dynamic incorporation of the H2A.Z histone variant in Exo1 processing, and it further suggests that the two resection pathways require distinct chromatin remodeling events to navigate chromatin structure.

Enhancement of SMN protein levels in a mouse model of spinal muscular atrophy using novel drug-like compounds

Thu, 05/15/2014 - 5:14pm

Spinal muscular atrophy (SMA) is a neurodegenerative disease that causes progressive muscle weakness, which primarily targets proximal muscles. About 95% of SMA cases are caused by the loss of both copies of the SMN1 gene. SMN2 is a nearly identical copy of SMN1, which expresses much less functional SMN protein. SMN2 is unable to fully compensate for the loss of SMN1 in motor neurons but does provide an excellent target for therapeutic intervention. Increased expression of functional full-length SMN protein from the endogenous SMN2 gene should lessen disease severity. We have developed and implemented a new high-throughput screening assay to identify small molecules that increase the expression of full-length SMN from a SMN2 reporter gene. Here, we characterize two novel compounds that increased SMN protein levels in both reporter cells and SMA fibroblasts and show that one increases lifespan, motor function, and SMN protein levels in a severe mouse model of SMA.