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31.
Douglas N. Sanders Rong Zeng David A. Wenger Gary S. Johnson Gayle C. Johnson Jared E. Decker Martin L. Katz Simon R. Platt Dennis P. O'Brien 《Molecular genetics and metabolism》2013,108(1):70-75
GM2 gangliosidosis is a fatal lysosomal storage disease caused by a deficiency of β-hexosaminidase (EC 3.2.1.52). There are two major isoforms of the enzyme: hexosaminidase A composed of an α and a β subunit (encoded by HEXA and HEXB genes, respectively); and, hexosaminidase B composed of two β subunits. Hexosaminidase A requires an activator protein encoded by GM2A to catabolize GM2 ganglioside, but even in the absence of the activator protein, it can hydrolyze the synthetic substrates commonly used to assess enzyme activity. GM2 gangliosidosis has been reported in Japanese Chin dogs, and we identified the disease in two related Japanese Chin dogs based on clinical signs, histopathology and elevated brain GM2 gangliosides. As in previous reports, we found normal or elevated hexosaminidase activity when measured with the synthetic substrates. This suggested that the canine disease is analogous to human AB variant of GM2 gangliosidosis, which results from mutations in GM2A. However, only common neutral single nucleotide polymorphisms were found upon sequence analysis of the canine ortholog of GM2A from the affected Japanese Chins. When the same DNA samples were used to sequence HEXA, we identified a homozygous HEXA:c967G>A transition which predicts a p.E323K substitution. The glutamyl moiety at 323 is known to make an essential contribution to the active site of hexosaminidase A, and none of the 128 normal Japanese Chins and 92 normal dogs of other breeds that we tested was homozygous for HEXA:c967A. Thus it appears that the HEXA:c967G>A transition is responsible for the GM2 gangliosidosis in Japanese Chins. 相似文献
32.
Mr‐derived cerebral spinal fluid hydrodynamics as a marker and a risk factor for intracranial hypertension in astronauts exposed to microgravity 下载免费PDF全文
33.
Deydre S. Teyhen Scott W. Shaffer Robert J. Butler Stephen L. Goffar Kyle B. Kiesel Daniel I. Rhon Jared N. Williamson Phillip J. Plisky 《Clinical orthopaedics and related research》2015,473(9):2948-2958
Background
Musculoskeletal injury is the most common reason that soldiers are medically not ready to deploy. Understanding intrinsic risk factors that may place an elite soldier at risk of musculoskeletal injury may be beneficial in preventing musculoskeletal injury and maintaining operational military readiness. Findings from this population may also be useful as hypothesis-generating work for particular civilian settings such as law enforcement officers (SWAT teams), firefighters (smoke jumpers), or others in physically demanding professions.Questions/purposes
The purposes of this study were (1) to examine whether using baseline measures of self-report and physical performance can identify musculoskeletal injury risk; and (2) to determine whether a combination of predictors would enhance the accuracy for determining future musculoskeletal injury risk in US Army Rangers.Methods
Our study was a planned secondary analysis from a prospective cohort examining how baseline factors predict musculoskeletal injury. Baseline predictors associated with musculoskeletal injury were collected using surveys and physical performance measures. Survey data included demographic variables, injury history, and biopsychosocial questions. Physical performance measures included ankle dorsiflexion, Functional Movement Screen, lower and upper quarter Y-balance test, hop testing, pain provocation, and the Army Physical Fitness Test (consisting of a 2-mile run and 2 minutes of sit-ups and push-ups). A total of 320 Rangers were invited to enroll and 211 participated (66%). Occurrence of musculoskeletal injury was tracked for 1 year using monthly injury surveillance surveys, medical record reviews, and a query of the Department of Defense healthcare utilization database. Injury surveillance data were available on 100% of the subjects. Receiver operator characteristic curves and accuracy statistics were calculated to identify predictors of interest. A logistic regression equation was then calculated to find the most pertinent set of predictors. Of the 188 Rangers (age, 23.3 ± 3.7 years; body mass index, 26.0 ± 2.4 kg/m2) remaining in the cohort, 85 (45.2%) sustained a musculoskeletal injury of interest.Results
Smoking, prior surgery, recurrent prior musculoskeletal injury, limited-duty days in the prior year for musculoskeletal injury, asymmetrical ankle dorsiflexion, pain with Functional Movement Screen clearing tests, and decreased performance on the 2-mile run and 2-minute sit-up test were associated with increased injury risk. Presenting with one or fewer predictors resulted in a sensitivity of 0.90 (95% confidence interval [CI], 0.83–0.95), and having three or more predictors resulted in a specificity of 0.98 (95% CI, 0.93–0.99). The combined factors that contribute to the final multivariable logistic regression equation yielded an odds ratio of 4.3 (95% CI, 2.0–9.2), relative risk of 1.9 (95% CI, 1.4–2.6), and an area under the curve of 0.64.Conclusions
Multiple factors (musculoskeletal injury history, smoking, pain provocation, movement tests, and lower scores on physical performance measures) were associated with individuals at risk for musculoskeletal injury. The summation of the number of risk factors produced a highly sensitive (one or less factor) and specific (three or more factors) model that could potentially be used to effectively identify and intervene in those persons with elevated risk for musculoskeletal injury. Future research should establish if screening and intervening can improve musculoskeletal health and if our findings among US Army Rangers translate to other occupations or athletes.Level of Evidence
Level II, prognostic study. 相似文献34.
35.
Adrienne A. Taren Peter J. Gianaros Carol M. Greco Emily K. Lindsay April Fairgrieve Kirk Warren Brown Rhonda K. Rosen Jennifer L. Ferris Erica Julson Anna L. Marsland James K. Bursley Jared Ramsburg J. David Creswell 《Social cognitive and affective neuroscience》2015,10(12):1758-1768
Recent studies indicate that mindfulness meditation training interventions reduce stress and improve stress-related health outcomes, but the neural pathways for these effects are unknown. The present research evaluates whether mindfulness meditation training alters resting state functional connectivity (rsFC) of the amygdala, a region known to coordinate stress processing and physiological stress responses. We show in an initial discovery study that higher perceived stress over the past month is associated with greater bilateral amygdala-subgenual anterior cingulate cortex (sgACC) rsFC in a sample of community adults (n = 130). A follow-up, single-blind randomized controlled trial shows that a 3-day intensive mindfulness meditation training intervention (relative to a well-matched 3-day relaxation training intervention without a mindfulness component) reduced right amygdala-sgACC rsFC in a sample of stressed unemployed community adults (n = 35). Although stress may increase amygdala-sgACC rsFC, brief training in mindfulness meditation could reverse these effects. This work provides an initial indication that mindfulness meditation training promotes functional neuroplastic changes, suggesting an amygdala-sgACC pathway for stress reduction effects. 相似文献
36.
Moria J. Smoski Shian-Ling Keng Jie Lisa Ji Tyler Moore Jared Minkel Gabriel S. Dichter 《Social cognitive and affective neuroscience》2015,10(9):1187-1194
Mood disorders are characterized by impaired emotion regulation abilities, reflected in alterations in frontolimbic brain functioning during regulation. However, little is known about differences in brain function when comparing regulatory strategies. Reappraisal and emotional acceptance are effective in downregulating negative affect, and are components of effective depression psychotherapies. Investigating neural mechanisms of reappraisal vs emotional acceptance in remitted major depressive disorder (rMDD) may yield novel mechanistic insights into depression risk and prevention. Thirty-seven individuals (18 rMDD, 19 controls) were assessed during a functional magnetic resonance imaging task requiring reappraisal, emotional acceptance or no explicit regulation while viewing sad images. Lower negative affect was reported following reappraisal than acceptance, and was lower following acceptance than no explicit regulation. In controls, the acceptance > reappraisal contrast revealed greater activation in left insular cortex and right prefrontal gyrus, and less activation in several other prefrontal regions. Compared with controls, the rMDD group had greater paracingulate and right midfrontal gyrus (BA 8) activation during reappraisal relative to acceptance. Compared with reappraisal, acceptance is associated with activation in regions linked to somatic and emotion awareness, although this activation is associated with less reduction in negative affect. Additionally, a history of MDD moderated these effects. 相似文献
37.
Aryun Kim Amy Kutschke David E. Ehmann Sara A. Patey Jared L. Crandon Elise Gorseth Alita A. Miller Robert E. McLaughlin Christina M. Blinn April Chen Asha S. Nayar Brian Dangel Andy S. Tsai Michael T. Rooney Kerry E. Murphy-Benenato Ann E. Eakin David P. Nicolau 《Antimicrobial agents and chemotherapy》2015,59(12):7743-7752
The objective of this study was to investigate the risk of attenuated efficacy due to adaptive resistance for the siderophore-conjugated monocarbam SMC-3176 in Pseudomonas aeruginosa by using a pharmacokinetic/pharmacodynamic (PK/PD) approach. MICs were determined in cation-adjusted Mueller-Hinton broth (MHB) and in Chelex-treated, dialyzed MHB (CDMHB). Spontaneous resistance was assessed at 2× to 16× the MIC and the resulting mutants sequenced. Efficacy was evaluated in a neutropenic mouse thigh model at 3.13 to 400 mg/kg of body weight every 3 h for 24 h and analyzed for association with free time above the MIC (fT>MIC). To closer emulate the conditions of the in vivo model, we developed a novel assay testing activity mouse whole blood (WB). All mutations were found in genes related to iron uptake: piuA, piuC, pirR, fecI, and pvdS. Against four P. aeruginosa isolates, SMC-3176 displayed predictable efficacy corresponding to the fT>MIC using the MIC in CDMHB (R2 = 0.968 to 0.985), with stasis to 2-log kill achieved at 59.4 to 81.1%. Efficacy did not translate for P. aeruginosa isolate JJ 4-36, as the in vivo responses were inconsistent with fT>MIC exposures and implied a threshold concentration that was greater than the MIC. The results of the mouse WB assay indicated that efficacy was not predictable using the MIC for JJ 4-36 and four additional isolates, against which in vivo failures of another siderophore-conjugated β-lactam were previously reported. SMC-3176 carries a risk of attenuated efficacy in P. aeruginosa due to rapid adaptive resistance preventing entry via the siderophore-mediated iron uptake systems. Substantial in vivo testing is warranted for compounds using the siderophore approach to thoroughly screen for this in vitro-in vivo disconnect in P. aeruginosa. 相似文献
38.
Corinne Antignac James P. Calvet Gregory G. Germino Jared J. Grantham Lisa M. Guay-Woodford Peter C. Harris Friedhelm Hildebrandt Dorien J.M. Peters Stefan Somlo Vicente E. Torres Gerd Walz Jing Zhou Alan S.L. Yu 《Journal of the American Society of Nephrology : JASN》2015,26(9):2081-2095
Polycystic kidney disease (PKD) is one of the most common life-threatening genetic diseases. Jared J. Grantham, M.D., has done more than any other individual to promote PKD research around the world. However, despite decades of investigation there is still no approved therapy for PKD in the United States. In May 2014, the University of Kansas Medical Center hosted a symposium in Kansas City honoring the occasion of Dr. Grantham''s retirement and invited all the awardees of the Lillian Jean Kaplan International Prize for Advancement in the Understanding of Polycystic Kidney Disease to participate in a forward-thinking and interactive forum focused on future directions and innovations in PKD research. This article summarizes the contributions of the 12 Kaplan awardees and their vision for the future of PKD research. 相似文献
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