Femoral Structure and Biomechanical Characteristics in Sanfilippo Syndrome Type-B Mice.

Sanfilippo syndrome Type-B, also known as mucopolysaccharidosis IIIB (MPS IIIB), accounts for approximately one-third of all Sanfilippo syndrome patients and is characterized by a similar natural history as Type-A. Patients suffer from developmental regression, bone malformation, organomegaly, GI distress, and profound neurological deficits. Despite human trials of enzyme replacement therapy (ERT) (SBC-103, AX250) in MPS IIIB, there is currently no FDA approved treatment and a few palliative options. The major concerns of ERT and gene therapy for the treatment of bone malformation are the inadequate biodistribution of the missing enzyme, N-acetyl-α-glucosaminidase (NAGLU), and that the skeleton is a poorly hit target tissue in ERT and gene therapy. Each of the four known human types of MPS III (A, B, C, and D) is usually regarded as having mild bone manifestations, yet it remains poorly characterized. This study aimed to determine bone mineral content (BMC), volumetric bone mineral density (vBMD), and biomechanical properties in femurs MPS IIIB C57BL/6 mice compared to phenotypic control C57BL/6 mice. Significant differences were observed in MPS IIIB mice within various cortical and cancellous bone parameters for both males and females (p < 0.05). Here, we establish some osteogenic manifestations of MPS IIIB within the mouse model by radiographic and biomechanical tests, which are also differentially affected by age and sex. This suggests that some skeletal features of the MPS IIIB mouse model may be used as biomarkers of peripheral disease correction for preclinical treatment of MPS IIIB.

Effects of 8-Week Exhausting Deep Knee Flexion Flywheel Training on Persistent Quadriceps Weakness in Well-Trained Athletes Following Anterior Cruciate Ligament Reconstruction.

Persistent quadriceps weakness after anterior cruciate ligament (ACL) reconstruction is a common hurdle to efficient rehabilitation. Therefore, we evaluated a new treatment strategy for athletes with ACL reconstruction. Eleven athletes with unilateral ACL reconstruction performed one set of flywheel Bulgarian split squats to exhaustion with a maximum knee extension of 60°, over 16 sessions, on their reconstructed limb. Quadriceps rate of force development (RFD) 0-50 ms (RFD0-50 ms), and 0-150 ms (RFD0-150 ms), maximum voluntary isometric contraction (MVIC), and central activation ratio (CAR) were measured bilaterally on the week before and after the intervention. In the reconstructed limb, the RFD0-50 ms (p = 0.04; Cohen's d = 0.8) and RFD0-150 ms (p = 0.03; d = 0.9) increased after training. Before-after changes in MVIC and CAR were not significant (p > 0.05), but the lower the baseline MVIC, the greater the gain in MVIC (r = -0.71, p = 0.02). The between-leg difference in MVIC changed from large before (p = 0.01; d = 0.8) to small after training (p = 0.04; d = 0.4). One set of deep knee flexion flywheel Bulgarian split squats to exhaustion improved quadriceps deficits in well-trained athletes with ACL-reconstruction, particularly those with relatively low quadriceps force production.

Subacute thyroiditis presenting as a painful suspicious thyroid nodule.

Summary: We report a case of subacute thyroiditis in a 40-year-old female who initially presented with painful thyroid nodules without clinical and biochemical evidence of hyperthyroidism. Thyroid ultrasound was done to evaluate the thyroid nodules and fine-needle aspiration (FNA) was performed in view of the suspicious features. As the FNA showed a follicular lesion of undetermined significance or atypia of undetermined significance (FLUS/AUS, Bethesda III), she was advised for surgical excision. She was subsequently diagnosed with subacute thyroiditis based on her clinical symptoms, biochemical evidence of hyperthyroidism, raised erythrocyte sedimentation rate (ESR) as well as low uptake on thyroid scintigraphy. The thyroid lesions disappeared after symptomatic treatment. It is important to recognise that subacute thyroiditis can present with painful thyroid lesions with ultrasound features similar to suspicious thyroid nodules which can resolve with the resolution of the thyroiditis. Learning points: Subacute thyroiditis can present with atypical features such as the absence of pain, normal erythrocyte sedimentation rate or absence of hyperthyroidism. In subacute thyroiditis, ultrasound findings are commonly described as focal or multifocal lesions with poorly defined and heterogeneous and hypoechoic echogenicity which can be misdiagnosed as malignancy. Thyroid lesions can resolve with the resolution of thyroiditis with or without symptomatic treatment.

Practice based research in dentistry: an alternative to deal with clinical questions.

Clinical interventions in dental practice should be determined based on the best scientific evidence available. Well-designed randomized clinical trials (RCTs) provide important evidence supporting the efficacy of interventions and are usually considered as the best primary evidence. However, the strict criteria adopted by most RCTs reduce their external validity since some findings from these studies might not work under usual conditions. On the other hand, practice-based research (PBR) studies have been designed to better define the effectiveness of clinical interventions under settings closer to "real-world" conditions. Therefore, this review aimed to describe different PBR designs discussing some advantages and limitations of such studies. The stimulus to organization PBR networks is discussed since the studies performed by these networks involve large number of clinicians and important conclusions can be drawn. Designs of observational studies including surveys and cohort studies based on practice are presented. Survey methods are important to know the behavior of practitioners regarding diagnostic and decision of treatment. Cohorts allow assessing different cofounders contributing to some outcome since large sample sizes and long follow-up periods can be observed in some of these studies. Pragmatic trials designed to take place in real-world clinical practice settings are also discussed as a useful design to assess the effectiveness of clinical interventions. In conclusion, this review sought to present PBR studies as alternative designs to answer clinical questions, but not replacing randomized clinical trials.

Practice based research in dentistry: an alternative to deal with clinical questions

Abstract Clinical interventions in dental practice should be determined based on the best scientific evidence available. Well-designed randomized clinical trials (RCTs) provide important evidence supporting the efficacy of interventions and are usually considered as the best primary evidence. However, the strict criteria adopted by most RCTs reduce their external validity since some findings from these studies might not work under usual conditions. On the other hand, practice-based research (PBR) studies have been designed to better define the effectiveness of clinical interventions under settings closer to "real-world" conditions. Therefore, this review aimed to describe different PBR designs discussing some advantages and limitations of such studies. The stimulus to organization PBR networks is discussed since the studies performed by these networks involve large number of clinicians and important conclusions can be drawn. Designs of observational studies including surveys and cohort studies based on practice are presented. Survey methods are important to know the behavior of practitioners regarding diagnostic and decision of treatment. Cohorts allow assessing different cofounders contributing to some outcome since large sample sizes and long follow-up periods can be observed in some of these studies. Pragmatic trials designed to take place in real-world clinical practice settings are also discussed as a useful design to assess the effectiveness of clinical interventions. In conclusion, this review sought to present PBR studies as alternative designs to answer clinical questions, but not replacing randomized clinical trials.

Yield of Low-Dose Computerized Tomography Screening for Lung Cancer in High-Risk Workers: The Case of 7189 US Nuclear Weapons Workers.

OBJECTIVES: To determine the lung cancer screening yield and stages in a union-sponsored low-dose computerized tomography scan program for nuclear weapons workers with diverse ages, smoking histories, and occupations. METHODS: We implemented a low-dose computerized tomography program among 7189 nuclear weapons workers in 9 nonmetropolitan US communities during 2000 to 2013. Eligibility criteria included age, smoking, occupation, radiographic asbestos-related fibrosis, and a positive beryllium lymphocyte proliferation test. RESULTS: The proportion with screen-detected lung cancer among smokers aged 50 years or older was 0.83% at baseline and 0.51% on annual scan. Of 80 lung cancers, 59% (n = 47) were stage I, and 10% (n = 8) were stage II. Screening yields of study subpopulations who met the National Lung Screening Trial or the National Comprehensive Cancer Network Group 2 eligibility criteria were similar to those found in the National Lung Screening Trial. CONCLUSIONS: Computerized tomography screening for lung cancer among high-risk workers leads to a favorable yield of early-stage lung cancers. Public Health Implications. Health equity and efficiency dictate that screening high-risk workers for lung cancer should be an important public health priority.

The choice of facilitators in medical tourism.

The study identified which of the four facilitators (themselves, agents, insurers, or doctors) consumers are most likely to use when they travel for various medical procedures. A survey conducted between 2011 and 2014 yielded 964 responses. The multinomial logistic regression results showed that being 51-64 years old was positively related to going on their own or using agents to arrange for knee replacements. Having a high school education or less was positively linked to using both agents and insurers to facilitate knee replacements, whereas having a bachelor's degree was negatively associated with going on their own for stem cell therapy.

Meiotic Recombination in Neurospora crassa Proceeds by Two Pathways with Extensive Holliday Junction Migration.

Analysis of thousands of Δmsh-2 octads using our fluorescent recombination system indicates that, as in other filamentous fungi, symmetric heteroduplex is common in the his-3 region of Neurospora crassa. Symmetric heteroduplex arises from Holliday junction migration, and we suggest this mechanism explains the high frequency of His+ spores in heteroallelic crosses in which recombination is initiated cis to the his-3 allele further from the initiator, cog+. In contrast, when recombination is initiated cis to the his-3 allele closer to cog+, His+ spores are mainly a result of synthesis-dependent strand annealing, yielding asymmetric heteroduplex. Loss of Msh-2 function increases measures of allelic recombination in both his-3 and the fluorescent marker gene, indicating that mismatches in asymmetric heteroduplex, as in Saccharomyces cerevisiae, tend to be repaired in the direction of restoration. Furthermore, the presence of substantial numbers of conversion octads in crosses lacking Msh-2 function suggests that the disjunction pathway described in S. cerevisiae is also active in Neurospora, adding to evidence for a universal model for meiotic recombination.

Medical tourists: who goes and what motivates them?

This study relates consumers' attitudes toward medical tourism to a number of consumer characteristics, such as age, education, income, and insurance status. Principal components analysis of the attitudes of 289 consumers from various communities of North Carolina resulted in three attitude-related factors: economic, treatment-related, and travel-related. Major findings include: (a) the uninsured and low-income consumers are more sensitive to economic factors than the insured and the middle-income consumers; (b) the 51- to 64-year-olds are less motivated by economic factors than young adults; (c) surprisingly, the better one's health, the more one is motivated by treatment-related factors.

Triangle of prevention: a union's experience promoting a systems-of-safety health and safety program.

After years of watching company health and safety programs fail to prevent major incidents, injuries, illness, and death in industrial workplaces, union health and safety staff and rank and file activists took up the challenge of creating a union-run alternative program. Named the Triangle of Prevention (TOP), the program successfully engages both local unions and management in incident and near-miss reporting and investigation, root cause analysis, recommending and tracking solutions, and learning and sharing lessons. In all phases, TOP uses a hierarchical, systems-of-safety-based approach to hazard identification, reporting, prevention and control while aiming to engage the union, its members, and all other employees of a worksite. This article explains the foundations and workings of this program, the role of an expansive worker-to-worker training regimen, and the ways in which the program has transformed workplaces.

The Union RAP: industry-wide research-action projects to win health and safety improvements.

Unions are ripe to engage in community-based participatory research (CBPR). We briefly profile 3 United Steelworker CBPR projects aimed at uncovering often-undocumented, industry-wide health and safety conditions in which US industrial workers toil. The results are to be used to advocate improvements at workplace, industry, and national policy levels. We offer details of our CBPR approach (Research-Action Project [RAP]) that engages workers and others in all research stages. Elements of RAPs include strategically constructed teams with knowledge of the industry and health and safety and with skills in research, participatory facilitation, and training; reciprocal training on these knowledge and skill areas; iterative processes of large and small group work; use of technology; and facilitator-developed tools and intermediate products.

Beyond Texas City: the state of process safety in the unionized U.S. oil refining industry.

The March 2005 British Petroleum (BP) Texas City Refinery disaster provided a stimulus to examine the state of process safety in the U.S. refining industry. Participatory action researchers conducted a nation-wide mail-back survey of United Steelworkers local unions and collected data from 51 unionized refineries. The study examined the prevalence of highly hazardous conditions key to the Texas City disaster, refinery actions to address those conditions, emergency preparedness and response, process safety systems, and worker training. Findings indicate that the key highly hazardous conditions were pervasive and often resulted in incidents or near-misses. Respondents reported worker training was insufficient and less than a third characterized their refineries as very prepared to respond safely to a hazardous materials emergency. The authors conclude that the potential for future disasters plagues the refining industry. In response, they call for effective proactive OSHA regulation and outline ten urgent and critical actions to improve refinery process safety.

Neuroprotection with delayed calpain inhibition after transient forebrain ischemia.

OBJECTIVE: Delayed neurodegeneration after transient global brain ischemia offers a therapeutic window for inhibiting molecular injury mechanisms. One such mechanism is calpain-mediated proteolysis, which peaks 24 to 48 hrs after transient forebrain ischemia in rats. This study tests the hypothesis that delayed calpain inhibitor therapy can reduce brain calpain activity and neurodegeneration after transient forebrain ischemia. DESIGN: Prospective randomized placebo-controlled animal trial. SETTING: University research laboratory. SUBJECTS: Adult male Long-Evans rats. INTERVENTIONS: Rats subjected to 10-min transient forebrain ischemia were randomized to intravenous infusion of calpain inhibitor CEP-3453 or vehicle beginning 22 hrs after injury. MEASUREMENTS AND MAIN RESULTS: In a dose-response study, a 60 mg/kg bolus followed by 30 mg/kg infusion was required to reduce postischemic brain calpain activity measured by Western blot of hippocampal homogenates at 48 hrs after injury. The same dosing protocol decreased degeneration of CA1 pyramidal neurons measured at 72 hrs after injury. CONCLUSIONS: These results suggest a causal role for calpains in delayed postischemic neurodegeneration, and demonstrate a broad therapeutic window for calpain inhibition in this model.

Developmental status of neurons selectively vulnerable to rapidly triggered post-ischemic caspase activation.

Caspase activation occurs within 1h of reperfusion in discrete cell populations of the adult rat brain following transient forebrain ischemia. Based on the proximity of these cells to regions of adult neurogenesis and the known susceptibility of developing neurons to apoptosis, we tested the hypothesis that rapidly triggered post-ischemic caspase activation occurs in immature neurons or neuroprogenitor cells. Adult male Long Evans rats were injected with BrdU to label mitotic cells 1, 7, or 28 days prior to being studied. Rats were then subjected to either sham surgery or 10-min transient forebrain ischemia. At 1h after reperfusion, rats underwent perfusion fixation and brains prepared for immunohistochemical analysis. Immunolabeling for caspase-substrate cleavage, using an antibody directed at the caspase derived fragment of alpha-spectrin, was observed in discrete cell populations of the rostral dentate gyrus, dorsal striatum, extreme paramedian CA1 hippocampus, indusium gresium, olfactory tubercle, and thalamus. No cells double-labeled for caspase-substrate cleavage and BrdU at any time point after BrdU injection. Furthermore, cells immunolabeled for caspase-substrate cleavage did not double-label for markers of immature neurons (doublecortin) or progenitor cells (nestin), but did double-label for the mature neuronal marker NeuN. These results indicate that the phenomenon of rapidly triggered caspase activation in the adult rat brain after transient forebrain ischemia is specific to mature neurons and does not occur in neuroprogenitor cells or immature neurons.

Comparison of calpain and caspase activities in the adult rat brain after transient forebrain ischemia.

The role of calpain and caspase family proteases in postischemic neuronal death remains controversial. This study compared the timing, location, and relative activity of calpains and caspases in the adult rat brain following 10 min of transient forebrain ischemia. Western blots of cortical, striatal, and hippocampal homogenates demonstrated a alpha-spectrin cleavage pattern indicative of predominant calpain activity, which peaked between 24 and 48 h after reperfusion. However, immunohistochemical evidence of both caspase 3 activation and caspase-mediated substrate cleavage was detected as early as 1 h and as late as 7 days after reperfusion in circumscribed neuronal populations. Simultaneous or sequential caspase and calpain activation was also observed suggesting the potential for interaction of these protease systems. The complex spatiotemporal pattern of calpain and caspase activity observed in this study provides important insights for the development and evaluation of therapeutic strategies to reduce protease-mediated injury following global brain ischemia.