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CLN2 disease (neuronal ceroid lipofuscinosis type 2) is a rare, autosomal recessive, pediatric-onset, rapidly progressive neurodegenerative lysosomal storage disorder caused by tripeptidyl peptidase 1 (TPP1) enzyme deficiency, and is characterized by language delay, seizures, rapid cognitive and motor decline, blindness, and early death. No management guidelines exist and there is a paucity of published disease-specific evidence to inform clinical practice, which currently draws upon experience from the field of childhood neurodisability. Twenty-four disease experts were surveyed on CLN2 disease management and a subset met to discuss current practice. Management goals and strategies are consistent among experts globally and are guided by the principles of pediatric palliative care. Goals and interventions evolve as the disease progresses, with a shift in focus from maintenance of function early in the disease to maintenance of quality of life. A multidisciplinary approach is critical for optimal patient care. This work represents an initial step toward the development of consensus-based management guidelines for CLN2 disease., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Voriconazole, a broad-spectrum triazole antifungal agent, is metabolized by cytochrome P450 (CYP) 2C19 and, to a lesser extent, by CYP3A. Genetic polymorphism of CYP2C19 not only plays a prominent role in its disposition but may also influence potential drug interactions with CYP450 modulators such as ritonavir. This study assessed 2-way drug interactions of voriconazole added on to ritonavir-boosted atazanavir in both CYP2C19 extensive-metabolizer (EM) and poor-metabolizer (PM) healthy subjects. Each subject received voriconazole alone on days 1-3, followed by a 7-day washout. Atazanavir/ritonavir 300/100 mg once daily was given on days 11-30 and voriconazole on days 21-30. Voriconazole doses were 200 mg (400 mg on days 1 and 21) twice daily and 50 mg (100 mg on days 1 and 21) twice daily for CYP2C19 EM and PM subjects, respectively. On coadministration, voriconazole AUC and C min decreased by 33% (90%CI, 22%-42%) and 39% (90%CI, 28%-49%), respectively, in CYP2C19 EMs, whereas voriconazole C max and AUC increased 4.4-fold (90%CI, 3.6-fold to 5.4-fold) and 5.6-fold (90%CI, 4.5-fold to 7.0-fold), respectively, in PMs. Adding voriconazole resulted in a 20%-30% decrease in atazanavir C min in both EMs and PMs. Ritonavir exposure was generally unchanged in either population. The safety and tolerability profiles of the combination were comparable with atazanavir/ritonavir and voriconazole administered alone. The most frequent adverse events with voriconazole were visual disturbance and headache. Coadministration of voriconazole and atazanavir/ritonavir is not recommended unless the benefit/risk to the patient justifies the use of the combination., (© 2016, The American College of Clinical Pharmacology.)

Background: Contemporary data regarding pregnancy outcomes in US patients with primary glomerular diseases are lacking. We aimed to report fetal and maternal outcomes among women with biopsy-proven primary glomerular disease who received obstetric care at a single large academic US center., Methods: All women with a biopsy-confirmed primary glomerular disease diagnosis and without end-stage kidney disease who received obstetric care at the University of North Carolina (UNC) Hospitals (1996-2015) were identified using the Glomerular Disease Collaborative Network registry and the UNC Hospitals Perinatal Database. The primary study outcome was perinatal death (stillbirth at >20 weeks or neonatal death). Secondary outcomes included premature birth (<37 weeks), birth weight, preeclampsia, and kidney function changes (postpartum vs. baseline). Demographics, clinical characteristics, and outcomes were compared across glomerular disease subtypes., Results: Among 48 pregnancies in 43 women (IgA nephropathy n = 17, focal segmental glomerulosclerosis [FSGS] n = 16, membranous nephropathy n = 6, minimal change disease n = 4), 13% of pregnancies resulted in perinatal death and 48% of babies were born prematurely. From a maternal perspective, 33% of pregnancies were complicated by preeclampsia, 39% by a doubling of urinary protein, and 27% by a ≥50% increase in serum creatinine. Outcome differences across glomerular disease subtypes were not statistically significant, although decline in kidney function appeared most frequent in FSGS., Conclusion: Adverse pregnancy outcomes are frequently observed in women with glomerular disease. The independent influence of glomerular disease subtype on outcomes requires further study. More widespread reporting and analysis of pregnancy outcomes in women with glomerular disease are urgently needed., (© 2017 S. Karger AG, Basel.)

Background: T20 (Twenty20 or 20 over) cricket has emerged in the last decade as the most popular form of cricket (in terms of spectator attendances). International consensus cricket definitions, first published in 2005, were updated in 2016 to better reflect the rise to prominence of T20 cricket., Methods: Injury incidence and prevalence rates were calculated using the new international methods and units for elite senior male Australian cricketers over the past decade (season 2006-2007 to season 2015-2016 inclusive)., Results: Over the past 10 seasons, average match injury incidence, for match time-loss injuries, was 155 injuries/1,000 days of play, with the highest daily rates in 50-over cricket, followed by 20-over cricket and First-Class matches. Annual injury incidence was 64 injuries/100 players per season, and average annual injury prevalence was 12.5% (although fast bowlers averaged 20.6%, much higher than other positions). The most common injury was the hamstring strain (seasonal incidence 8.7 injuries/100 players per season). The most prevalent injury was lumbar stress fractures (1.9% of players unavailable at all times owing to these injuries, which represents 15% of all missed playing time)., Discussion: The hamstring strain has emerged from being one of the many common injuries in elite cricket a decade ago to being clearly the most common injury in the sport at the elite level. This is presumably in association with increased T20 cricket. Lumbar stress fractures in fast bowlers are still the most prevalent injury in the sport of cricket at the elite level, although these injuries are more associated with high workloads arising from the longer forms of the game. Domestic and international matches have very similar match injury incidence rates across the formats, but injury prevalence is higher in international players as they play for most of the year without a substantial off-season., Competing Interests: All three authors are employed by Cricket Australia to provide medical services to players. Other than this relationship, no author has any financial conflict with the material presented in this study. The authors report no other conflicts of interest in this work.

Background: Fabry disease, an X-linked lysosomal storage disorder, causes intracellular accumulation of glycosphingolipids leading to progressive renal, cardiovascular, and cerebrovascular disease, and premature death., Methods: This longitudinal Fabry Registry study analyzed data from patients with Fabry disease to determine the incidence and type of severe clinical events following initiation of enzyme replacement therapy (ERT) with agalsidase beta, as well as risk factors associated with occurrence of these events. Severe events assessed included chronic dialysis, renal transplantation, cardiac events, stroke, and death., Results: The analyses included 969 male and 442 female Fabry patients. The mean age at first agalsidase beta infusion was 35 and 44, and median treatment follow-up 4.3years and 3.2years, respectively. Among males, cardiac events were the most common on-ERT events, followed by renal, stroke, and non-cardiac death. Among females, cardiac events were also most common followed by stroke and renal events. Patients with on-ERT events had significantly more advanced cardiac and renal disease at baseline as compared with patients without on-ERT events. Severe events were also associated with older age at ERT initiation (males and females), a history of pre-ERT events (females; approaching statistical significance in males), and a higher urinary protein/creatinine ratio (females). Approximately 65% of patients with pre-ERT events did not experience subsequent on-ERT events. Of patients without pre-ERT events, most (84% of males, 92% of females) remained event-free., Conclusions: Patients with on-ERT severe events had more advanced Fabry organ involvement at baseline than those without such events and patients who initiated ERT at a younger age had less residual risk of on-ERT events. The observed patterns of residual risk may aid clinicians in multidisciplinary monitoring of male and female patients with Fabry disease receiving ERT, and in determining the need for administration of adjunctive therapies., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Exsanguination from wounds in the so-called junctional regions of the body (i.e., the neck, the axilla, and the groin) was responsible for 19% of the combat fatalities who died from potentially survivable wounds sustained in Afghanistan or Iraq during 2001 to 2011. The development of improved techniques and technology to manage junctional hemorrhage has been identified in the past as a high-priority item by the Committee on Tactical Combat Casualty Care (CoTCCC) and the Army Surgeon General's Dismounted Complex Blast Injury (DCBI) Task Force. Additionally, prehospital care providers have had limited options with which to manage hemorrhage resulting from deep, narrow-track, penetrating trauma. XStat™ is a new product recently approved by the US Food and Drug Administration as a hemostatic adjunct to aid in the control of bleeding from junctional wounds in the groin or axilla. XStat has now been recommended by the CoTCCC as another tool for the combat medical provider to use in the management of junctional hemorrhage. The evidence that supports adding XStat to the TCCC Guidelines for the treatment of external hemorrhage is summarized in this paper., (2016.)

Background: Daclatasvir is an NS5A inhibitor approved for treatment of infection due to hepatitis C virus (HCV) genotypes (GTs) 1-4. To support daclatasvir use in HCV genotype 4 infection, we examined a diverse genotype 4-infected population for HCV genotype 4 subtype prevalence, NS5A polymorphisms at residues associated with daclatasvir resistance (positions 28, 30, 31, or 93), and their effects on daclatasvir activity in vitro and clinically., Methods: We performed phylogenetic analysis of genotype 4 NS5A sequences from 186 clinical trial patients and 43 sequences from the European HCV database, and susceptibility analyses of NS5A polymorphisms and patient-derived NS5A sequences by using genotype 4 NS5A hybrid genotype 2a replicons., Results: The clinical trial patients represented 14 genotype 4 subtypes; most prevalent were genotype 4a (55%) and genotype 4d (27%). Daclatasvir 50% effective concentrations for 10 patient-derived NS5A sequences representing diverse phylogenetic clusters were ≤0.080 nM. Most baseline sequences had ≥1 NS5A polymorphism at residues associated with daclatasvir resistance; however, only 3 patients (1.6%) had polymorphisms conferring ≥1000-fold daclatasvir resistance in vitro. Among 46 patients enrolled in daclatasvir trials, all 20 with baseline resistance polymorphisms achieved a sustained virologic response., Conclusions: Circulating genotype 4 subtypes are genetically diverse. Polymorphisms conferring high-level daclatasvir resistance in vitro are uncommon before therapy, and clinical data suggest that genotype 4 subtype and baseline polymorphisms have minimal impact on responses to daclatasvir-containing regimens., (© The Author 2015. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: The Argentinean program was initiated more than a decade ago as the first experience of systematic translational research focused on NCL in Latin America. The aim was to overcome misdiagnoses and underdiagnoses in the region., Subjects: 216 NCL suspected individuals from 8 different countries and their direct family members., Methods: Clinical assessment, enzyme testing, electron microscopy, and DNA screening., Results and Discussion: 1) The study confirmed NCL disease in 122 subjects. Phenotypic studies comprised epileptic seizures and movement disorders, ophthalmology, neurophysiology, image analysis, rating scales, enzyme testing, and electron microscopy, carried out under a consensus algorithm; 2) DNA screening and validation of mutations in genes PPT1 (CLN1), TPP1 (CLN2), CLN3, CLN5, CLN6, MFSD8 (CLN7), and CLN8: characterization of variant types, novel/known mutations and polymorphisms; 3) Progress of the epidemiological picture in Latin America; and 4) NCL-like pathology studies in progress. The Translational Research Program was highly efficient in addressing the misdiagnosis/underdiagnosis in the NCL disorders. The study of "orphan diseases" in a public administrated hospital should be adopted by the health systems, as it positively impacts upon the family's quality of life, the collection of epidemiological data, and triggers research advances. This article is part of a Special Issue entitled: "Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease)"., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The LRRK2 G2019S mutation is found at higher frequency among Parkinson disease (PD) patients of Ashkenazi Jewish (AJ) ancestry. This study was designed to test whether an internet-based approach could be an effective approach to screen and identify mutation carriers. Individuals with and without PD of AJ ancestry were recruited and consented through an internet-based study website. An algorithm was applied to a series of screening questions to identify individuals at increased risk to carry the LRRK2 G2019S mutation. About 1000 individuals completed the initial screening. Around 741 qualified for mutation testing and 650 were tested. Seventy-two individuals carried at least one LRRK2 G2019S mutation; 38 with PD (12.5%) and 34 without (10.1%). Among the AJ PD participants, each affected first-degree relative increased the likelihood the individual was LRRK2+ [OR = 4.7; 95% confidence interval = (2.4-9.0)]. The same was not observed among the unaffected AJ subjects (P = 0.11). An internet-based approach successfully screened large numbers of individuals to identify those with risk factors increasing the likelihood that they carried a LRRK2 G2019S mutation. A similar approach could be implemented in other disorders to identify individuals for clinical trials, biomarker analyses and other types of research studies.

Background: Noncompressible hemorrhage is the leading cause of potentially survivable death on the battlefield. In Special Operations Forces (SOF), 50% of potentially survivable deaths have been related to noncompressible hemorrhage. Currently, there are no widely available presurgical interventions that can slow abdominal bleeding. Consequently, many of the preventable deaths occur en route to definitive care as a failure to rescue from exsanguination. A self-expanding polyurethane foam has been developed as a percutaneous damage control intervention to rescue casualties who would otherwise die of noncompressible hemorrhage, and allow them to survive long enough to reach surgical intervention. The purpose of this paper is to summarize the existing preclinical data, describe the role of SOF personnel in foam delivery-system development, and to integrate these together to conceptualize how foam could be incorporated into SOF medical care., Methods: All existing publications on self-expanding foam are reviewed. Additionally, eight SOF medical providers with combat experience provided end-user input to delivery-device design through an interactive human-factors testing process., Results: Ten preclinical publications described efficacy, safety, dose translation, and risk-benefit analysis of exsanguination rescue with percutaneous-foam damage control. SOF medical providers guided weight, cubic, operational requirements, and limits for the foam delivery device., Conclusion: Presurgical exsanguination rescue with percutaneous foam damage control is safe and effective with a favorable risk-benefit profile in preclinical studies. Battlefield, presurgical use by SOF medical providers is conceptually possible. Adoption of the technology on the battlefield should proceed with SOF medical provider input., (2015.)

Purpose: To identify the personal strengths of Canadian physical therapists who hold leadership positions and compare them with the strengths of Canadian physical therapists who do not occupy positions of leadership., Methods: A quantitative, cross-sectional online survey was distributed to registered Canadian physical therapists. We used the Clifton StrengthsFinder to evaluate 34 characteristics and determine which characteristics described a participant's strengths. Population demographics and leadership strengths were described via frequency distributions and percentages; chi-square analyses and Fisher's exact tests were used to compare differences between groups., Results: Of 173 physical therapists who completed the survey, 108 occupied a position of leadership, and 65 did not. Those in the leader group had significantly more experience and achieved a higher level of education. Leaders most frequently exhibited the strengths of learner, achiever, responsibility, input, and strategic, whereas non-leaders most frequently displayed strengths of learner, achiever, input, relator, and harmony. Leaders were significantly more likely than non-leaders to possess the achiever strength. Gender, level of education, and years of experience did not significantly influence which strengths were present in the leadership profile., Conclusions: There is substantial overlap between leaders and non-leaders in terms of leadership profiles. Future research should investigate whether leadership strengths vary depending on the leadership position occupied and whether leadership development initiatives promote leadership strengths.

This study tested two contrasting theories of adaptation of postural control to pain. One proposes alteration to the postural strategy including inhibition of muscles that produce painful movement; another proposes amplification of the postural adjustment to recruit strategies normally reserved for higher load. This study that aimed to determine which of these alternatives best explains pain-related adaptation of the hip muscle activity associated with stepping down from steps of increasing height adaptation of postural control to increasing load was evaluated from hip muscle electromyography (fine-wire and surface electrodes) as ten males stepped from steps of increasing height (i.e. increasing load). In one set of trials, participants stepped from a low step (5 cm) and pain was induced by noxious electrical stimulation over the sacrum triggered from foot contact with a force plate or was anticipated. Changes in EMG amplitude and onset timing were compared between conditions. Hip muscle activation was earlier and larger when stepping from higher steps. Although ground reaction forces (one of the determinants of joint load) were unchanged before, during and after pain, trials with real or anticipated noxious stimulation were accompanied by muscle activity indistinguishable from that normally reserved for higher steps (EMG amplitude increased from 9 to 17 % of peak). These data support the notion that muscle activation for postural control is augmented when challenged by real/anticipated noxious stimulation. Muscle activation was earlier and greater than that required for the task and is likely to create unnecessary joint loading. This could have long-term consequences if maintained.

Purpose: The purpose of this statement is to review the literature regarding mitochondrial disease and to provide recommendations for optimal diagnosis and treatment. This statement is intended for physicians who are engaged in diagnosing and treating these patients., Methods: The Writing Group members were appointed by the Mitochondrial Medicine Society. The panel included members with expertise in several different areas. The panel members utilized a comprehensive review of the literature, surveys, and the Delphi method to reach consensus. We anticipate that this statement will need to be updated as the field continues to evolve., Results: Consensus-based recommendations are provided for the diagnosis and treatment of mitochondrial disease., Conclusion: The Delphi process enabled the formation of consensus-based recommendations. We hope that these recommendations will help standardize the evaluation, diagnosis, and care of patients with suspected or demonstrated mitochondrial disease.

Objective: To assess workload-related risk factors for injuries to particular tissue types in cricket fast bowlers., Design: 235 fast bowlers who bowled in 14600 player innings over a period of 15 years were followed in a prospective cohort risk factor study to compare overs bowled in each match (including preceding workload patterns) and injury risk in the 3-4 weeks subsequent to the match. Injuries were categorised according to the affected tissue type as either: bone stress, tendon injuries, muscle strain or joint injuries. Workload risk factors were examined using binomial logistic regression multivariate analysis, with a forward stepwise procedure requiring a significance of <0.05., Results: High acute match workload and high previous season workload were risk factors for tendon injuries, but high medium term (3-month workload) was protective. For bone stress injuries, high medium term workload and low career workload were risk factors. For joint injuries, high previous season and career workload were risk factors. There was little relationship between muscle injury and workload although high previous season workload was slightly protective., Conclusions: The level of injury risk for some tissue types varies in response to preceding fast bowling workload, with tendon injuries most affected by workload patterns. Workload planning may need to be individualised, depending on individual susceptibility to various injury types. This study supports the theory that tendons are at lowest risk with consistent workloads and susceptible to injury with sudden upgrades in workload. Gradual upgrades are recommended, particularly at the start of a bowler's career to reduce the risk of bone stress injury., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Asunaprevir (ASV), an investigational, highly protein-bound inhibitor of hepatitis C virus NS3 protease, shows considerable hepatic compartmentalization in animal models. Preclinical data showed ASV inhibition of human OATP1B1 (IC50 = 0.3 μM), OATP2B1 (0.27 μM), and, to a lesser extent OATP1B3 (3.0 μM), confirmed by modest (<2-fold) clinical elevations in rosuvastatin exposure with concomitant ASV. Although no significant OATP transport of ASV was observed in vitro at standard micromolar assay concentrations, clinical coadministration of ASV with a single dose of the OATP inhibitor rifampin gave large, variable increases in ASV plasma Cmax (21-fold mean) and AUCinf (15-fold mean), consistent with reduced hepatic uptake. In vitro reevaluation at therapeutically relevant low-nanomolar concentrations of unbound ASV showed active, saturable human hepatocyte uptake (Km = 0.685 μM) and rifampin-reversible transport by OATP1B1 and OATP2B1, but not OATP1B3. At therapeutically relevant concentrations, ASV is therefore a sensitive substrate for, and weak inhibitor of, human OATP1B1, 1B3 and 2B1., (© 2014 American Society for Clinical Pharmacology and Therapeutics.)

Background: Cobicistat (COBI) is an alternative pharmacoenhancer to ritonavir. A fixed-dose combination (FDC) tablet containing atazanavir (ATV) and COBI has been developed for the treatment of HIV-1-infected patients., Methods: This open-label, single-centre, single-dose, crossover study, randomized 64 healthy subjects to one of eight treatment sequences. Under light meal conditions, maximum plasma concentration (Cmax), area under the plasma concentration-time curve (AUC) to infinity (AUCINF) and AUC to the last measurable concentration (AUC0-T) for ATV and COBI administered as an FDC of ATV/COBI (300/150 mg) were compared to those following administration as separate agents given together; bioequivalence was concluded if the 90% CIs of the geometric mean ratios fell within the predetermined range of 0.80, 1.25. ATV and COBI pharmacokinetic parameters following administration as the FDC or as separate agents were also compared under fasted conditions. The effect of food (light and high-fat meals) on the pharmacokinetics of ATV and COBI for the FDC was also assessed., Results: ATV and COBI administered in an FDC tablet were bioequivalent to the individual agents when given with a light meal. Under fasted conditions, pharmacokinetic parameters for ATV and COBI were similar for the individual components and the FDC. For the FDC, systemic exposure to ATV increased with a light meal compared to fasted conditions, and ATV concentration 24 h post-dose was similar with a light meal compared with a high-fat meal., Conclusions: ATV/COBI (300/150 mg) FDC tablet was bioequivalent to coadministration as separate agents with a light meal in healthy subjects. Clinicaltrials.gov identifier NCT01837719.

Objectives: This study examined whether high match fast bowling workloads in the short to medium term were associated with increased bowling injury rates., Design: Prospective cohort study., Methods: Over a 15 year period, workload patterns for 235 individual fast bowlers during time periods from 5 to 26 days were examined to consider whether there was an increased injury rate during the month (28 days) subsequent to the workload., Results: Fast bowlers who bowled more than 50 match overs in a 5 day period had a significant increase in injury over the next month compared to bowlers who bowled 50 overs or less RR 1.54 (95% CI 1.04-2.29). For periods ranging from 12 to 26 days, there was no statistically-significant increase in injury over the next month from exceeding thresholds of certain amounts of overs, although bowlers who bowled more than 100 overs in 17 days had a non-significant increase in injury over the next month RR 1.78 (95% CI 0.90-3.50)., Conclusion: There were no statistically-significant increases in subsequent injury risk for high workloads for periods of 12-26 days, although exceeding 100 overs in 17 days (or less) was associated with higher injury rates. Compression of cricket fixtures is likely to have only a minimal contribution to increased fast bowling injury rates being seen in the T20 era (along with sudden workload increases due to transferring between forms of the game, which has been previously established as a major contributor)., (Copyright © 2014 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Ceramides are synthesized by six mammalian ceramide synthases (CerSs), each of which uses fatty acyl-CoAs of different chain lengths for N-acylation of the sphingoid long-chain base. We now describe a rapid and reliable CerS assay that uses a fluorescent N-[6-[(7-nitrobenzo-2-oxa-1,3-diazol-4-yl) (NBD) sphinganine substrate followed by separation of the NBD-lipid substrate and products using solid phase extraction (SPE) C18 chromatography. SPE chromatography is a quick and reliable alternative to TLC, and moreover, there is no degradation of either NBD-sphinganine or NBD-ceramide. We have optimized the assay for use with minimal amounts of protein in a minimal volume. This assay will prove useful for the analysis of CerS activity, which is of particular importance in light of the growing involvement of CerS in cell regulation and in the pathology of human diseases., (Copyright © 2015 by the American Society for Biochemistry and Molecular Biology, Inc.)

We examined the feasibility of recruiting US adults ≥45 years old with Fabry disease (FD) for telephone assessments of cognitive functioning. A case-control design matched each FD participant on age, sex, race, and education to four participants from a population-based study. Fifty-four participants with FD age 46-72 years were matched to 216 controls. Standardized cognitive assessments, quality of life (QOL), and medical histories were obtained by phone, supplemented by objective indices of comorbidities. Normalized scores on six cognitive tasks were calculated. On the individual tasks, scores on list recall and semantic fluency were significantly lower among FD participants (p-values < 0.05), while scores on the other four tasks did not differ. After averaging each participant's normalized scores to form a cognitive composite, we examined group differences in composite scores, before and after adjusting for multiple covariates using generalized estimating equations. The composite scores of FD cases were marginally lower than controls before covariate adjustments (p = 0.08). QOL and mental health variables substantially attenuated this finding (p = 0.75), highlighting the influence of these factors on cognition in FD. Additional adjustment for cardiovascular comorbidities, kidney function, and stroke had negligible impact, despite higher prevalence in the FD sample. Telephone-based cognitive assessment methods are feasible among adults with FD, affording access to a geographically dispersed sample. Although decrements in discrete cognitive domains were observed, the overall cognitive function of older adults with FD was equivalent to that of well-matched controls before and after accounting for multiple confounding variables.

Coenzyme Q10 (CoQ10) deficiency can manifest diversely, from isolated myopathy to multisystem involvement. Immune dysregulation has not been reported as a feature of the disease. We report a four-year old girl with failure to thrive, recurrent infections, developmental delay with hypotonia, and CoQ10 deficiency with impaired immune function, which improved after CoQ10 and immunoglobulin replacement therapy. Immune dysfunction in CoQ10 deficiency should be considered and treated appropriately., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: The aims of this study were to: i) to compare physical impairments in people with chondrolabral pathology identified at hip arthroscopy 12-24 months previously to age-matched healthy people; and ii) to understand whether sex has any influence on impairments., Methods: 84 patients (42 female; age=36±10) 12-24 months post hip arthroscopy and 60 controls (41 female; age=36±10) were included. Measurements of active hip ROM and strength were assessed. Two-way analyses of co-variance examined the effect of sex and chondrolabral pathology on hip ROM and strength., Results: Patients exhibited less hip internal rotation (IR) ROM (p=0.001) and more extension (p=0.014) ROM; and less hip adduction (p<0.001), extension (p=0.001), flexion (p<0.001), ER (p=0.044) and IR (p<0.001) strength when compared to controls. For abduction strength, a significant interaction was found between the presence of chondrolabral pathology and sex (p=0.035)., Conclusions: People with hip chondrolabral pathology have differences in hip ROM and strength when compared to controls. Rehabilitation programs should focus on addressing these specific physical impairments in order to enhance outcomes. This information may be of great value to both researchers and clinicians alike in determining interventions to improve outcomes in people with early hip OA.

Background: Hemorrhage from the trunk?appendage junctions is a common, preventable cause of death on the battlefield. The recently U.S. Food and Drug Administration (FDA)-cleared SAM? Junctional Tourniquet (SJT) was designed to control out-of-hospital inguinal and axillary hemorrhage. The purpose of the present study was to provide safety and effectiveness data associated with use of the SJT. Such data provided support for regulatory clearance., Methods: The SJT was tested in a perfused cadaver experiment simulating inguinal or axillary wound hemorrhage., Results: No safety problems or tissue damage occurred, and flow normalized promptly after tourniquet removal. During SJT use, an average of 107 mmHg occluded the distal external iliac artery in an average of 7 seconds of inflation time; manual pressure as a control averaged 139 mmHg. In SJT use, an average of 739 mmHg occluded the axillary artery in an average of 5 seconds of inflation time; manual pressure as a control averaged 1237 mmHg. The control was a referent that achieved results that were similar in one body area but different in the other; both findings indicate the device is as safe as, if not safer than, manual compression., Conclusion: The SJT was shown to be safe and effective in hemorrhage control in a cadaver model for both the axillary and inguinal areas. The SJT's Target Compression Devices required pressures approximately equal to or lower than manual pressure to achieve hemostasis in these junctional regions., (2014.)

Importance: There is limited evidence supporting use of physical therapy for hip osteoarthritis., Objective: To determine efficacy of physical therapy on pain and physical function in patients with hip osteoarthritis., Design, Setting, and Participants: Randomized, placebo-controlled, participant- and assessor-blinded trial involving 102 community volunteers with hip pain levels of 40 or higher on a visual analog scale of 100 mm (range, 0-100 mm; 100 indicates worst pain possible) and hip osteoarthritis confirmed by radiograph. Forty-nine patients in the active group and 53 in the sham group underwent 12 weeks of intervention and 24 weeks of follow-up (May 2010-February 2013) INTERVENTIONS: Participants attended 10 treatment sessions over 12 weeks. Active treatment included education and advice, manual therapy, home exercise, and gait aid if appropriate. Sham treatment included inactive ultrasound and inert gel. For 24 weeks after treatment, the active group continued unsupervised home exercise while the sham group self-applied gel 3 times weekly., Main Outcomes and Measures: Primary outcomes were average pain (0 mm, no pain; 100 mm, worst pain possible) and physical function (Western Ontario and McMaster Universities Osteoarthritis Index, 0 no difficulty to 68 extreme difficulty) at week 13. Secondary outcomes were these measures at week 36 and impairments, physical performance, global change, psychological status, and quality of life at weeks 13 and 36., Results: Ninety-six patients (94%) completed week 13 measurements and 83 (81%) completed week 36 measurements. The between-group differences for improvements in pain were not significant. For the active group, the baseline mean (SD) visual analog scale score was 58.8 mm (13.3) and the week-13 score was 40.1 mm (24.6); for the sham group, the baseline score was 58.0 mm (11.6) and the week-13 score was 35.2 mm (21.4). The mean difference was 6.9 mm favoring sham treatment (95% CI, -3.9 to 17.7). The function scores were not significantly different between groups. The baseline mean (SD) physical function score for the active group was 32.3 (9.2) and the week-13 score was 27.5 (12.9) units, whereas the baseline score for the sham treatment group was 32.4 (8.4) units and the week-13 score was 26.4 (11.3) units, for a mean difference of 1.4 units favoring sham (95% CI, -3.8 to 6.5) at week 13. There were no between-group differences in secondary outcomes (except greater week-13 improvement in the balance step test in the active group). Nineteen of 46 patients (41%) in the active group reported 26 mild adverse effects and 7 of 49 (14%) in the sham group reported 9 mild adverse events (P = .003)., Conclusions and Relevance: Among adults with painful hip osteoarthritis, physical therapy did not result in greater improvement in pain or function compared with sham treatment, raising questions about its value for these patients., Trial Registration: anzctr.org.au Identifier: ACTRN12610000439044.

Background: The epidemiology of nontuberculous mycobacteria (NTM) disease in solid organ transplant recipients is poorly defined., Methods: We identified all solid organ transplant recipients with NTM disease at a single center over a 7.5-year period, and collected data on patient demographics, co-morbidities, immunosuppressive medications, and rejection. We conducted a case-control study to identify risk factors for disease, matching 3 control patients to each case patient by date of transplantation., Results: A total of 34 cases of NTM disease occurred during the study period, involving 6 single lung, 13 bilateral lung, 8 heart, 4 liver, 2 kidney, and 1 pancreas-kidney recipients. Cases were predominantly male (24/34), with a median age of 55 years (interquartile range [IQR]: 46-61 years), and developed after a median of 8 months post transplantation (IQR: 2-87 months). Mycobacterium abscessus and Mycobacterium avium complex were the most common pathogens, and the lung (including pleura) was the most common site of disease. In the adjusted case-control analysis, lung transplant recipients had the highest risk of NTM disease., Conclusions: Additional studies are needed to evaluate the role of targeted surveillance measures for NTM disease in high-risk patients, particularly lung transplant recipients, and to characterize the mechanisms of disease acquisition., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care., (© 2013.)

Background: The central nervous system manifestations in Fabry disease (FD) include progressive white matter lesions (WMLs) and stroke. Due to progressive microvascular involvement, men and women with FD over 35 years of age develop WMLs. Moreover, the prevalence of stroke has been estimated to be 12 times higher in FD compared with the general population. Enzyme replacement therapy (ERT) is available and has shown beneficial effects on renal, cardiac, and peripheral nerve function in FD, but the ERT effect on the progression of WMLs, or the reduction in cerebrovascular events, remains unknown., Methods: The WML burden and the effect of agalsidase beta 1 mg/kg biweekly on WML progression were assessed longitudinally in a Phase 4 agalsidase-beta placebo-controlled analysis of untreated and treated FD patients with mild-to-moderate renal involvement (serum creatinine measurements of ≥1.2 mg/dl and <3.0 mg/dl). The primary end point was the difference in the number of patients with increased WML burden between the agalsidase beta and placebo groups at the end of treatment. The diameters of the WMLs were determined manually using axial flow-attenuated-inversion-recovery-weighted magnetic resonance imaging (MRI) scans taken at baseline and follow-up., Results: MRI scans from 41 FD patients (mean age 43.9, age range 20-68, 3 females; n=25 on ERT, n=16 on placebo) were analyzed. WML burden was present in 63% of patients at baseline, increased over a mean of 27 months (range 12-33 months) follow-up, and correlated with left ventricular hypertrophy (LVPW). Patients with previous or recent strokes (n=11, 39-68 years) showed an increase in the number of WMLs (p=0.005). A greater proportion of younger patients (≤50 years) on ERT (n=18) had stable WML burden compared with younger patients in the placebo group (n=13): 44% (8 of 18) versus 31% (4 of 13), p=0.014. The number needed to treat was 8., Conclusions: This FD patient cohort, with mild-to-moderate renal involvement, had a significant WML burden and high inter-individual variability associated with the degree of LVPW but not the degree of kidney dysfunction. These advanced patients with increased LVPW and stroke evidence may have had a higher cerebrovascular risk. The WML burden in patients on ERT was more likely to remain stable, compared with patients on placebo. Thus, ERT may reduce the progression of vascular disease, even in advanced FD patients, suggesting that early treatment may stabilize WML progression and stroke risk., (© 2014 S. Karger AG, Basel.)

Purpose: The aim of this study was to evaluate the progression of left ventricular hypertrophy in untreated men with Fabry disease and to assess the effects of agalsidase-β (recombinant human α-galactosidase A) on left ventricular hypertrophy., Methods: Longitudinal Fabry Registry data were analyzed from 115 men treated with agalsidase-β (1 mg/kg/2 weeks) and 48 untreated men. Measurements included baseline left-ventricular mass and at least one additional left-ventricular mass assessment over ≥ 2 years. Patients were grouped into quartiles, based on left-ventricular mass slopes. Multivariate logistic regression analyses identified factors associated with left ventricular hypertrophy progression., Results: For men in whom treatment was initiated at the age of 18 to <30 years, mean left ventricular mass slope was -3.6 g/year (n = 31) compared with +9.5 g/year in untreated men of that age (n = 15) (P < 0.0001). Untreated men had a 3.4-fold higher risk of having faster increases in left-ventricular mass compared with treated men (odds ratio: 3.43; 95% confidence interval: 1.05-11.22; P = 0.0415). A baseline age of ≥ 40 years was also associated with left--ventricular hypertrophy progression (odds ratio: 5.03; 95% confidence interval: 1.03-24.49; P = 0.0457) compared with men younger than 30 years., Conclusion: Agalsidase-β treatment for ≥2 years may improve or stabilize left-ventricular mass in men with Fabry disease. Further investigations may determine whether early intervention and stabilization of LVM are correlated with clinical outcomes.

Background: Working mothers who place their infants into out-of-home child care face many challenges to sustaining breastfeeding. Child care providers, who are in frequent close contact with young families, may be potential resources for promoting breastfeeding., Objectives: This study focused on identifying child care providers' attitudes toward and knowledge about breastfeeding as well as providers' perceptions about strategies to increase breastfeeding rates among mothers of infants in child care centers., Methods: Seventy-five providers from 11 child care centers in the Baton Rouge, Louisiana, area were surveyed using paper and pencil questionnaires. Self-reported demographics, attitudes, knowledge, and perceptions about breastfeeding were collected., Results: Responses demonstrated a generally positive attitude toward breastfeeding among child care providers but a knowledge deficit in terms of the health impacts and proper handling of breast milk. A minority of providers reported that their center's staff currently receives breastfeeding education, but most providers believed that measures to promote the use of breast milk in their center should target parents rather than the center staff., Conclusion: Child care providers need resources about the benefits of human milk, proper handling of expressed milk, and ways to make centers more breastfeeding friendly. Many providers feel ineffective in supporting breastfeeding and are unaware of the role they may play in mothers' infant feeding decisions. Though child care providers do not appear to believe they can influence parents' decisions about breastfeeding, educating and empowering them could play an important role in increasing breastfeeding rates.

Identification and comprehensive care of individuals who have Fabry disease (FD) requires a multidisciplinary approach inclusive of genetic testing, test interpretation, genetic counseling, long term disease symptom monitoring, treatment recommendations, and coordination of therapy. The purpose of this document is to provide health care professionals with guidelines for testing, care coordination, identification of psychosocial issues, and to facilitate a better understanding of disease treatment expert recommendations for patients with Fabry disease. These recommendations are the opinions of a multicenter working group of genetic counselors, medical geneticists, and other health professionals with expertise in Fabry disease counseling, as well as representatives/founders of the two United States based Fabry disease patient advocacy groups who are themselves affected by Fabry disease. The recommendations are U.S. Preventive Task Force Class III, and they are based on clinical experience, a review of pertinent English-language articles, and reports of expert committees. This document reviews the genetics of Fabry disease, the indications for genetic testing, interpretation of results, psychosocial considerations, and references to professional and patient resources.

Tripeptidyl-peptidase 1 (TPP1) null or residual activity occurs in neuronal ceroid lipofuscinosis (NCL) with underlying TPP1/CLN2 mutations. A survey of 25 South American CLN2 affected individuals enabled the differentiation of two phenotypes: classical late-infantile and variant juvenile, each in approximately 50% of patients, with residual TPP1 activity occurring in approximately 32%. Each individual was assigned to one of three subgroups: (I) n=11, null TPP1 activity in leukocytes; (II) n=8, residual TPP1 activity of 0.60-15.85 nmol/h/mg (nr 110-476); (III) n=6, activity not measured in leukocytes. Curvilinear bodies (CB) appeared in almost all studied CLN2 subjects; the only exceptions occurred in cases of subgroup II: two individuals had combined CBs/fingerprints (FPs), and one case had pure FPs. There were 15 mutations (4 first published in this paper, 3 previously observed in South America by our group, and 8 previously observed by others). In subgroup I, mutations were either missense or nonsense; in subgroups II and III, mutations prevailed at the non-conserved intronic site, c.887-10A>G (intron 7), and to a lesser extent at c.89+5G>C (intron 2), in heterozygous combinations. Grouping phenotypically and genetically known individuals on the basis of TPP1 activity supported the concept that residual enzyme activity underlies a protracted disease course. The prevalence of intronic mutations at non-conserved sites in subgroup II individuals indicates that some alternative splicing might allow some residual TPP1 activity., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Balanced chromosomal abnormalities (BCAs) represent a relatively untapped reservoir of single-gene disruptions in neurodevelopmental disorders (NDDs). We sequenced BCAs in patients with autism or related NDDs, revealing disruption of 33 loci in four general categories: (1) genes previously associated with abnormal neurodevelopment (e.g., AUTS2, FOXP1, and CDKL5), (2) single-gene contributors to microdeletion syndromes (MBD5, SATB2, EHMT1, and SNURF-SNRPN), (3) novel risk loci (e.g., CHD8, KIRREL3, and ZNF507), and (4) genes associated with later-onset psychiatric disorders (e.g., TCF4, ZNF804A, PDE10A, GRIN2B, and ANK3). We also discovered among neurodevelopmental cases a profoundly increased burden of copy-number variants from these 33 loci and a significant enrichment of polygenic risk alleles from genome-wide association studies of autism and schizophrenia. Our findings suggest a polygenic risk model of autism and reveal that some neurodevelopmental genes are sensitive to perturbation by multiple mutational mechanisms, leading to variable phenotypic outcomes that manifest at different life stages., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Cytomegalovirus (CMV) disease typically occurs during the first year after solid organ transplantation, after cessation of antiviral prophylaxis. CMV occurring after the first year is uncommon and not well described., Methods: We conducted a case-control study to identify potential risk factors and a retrospective cohort study to evaluate 1-month mortality in solid organ transplant (SOT) recipients who developed CMV disease after the first year post transplant, or "very late CMV" (VLCMV), compared with those developing CMV within the first year (CMV Y1), adjusting for demographics, donor and recipient CMV serostatus, immunosuppression, rejection, and co-morbidities., Results: We identified 85 SOT recipients with CMV disease at a single transplant center between January 2006 and October 2008: 23 (27%) had VLCMV and 62 (73%) had CMV Y1. Heart transplantation was independently associated with increased risk (adjusted odd ratio [OR] 4.11; 95% confidence interval [CI] 1.34-12.61; P = 0.01) for VLCMV. Patients with VLCMV had increased 1-month mortality (unadjusted OR 5.39; 95% CI 1.06-27.48; P = 0.02). Mortality was uncommonly attributable to CMV., Conclusions: CMV disease continues to occur after the first year post solid organ transplantation, particularly in heart transplant recipients, and can be associated with poor outcomes. CMV should be suspected in patients with symptoms or laboratory findings consistent with CMV, even if the patients present >1 year post transplant., (© 2012 John Wiley & Sons A/S.)

The duplication of chromosome 3q is a rare disorder with varying chromosomal breakpoints and consequently symptoms. Even rarer is the unbalanced outcome from a parental inv(3) resulting in duplicated 3q and a deletion of 3p. Molecular karyotyping should aid in precisely determining the length and breakpoints of the 3q+/3p- so as to better understand a child's future development and needs. We report a case of an infant male with a 57.5 Mb duplication from 3q23-qter. This patient also has an accompanying 1.7 Mb deletion of 3p26.3. The duplicated segment in this patient encompasses the known critical region of 3q26.3-q27, which is implicated in the previously reported 3q dup syndrome; however, the accompanying 3p26.3 deletion is smaller than the previously reported cases. The clinical phenotype of this patient relates to previously reported cases of 3q+ that may suggest that the accompanying 1.7 Mb heterozygous deletion is not clinically relevant. Taken together, our data has refined the location and extent of the chromosome 3 imbalance, which will aid in better understanding the molecular underpinning of the 3q syndrome.

Background: The Neuronal Ceroid Lipofuscinoses (NCL) comprise at least nine progressive neurodegenerative genetic disorders. Kufs disease, an adult-onset form of NCL may be recessively or dominantly inherited. Our study aimed to identify genetic mutations associated with autosomal dominant Kufs disease (ADKD)., Methodology and Principal Findings: We have studied the family first reported with this phenotype in the 1970s, the Parry family. The proband had progressive psychiatric manifestations, seizures and cognitive decline starting in her mid 20 s. Similarly affected relatives were observed in seven generations. Several of the affected individuals had post-mortem neuropathological brain study confirmatory for NCL disease. We conducted whole exome sequencing of three affected family members and identified a pLeu116del mutation in the gene DNAJC5, which segregated with the disease phenotype. An additional eight unrelated affected individuals with documented autosomal dominant or sporadic inheritance were studied. All had diagnostic confirmation with neuropathological studies of brain tissue. Among them we identified an additional individual with a p.Leu115Arg mutation in DNAJC5. In addition, a pAsn477Ser change in the neighboring gene PRPF6, a gene previously found to be associated with retinitis pigmentosa, segregated with the ADKD phenotype. Interestingly, two individuals of the Parry family did report visual impairment., Conclusions: Our study confirmed the recently reported association of DNAJC5 mutations with ADKD in two out of nine well-defined families. Sequence changes in PRPF6 have not been identified in other unrelated cases. The association of vision impairment with the expected PRPF6 dysfunction remains possible but would need further clinical studies in order to confirm the co-segregation of the visual impairment with this sequence change.

Evaluating the efficacy of complex interventions such as multimodal, impairment-based physical therapy treatments in randomized controlled trials is essential to inform practice and compare relative benefits of available treatment options. Studies of physical therapy interventions using highly standardized intervention protocols, although methodologically rigorous, do not necessarily reflect "real-world" clinical practice, and in many cases results have been disappointing. Development of a complex intervention that includes multiple treatment modalities and individualized treatment technique selection requires a systematic approach to designing all aspects of the intervention based on theory, evidence, and practical constraints. This perspective article outlines the development of the rationale and structure of a multimodal physical therapy program for painful hip osteoarthritis to be assessed in a clinical trial. The resulting intervention protocol comprises a semi-structured program of exercises and manual therapy, advice, physical activity, and optional prescription of a gait aid that is standardized, yet can be individualized according to physical assessment and radiographic findings. The program is evidence based and reflects contemporary physical therapist practice, while also being reproducible and reportable. This perspective article aims to encourage physical therapy researchers involved in evaluation of complex interventions to better document their own intervention development, as well as the outcomes, thus generating a body of knowledge about the development processes and protocols that is generalizable to the real-world complexity of providing physical therapy to individual patients.

Background: Because the choroid plexus (CP) is uniquely suited to control the composition of cerebrospinal fluid (CSF), there may be therapeutic benefits to increasing the levels of biologically active proteins in CSF to modulate central nervous system (CNS) functions. To this end, we sought to identify peptides capable of ligand-mediated targeting to CP epithelial cells reasoning that they could be exploited to deliver drugs, biotherapeutics and genes to the CNS., Methods: A peptide library displayed on M13 bacteriophage was screened for ligands capable of internalizing into CP epithelial cells by incubating phage with CP explants for 2 hours at 37C and recovering particles with targeting capacity., Results: Three peptides, identified after four rounds of screening, were analyzed for specific and dose dependent binding and internalization. Binding was deemed specific because internalization was prevented by co-incubation with cognate synthetic peptides. Furthermore, after i.c.v. injection into rat brains, each peptide was found to target phage to epithelial cells in CP and to ependyma lining the ventricles., Conclusion: These data demonstrate that ligand-mediated targeting can be used as a strategy for drug delivery to the central nervous system and opens the possibility of using the choroid plexus as a portal of entry into the brain.

Activation of RAW264.7 cells with a lipopolysaccharide specific for the TLR4 receptor, Kdo(2)-lipid A (KLA), causes a large increase in cellular sphingolipids, from 1.5 to 2.6 × 10(9) molecules per cell in 24 h, based on the sum of subspecies analyzed by "lipidomic" mass spectrometry. Thus, this study asked the following question. What is the cause of this increase and is there a cell function connected with it? The sphingolipids arise primarily from de novo biosynthesis based on [U-(13)C]palmitate labeling, inhibition by ISP1 (myriocin), and an apparent induction of many steps of the pathway (according to the distribution of metabolites and microarray analysis), with the exception of ceramide, which is also produced from pre-existing sources. Nonetheless, the activated RAW264.7 cells have a higher number of sphingolipids per cell because KLA inhibits cell division; thus, the cells are larger and contain increased numbers of membrane vacuoles termed autophagosomes, which were detected by the protein marker GFP-LC3. Indeed, de novo biosynthesis of sphingolipids performs an essential structural and/or signaling function in autophagy because autophagosome formation was eliminated by ISP1 in KLA-stimulated RAW264.7 cells (and mutation of serine palmitoyltransferase in CHO-LYB cells); furthermore, an anti-ceramide antibody co-localizes with autophagosomes in activated RAW264.7 cells versus the Golgi in unstimulated or ISP1-inhibited cells. These findings establish that KLA induces profound changes in sphingolipid metabolism and content in this macrophage-like cell line, apparently to produce sphingolipids that are necessary for formation of autophagosomes, which are thought to play important roles in the mechanisms of innate immunity.

Because the choroid plexus normally controls the production and composition of cerebrospinal fluid and, as such, its many functions of the central nervous system, we investigated whether ligand-mediated targeting could deliver genes to its secretory epithelium. We show here that when bacteriophages are targeted with epidermal growth factor, they acquire the ability to enter choroid epithelial cells grown in vitro as cell cultures, ex vivo as tissue explants or in vivo by intracerebroventricular injection. The binding and internalization of these particles activate EGF receptors on targeted cells, and the dose- and time-dependent internalization of particles is inhibited by the presence of excess ligand. When the phage genome is further reengineered to contain like green fluorescent protein or firefly luciferase under control of the cytomegalovirus promoter, gene expression is detectable in the choroid plexus and ependymal epithelium by immunohistochemistry or by noninvasive imaging, respectively. Taken together, these data support the hypothesis that reengineered ligand-mediated gene delivery should be considered a viable strategy to increase the specificity of gene delivery to the central nervous system and bypass the blood-brain barrier so as to exploit the biological effectiveness of the choroid plexus as a portal of entry into the brain., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease., Methods: The SF-36® Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/² weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline., Results: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease., Conclusion: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men.

Background: Hip osteoarthritis (OA) is a common condition leading to pain, disability and reduced quality of life. There is currently limited evidence to support the use of conservative, non-pharmacological treatments for hip OA. Exercise and manual therapy have both shown promise and are typically used together by physiotherapists to manage painful hip OA. The aim of this randomised controlled trial is to compare the efficacy of a physiotherapy treatment program with placebo treatment in reducing pain and improving physical function., Methods: The trial will be conducted at the University of Melbourne Centre for Health, Exercise and Sports Medicine. 128 participants with hip pain greater or equal to 40/100 on visual analogue scale (VAS) and evidence of OA on x-ray will be recruited. Treatment will be provided by eight community physiotherapists in the Melbourne metropolitan region. The active physiotherapy treatment will comprise a semi-structured program of manual therapy and exercise plus education and advice. The placebo treatment will consist of sham ultrasound and the application of non-therapeutic gel. The participants and the study assessor will be blinded to the treatment allocation. Primary outcomes will be pain measured by VAS and physical function recorded on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) immediately after the 12 week intervention. Participants will also be followed up at 36 weeks post baseline., Conclusions: The trial design has important strengths of reproducibility and reflecting contemporary physiotherapy practice. The findings from this randomised trial will provide evidence for the efficacy of a physiotherapy program for painful hip OA.

Aims: Fabry disease is a rare X-linked deficiency of alpha-galactosidase A (alphagal), which causes glycosphingolipid accumulation. This study analysed the cardiovascular manifestations of a cohort of Fabry patients, and sought to define relationships between disease severity, alphagal activity, and cardiac abnormalities., Methods and Results: We prospectively analysed Fabry patients (139 subjects: 92 males and 47 females) undergoing screening for potential enzyme replacement therapy. Baseline echocardiograms, electrocardiograms, and exams were obtained as part of two multinational clinical trials. Cardiovascular symptoms were present in 60.4%. By echocardiography, the mean left ventricular mass index (LVMI) was increased at 165.5 +/- 66.9 g/m(2), and 84.8% of patients displayed concentric left ventricular hypertrophy (LVH). Electrocardiographic LVH was present in >50% of adult subjects. In females, log-corrected plasma alphagal activity was inversely associated with LVMI (r = -0.45, P < 0.040). Males with extremely low alphagal activity and renal disease displayed the most LVH and cardiac symptoms, but LVH was prevalent even in females <20 years old., Conclusion: Concentric LVH was the predominant cardiac pathology seen in patients with Fabry disease, and was prevalent in both genders by the third decade of life. Left ventricular mass index was inversely correlated with alphagal activity, but was prevalent even in younger females.

Background: In previous studies, we showed that gene activated matrices (GAMs) containing nonviral vectors successfully deliver genes to neurons after optic nerve and spinal cord injury. In the present study, we evaluated whether adenoviral vectors delivered within a GAM increase the efficiency of local gene delivery to injured CNS neurons. Lyophilized GAMs containing collagen and adenoviral vectors were assessed in vitro and in vivo., Methods: We evaluated viral vector stability, release kinetics and efficiency of transduction for this GAM formulation in vitro using the quantitative polymerase chain reaction (qPCR), flow cytometry and fluorescence microscopy. Using PCR, reverse transcriptase-PCR and confocal microscopy, we assessed viral DNA retrograde axonal transport, green fluorescent protein (GFP) expression in retinal ganglion cells (RGCs) after GAM implantation into the wound of the rat transected optic nerve., Results: qPCR analyses demonstrated that 100% of viral particles were retained within the collagen after lyophilization. In vitro studies demonstrated that 60% of the particles within the GAM were infective and not released from the collagen matrix when placed in water. By 24 h, GFP expression was detected within cells that have invaded the GAM. In vivo studies demonstrated that adenoviral particles were retrogradely transported in axons from the GAM implanted at the lesion site to the RGC in the retina where the corresponding mRNA was expressed. Analysis of the efficiency of cell transduction indicated that 69% of RGC express GFP., Conclusions: These studies demonstrate that lyophilized GAMs containing adenoviral particles within collagen are stable, retain a significant proportion of their infectivity and successfully and efficiently deliver genes to neurons after central nervous system injury.

Epstein-Barr virus (EBV) nuclear antigen 3C (EBNA3C) is one of the essential latent antigens for primary B-cell transformation. Previous studies established that EBNA3C facilitates degradation of several vital cell cycle regulators, including the retinoblastoma (pRb) and p27(KIP) proteins, by recruitment of the SCF(Skp2) E3 ubiquitin ligase complex. EBNA3C was also shown to be ubiquitinated at its N-terminal residues. Furthermore, EBNA3C can bind to and be degraded in vitro by purified 20S proteasomes. Surprisingly, in lymphoblastoid cell lines, EBNA3C is extremely stable, and the mechanism for this stability is unknown. In this report we show that EBNA3C can function as a deubiquitination enzyme capable of deubiquitinating itself in vitro as well as in vivo. Functional mapping using deletion and point mutational analysis showed that both the N- and C-terminal domains of EBNA3C contribute to the deubiquitination activity. We also show that EBNA3C efficiently deubiquitinates Mdm2, an important cellular proto-oncogene, which is known to be overexpressed in several human cancers. The data presented here further demonstrate that the N-terminal domain of EBNA3C can bind to the acidic domain of Mdm2. Additionally, the N-terminal domain of EBNA3C strongly stabilizes Mdm2. Importantly, EBNA3C simultaneously binds to both Mdm2 and p53 and can form a stable ternary complex; however, in the presence of p53 the binding affinity of Mdm2 toward EBNA3C was significantly reduced, suggesting that p53 and Mdm2 might share a common overlapping domain of EBNA3C. We also showed that EBNA3C enhances the intrinsic ubiquitin ligase activity of Mdm2 toward p53, which in turn facilitated p53 ubiquitination and degradation. Thus, manipulation of the oncoprotein Mdm2 by EBNA3C potentially provides a favorable environment for transformation and proliferation of EBV-infected cells.

Background: Polymer coating of adenovirus type 5 (Ad5) particles produces a 'stealth' Ad5 (sAd5) that confers protection from immune recognition, blocks receptor-mediated uptake, and favours uptake into pinocytic cells., Methods: In mixed cultures of primary adult rat dorsal root ganglion neurones (DRGN), rat C6 glioma cells, A9 non-Coxsackie and Ad Receptor (CAR)- and CAR-expressing fibroblasts, reporter gene expression after sAd5 pinocytotic uptake was monitored using the green fluorescent protein (gfp) gene, and viral particle trafficking and polymer coat dismantling was followed using Yoyo-1 tagged Ad5 DNA and Texas Red (TR) to label the coat., Results: sAd5.gfp was pinocytosed by significantly higher proportions of neurones, than other cells, but GFP was not expressed. The TR-labelled coat remained co-localised with tagged viral DNA within transfected DRGN, showing that sAd5 did not uncoat and viral DNA did not traffic to the nucleus. Noncoated Ad5 transduced non-neuronal DRG cells more efficiently than DRGN, whereas A9(CAR) cells were more significantly transduced than any other cell type. Retargeting of the sAd5.gfp with either fibroblast growth factor-2 or nerve growth factor (NGF) enhanced internalisation by DRGN into endocytic vesicles allowing uncoating and thus GFP expression. Retargeting with NGF resulted in significantly higher numbers of DRGN expressing GFP than non-neuronal DRG cells., Conclusions: These findings indicate that DRGN pinocytose atropic genetic particles at higher levels than non-neuronal DRG cells and the environment of pinocytic vesicles is not conducive to sAd5 uncoating and capsid dismantling, requiring reformulation of sAd5 with either a neurone specific ligand or a self-dismantling coat to target sAd5 transgene expression to neurones.

Joints are essential for skeletal form and function, yet their development remains poorly understood. In zebrafish fins, joints form between the bony fin ray segments providing essentially unlimited opportunities to evaluate joint morphogenesis. Mutations in cx43 cause the short segment phenotype of short fin (sof(b123)) mutants, suggesting that direct cell-cell communication may regulate joint location. Interestingly, increased cx43 expression in the another long fin (alf(dty86)) mutant appears to cause joint failure typical of that mutant. Indeed, knockdown of cx43 in alf(dty86) mutant fins rescues joint formation. Together, these data reveal a correlation between the level of Cx43 expression in the fin ray mesenchyme and the location of joints. Cx43 was also observed laterally in cells associated with developing joints. Confocal microscopy revealed that the Cx43 protein initially surrounds the membranes of ZNS5-positive joint cells, but at later stages becomes polarized toward the underlying Cx43-positive mesenchymal cells. One possibility is that communication between the Cx43-positive mesenchyme and the overlying ZNS5-positive cells regulates joint location, and upregulation of Cx43 in joint-forming cells contributes to joint morphogenesis.

Myoclonus-dystonia (M-D) is characterized by early-onset myoclonus and dystonia, and is often due to mutations in the epsilon-sarcoglycan gene (SCGE) at locus 7q21. The pathogenesis of M-D is poorly understood, and in a murine knockout model, dopaminergic hyperactivity has been postulated as a mechanism. We present two unrelated individuals with M-D due to SCGE deletions who displayed a robust and sustained response to levodopa (L-dopa) treatment. In contrast to using dopamine blocking agents suggested by the hyperdopaminergic knockout model, we propose that a trial of L-dopa may be considered in patients with myoclonus-dystonia., ((c) 2008 Movement Disorder Society.)

Objective: To describe disease progression and treatment outcomes over a 20-year period (ages 5-25) in a young man with Norrie disease (occuloacousticocerebral dysplasia), ND; OMIM #310600. Affected individuals are born blind and develop progressive sensory loss with onset in adolescence. This disease is X-linked and has been associated with mutations of the NDP gene (Xp11.4)., Methods: The patient was followed using repeated audiograms, as well as reports of educational progress and hearing aid use. The specific mutation was found by molecular analysis., Results: The patient demonstrated progressive sensory loss with good preservation of word recognition. The loss was initially high frequency and asymmetric in adolescence and became more severe, more symmetric and affected practically all frequencies by the end of childhood. Educational progress was affected by the cognitive effects of the syndrome, and hearing aid use was very effective., Conclusions: A bilateral progressive sensory loss with good preservation of word recognition was documented in detail. The residual word recognition supported good use of hearing aids in this case.

Adenovirus (Ad) is an efficient and safe vector for CNS gene delivery since it infects non-replicating neurons and does not cause insertional mutagenesis of host cell genomes. However, the promiscuous Ad CAR receptor targets cells non-specifically and activates a host immune response. Using Ad5 containing an expression cassette encoding the gene for green fluorescent protein, gfp, regulated by the neuron specific promoter synapsin-1 and the woodchuck post-transcriptional regulatory element (WPRE), we demonstrate efficient, prolonged and promoter-restricted gfp expression in neurons of mixed primary adult rat dorsal root ganglion (DRG) and retinal cell cultures. We also demonstrate restricted gfp expression in DRG neurons after direct injections of Ad5 containing the synapsin-1(gfp)/WPRE construct into L4 DRG in vivo, while Ad5 CMV(gfp) transfected both DRG glia and neurons. Moreover, since the effective titres of delivered Ad5 are reduced with this neuron specific promoter/WPRE expression cassette, the viral immune challenge should be attenuated when used in vivo.