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Background: The prosthetic socket is a key component that influences prosthesis satisfaction, with a poorly fitting prosthetic socket linked to prosthesis abandonment and reduced community participation. This paper reviews adjustable socket designs, as they have the potential to improve prosthetic fit and comfort through accommodating residual limb volume fluctuations and alleviating undue socket pressure., Methods: Systematic literature and patent searches were conducted across multiple databases to identify articles and patents that discussed adjustable prosthetic sockets. The patents were used to find companies, organisations, and institutions who currently sell adjustable sockets or who are developing devices., Results: 50 literature articles and 63 patents were identified for inclusion, representing 35 different designs used in literature and 16 commercially available products. Adjustable sockets are becoming more prevalent with 73% of publications (literature, patents, and news) occurring within the last ten years. Two key design characteristics were identified: principle of adjustability (inflatable bladders, moveable panels, circumferential adjustment, variable length), and surface form (conformable, rigid multi-DOF, and rigid single DOF). Inflatable bladders contributed to 40% of literature used designs with only one identified commercially available design (n = 16) using this approach. Whereas circumferential adjustment designs covered 75% of identified industry designs compared to only 36% of literature devices. Clinical studies were generally small in size and only 17.6% of them assessed a commercially available socket., Discussion: There are clear differences in the design focus taken by industry and researchers, with justification for choice of design and range of adjustment often being unclear. Whilst comfort is often reported as improved with an adjustable socket, the rationale behind this is not often discussed, and small study sizes reduce the outcome viability. Many adjustable sockets lack appropriate safety features to limit over or under tightening, which may present a risk of tissue damage or provide inadequate coupling, affecting function and satisfaction. Furthermore, the relationship between design and comfort or function are rarely investigated and remain a significant gap in the literature. Finally, this review highlights the need for improved collaboration between academia and industry, with a strong disconnect observed between commercial devices and published research studies., (© 2023. The Author(s).)

Bruising or bleeding in a child can raise the concern for child abuse. Assessing whether the findings are the result of trauma and/or whether the child has a bleeding disorder is critical. Many bleeding disorders are rare, and not every child with bruising/bleeding that may raise a concern for abuse requires an evaluation for bleeding disorders. However, in some instances, bleeding disorders can present in a manner similar to child abuse. Bleeding disorders cannot be ruled out solely on the basis of patient and family history, no matter how extensive. The history and clinical evaluation can be used to determine the necessity of an evaluation for a possible bleeding disorder, and prevalence and known clinical presentations of individual bleeding disorders can be used to guide the extent of laboratory testing. This clinical report provides guidance to pediatricians and other clinicians regarding the evaluation for bleeding disorders when child abuse is suspected., (Copyright © 2022 by the American Academy of Pediatrics.)

Recognition and misrecognition have been theorized as key concepts for social justice. Misrecognition involves being disrespected or labelled in ways which do not accord with a person's self-identify. Racism can be understood as a specific form of misrecognition but little research has explored this form or drawn on notions of misrecognition in the discursive psychological study of racism. Our study addresses this gap by drawing on discursive psychology and conversation analysis to examine reports of racial encounters in public spaces, where misrecognition of the targets' nationality is invoked. We demonstrate that instances of misrecognition are judged as racism through the selection and use of categories and/or category-sensitive predicates that exclude the target of them from (national) category membership to which they claim entitlement. People reporting racialized encounters and those responding to them treat the description and evaluation of such incidents sensitively, orienting to the delicacy of alleging racism. In this article, we enhance theoretical understandings of misrecognition by showing how it is constructed interactionally and demonstrate the value of notions of recognition and misrecognition for the study of racism., (© 2021 The Authors. British Journal of Social Psychology published by John Wiley & Sons Ltd on behalf of British Psychological Society.)

Background: Almost 20 years have elapsed since the last workforce survey of pediatric infectious disease (PID) subspecialists was conducted in 1997-1998. The American Academy of Pediatrics Section on Infectious Diseases in collaboration with the Pediatric Infectious Diseases Society sought to assess the status of the current PID workforce., Methods: A Web-based survey conducted in 2015 collected data on demographics, practice patterns, and job satisfaction among the PID workforce, and identified factors related to job placement among recent fellowship graduates., Results: Of 946 respondents (48% response rate), 50% were female. The average age was 51 years (range, 29-88 years); 63% were employed by an academic center/hospital, and 85% provided direct patient care; and 18% were not current PID practitioners. Of the 138 (21%) respondents who had completed a PID fellowship within the previous 5 years, 83% applied for <5 PID positions; 43% reported that their first position was created specifically for them; 47% had 1 job offer, and 41% had 2 or 3 job offers; 82% were employed within 6 months; and 74% remained at the institution of their first job. Respondents who were practicing PID full-time or part-time (n = 778) indicated desiring more focused training in immunodeficiencies (31%), transplant-related care (31%), and travel/tropical medicine (28%). Overall, 70% of the respondents would "definitely" or "probably" choose PID again., Conclusions: Most respondents were satisfied with their career choice in PID. Most of the recent fellowship graduates were employed within 6 months after training. We identified potential areas in which the PID community can focus efforts to maintain the pipeline and improve satisfaction among its physicians., (© The Author(s) 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Polar mesosphere winter echoes (PMWE) were observed at 70 km over Tromsø, Norway, on 8 January 2014 using the tristatic configuration of the European incoherent scatter VHF radar. For the interval 11:00-13:00 UT where the strongest patch of PMWE of about 6-min duration was detected, the spectra of the received signal were analysed for the Tromsø site and altitude profiles of spectral parameters were derived. For the remote sites Kiruna and Sodankylä, the Doppler velocities and their vertical shear were determined by using the measured autocorrelation functions. Ducted gravity waves with periods of 5-10 min were found in the vertical wind velocity between 66 and 81 km altitudes. The duct might be formed around 70 and 77 km altitude where horizontal wind maxima were observed with the Kiruna receiver. However, we did not find any close relation between wind shear at 70 km altitude and PMWE at the same height: the wind shear was present for 2 h, but PMWE for only 6 min. Enhanced spectral width in the vertical Tromsø beam was observed for the PMWE patch. We discussed these experimental findings in relation to the winter echo generation mechanism. Our conclusion is that the presence of patchy negatively charged small-sized dust might explain the observations although a gravity wave breaking mechanism cannot be completely rejected., Competing Interests: The authors declare that they have no competing interests.

Research indicates that in experimental settings, young children of 3-7 years old are unlikely to devise a simple tool to solve a problem. This series of exploratory studies done in museums in the US and UK explores how environment and ownership of materials may improve children's ability and inclination for (i) tool material selection and (ii) innovation. The first study takes place in a children's museum, an environment where children can use tools and materials freely. We replicated a tool innovation task in this environment and found that while 3-4 year olds showed the predicted low levels of innovation rates, 4-7 year olds showed higher rates of innovation than the younger children and than reported in prior studies. The second study explores the effect of whether the experimental materials are owned by the experimenter or the child on tool selection and innovation. Results showed that 5-6 year olds and 6-7 year olds were more likely to select tool material they owned compared to tool material owned by the experimenter, although ownership had no effect on tool innovation. We argue that learning environments supporting tool exploration and invention and conveying ownership over materials may encourage successful tool innovation at earlier ages., (© 2016 The Author(s).)

Purpose of Review: Gestational diabetes mellitus (GDM) increases the lifetime risk of developing type 2 diabetes mellitus (T2DM) in the mother. We undertook a systematic review to assess the effectiveness of interventions that delay or prevent the onset of T2DM in women with previous gestational diabetes., Recent Findings: Diet and lifestyle interventions show differing effects on women with GDM and their long-term risk of T2DM. Pharmacological interventions, such as metformin, appear to have a beneficial role. Breastfeeding may have a protective role by reducing the risk of progression to T2DM. The findings were limited by the small number of heterogeneous studies that varied in their population, intervention, outcome and duration of follow-up., Summary: Women with GDM should be informed about the future risk of T2DM and the potential benefit with lifestyle interventions. Further studies are needed prior to routine use of metformin as a preventive strategy for T2DM in women with GDM.

Previous discursive research has found that minority group members may deny or downplay the existence of discrimination. However, to date, little research has addressed the issue of violence against minority group members. This study therefore draws on interviews with asylum seekers and refugees in a Scottish city to analyse their reports of violence committed against them. One form of reporting violence was by way of a complaint available to any speaker, in making no reference to attributes of attackers or victim. When racism was alleged, it was presented as a tentative, reluctant or 'last resort' explanation. The descriptions offered by interviewees reflected the contributions made by the interviewer, highlighting the ways in which these reports are interactional co-productions. The results suggest that accounts from victims of seemingly racially motivated violence may function in similar ways to 'new racism' in making racism seem to 'disappear'. These findings point to the potential difficulties that arise in identifying and looking to challenge instances of 'new racism'., (© 2012 The British Psychological Society.)

Using a chirped pulse probe technique, we have obtained single-shot measurements of temporal evolution of ac conductivity at 1.55 eV (800 nm) during electron energy relaxation in nonequilibrium warm dense gold with energy densities up to 4.1  MJ/kg (8×10(10)  J/m3). The results uncover important changes that have been masked in an earlier experiment. Equally significant, they provide valuable tests of an ab initio model for the calculation of electron heat capacity, electron-ion coupling, and ac conductivity in a single, first principles framework. While measurements of the real part of ac conductivity corroborate our theoretical temperature-dependent electron heat capacity, they point to an electron-ion coupling factor of ∼2.2×10(16)  W/m3 K, significantly below that predicted by theory. In addition, measurements of the imaginary part of ac conductivity reveal the need to improve theoretical treatment of intraband contributions at very low photon energy.

Enzymes used in cleaning products have an excellent safety profile, with little ability to cause adverse responses in humans. For acute toxicity, genotoxicity, sub-acute and repeated dose toxicity, enzymes are unremarkable. Reproductive toxicity and carcinogenicity are also not endpoints of concern. Exceptions are the ability of some proteases to produce irritating effects at high concentrations and more importantly, the intrinsic potential of these bacterial/fungal proteins to act as respiratory sensitizers. It is a reasonable assumption that the majority of enzyme proteins possess this hazard. However, methods for characterising the respiratory sensitisation hazard of enzymes are lacking and the information required for risk assessment and risk management, although sufficient, remains limited. Previously, most data was generated in animal models and in in vitro immunoassays that assess immunological cross-reactivity. Nevertheless, by the establishment of strict limits on airborne exposure (based on a defined minimal effect limit of 60ng active enzyme protein/m(3)) and air and health monitoring, occupational safety can be assured. Similarly, by ensuring that airborne exposure is kept similarly low, coupled with knowledge of the fate of these enzymes on skin and fabrics, it has proven possible to establish a long history of safe consumer use of enzyme containing products., (Copyright © 2012 Elsevier Inc. All rights reserved.)

A wide range of substances have been recognized as sensitizing, either to the skin and/or to the respiratory tract. Many of these are useful materials, so to ensure that they can be used safely it is necessary to characterize the hazards and establish appropriate exposure limits. Under new EU legislation (REACH), there is a requirement to define a derived no effect level (DNEL). Where a DNEL cannot be established, e.g. for sensitizing substances, then a derived minimal effect level (DMEL) is recommended. For the bacterial and fungal enzymes which are well recognized respiratory sensitizers and have widespread use industrially as well as in a range of consumer products, a DMEL can be established by thorough retrospective review of occupational and consumer experience. In particular, setting the validated employee medical surveillance data against exposure records generated over an extended period of time is vital in informing the occupational DMEL. This experience shows that a long established limit of 60 ng/m(3) for pure enzyme protein has been a successful starting point for the definition of occupational health limits for sensitization in the detergent industry. Application to this of adjustment factors has limited sensitization induction, avoided any meaningful risk of the elicitation of symptoms with known enzymes and provided an appropriate level of security for new enzymes whose potency has not been fully characterized. For example, in the detergent industry, this has led to general use of occupational exposure limits 3-10 times lower than the 60 ng/m(3) starting point. In contrast, consumer exposure limits vary because the types of exposure themselves cover a wide range. The highest levels shown to be safe in use, 15 ng/m(3), are associated with laundry trigger sprays, but very much lower levels (e.g. 0.01 ng/m(3)) are commonly associated with other types of safe exposure. Consumer limits typically will lie between these values and depend on the actual exposure associated with product use., ((c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Traditions and ceremonies don't just happen on their own--they require vision and effort. When honor guard services are required, it is too late to think about getting one organized. Advance preparation and training are necessary if a ceremonial unit is to accomplish its mission in a manner that brings credit to the organization. A wise EMS leader will scan the environment and seek out opportunities to develop the capabilities, nurture traditions and arrange ceremonies that will contribute to organizational morale and support the achievement of the organization's mission.

The combined effects of multiple polymorphisms in several drug-metabolizing enzyme and transporter genes can contribute to considerable interindividual variation in drug disposition and response. Therefore, it has been of increasing interest to generate scalable, flexible and cost-effective technologies for large-scale genotyping of the drug-metabolizing enzyme and transporter genes. However, the number of drug-metabolizing enzyme and transporter gene variants exceeds the capacity of current technologies to comprehensively assess multiple polymorphisms in a single, multiplexed assay. The Targeted Genotyping System (Affymetrix, CA, USA) provides a solution to this challenge, by combining molecular inversion probe technology with universal microarrays to provide a method that is capable of analyzing thousands of variants in a single reaction, while remaining relatively insensitive to cross-reactivity between reaction components. This review will focus on the Targeted Genotyping System and how this technology was adapted to enable comprehensive analysis of drug-metabolizing enzyme and transporter gene polymorphisms.

We compared oculomotor control among individuals in the early stages of Huntington's disease (HD), with that of individuals who are presymptomatic HD gene carriers (PSGC) and nongene carriers (NGC). The oculomotor testing paradigm included both traditional tests and a novel experimental procedure to assess visual scanning. Traditional tests elicited saccades, pursuit and optokinetic nystagmus (OKN). HD patients demonstrated marked delay in the initiation of volitional saccades (anti-saccade and memory-guided saccades), a reduced number of correct volitional saccades, reduced velocity of saccades, and a decreased OKN gain. We also studied visual scanning while the participants completed the Digit Symbol Subscale of the Wechsler Adult Intelligence Survey-Revised (WAIS-R). The HD participants demonstrated an abnormal gaze strategy, which may be associated with attention and/or planning deficits. Differences between the PSGC and NGC groups were only observed for two measures: PSGC had a decreased number of memory-guided saccades and a subtle delay in the initiation of volitional saccades. Our results suggest that oculomotor measures are a sensitive biomarker in the early stage of HD and demonstrate that the combination of more traditional oculomotor tests with visual scanning tests is useful in the evaluation of visual performance.

Yannawa Wastewater Treatment plant (Phase 1) serves a population equivalent of 500,000 and is located on a restricted site within the city of Bangkok, Thailand. Secondary treatment is based on the CASS sequencing batch reactor (SBR) process and the plant is one of the largest multi-storey SBRs in the world. The limitation of available site area, the ground conditions and the characteristics of the wastewater to be treated set a series of challenges for the designers, contractors and commissioning and operational staff. This paper briefly describes the collection system, the process selection and the treatment streams of the wastewater treatment plant. The SBR secondary treatment plant is described in more detail. The problems that arose during commissioning and operation and the solutions made possible by the use of an SBR type of process are discussed. Details of plant performance during performance testing and during the first three years of plant operation are provided.

Individuals at-risk for Huntington disease (HD), both HD gene carriers and nongene carriers, were recruited to determine whether psychological changes are detectable among clinically presymptomatic individuals who carry the HD allele. Each participant underwent genotyping to determine HD gene carrier status and a clinical assessment that included a quantified neurological examination and an abbreviated Minnesota Multiphasic Personality Inventory (MMPI): the Hypochondriasis, Depression, Psychasthenia, Neuroticism, Cynical Hostility, and Irritability Scales and the Harris Subscales of Depression. The results of the MMPI were evaluated for differences between nongene carriers (NGC) (n = 363), presymptomatic gene carriers (PSGC) (n = 149), and those with manifest HD (MHD) (n = 26). The overall multiple analysis of variance was not significant, indicating that there was no overall difference among the three groups. However, when subscales of the MMPI were examined individually, participants with manifest HD scored higher on the Psychasthenia scale (MHD vs. PSGC, P = 0.005; MHD vs. NGC, P = 0.03) and the Harris Depression subscale, Brooding (MHD vs. PSGC, P=0.0005; MHD vs. NGC, P = 0.003). No significant correlation was found between the number of trinucleotide repeats on the disease-producing allele and any of the MMPI scales for the gene carriers, MHD or PSGC. These results verify the presence of psychological symptoms in the early phases of MHD but not in PSGC. Thus, further study of the behavioral and mood symptoms thought to accompany HD using measures designed specifically to detect depressive symptoms and changes in behavior specific to HD is warranted to delineate the timing of onset of the psychological symptoms., (Copyright 2002 Elsevier Science Ltd.)

Purpose: To determine technical success and complications with weight-adjusted dosing of recombinant tissue plasminogen activator (rt-PA) for arterial and bypass graft occlusions., Materials and Methods: During an 8-month period, prospective data were collected on patients undergoing catheter-directed thrombolysis. Retrospective review of all medical charts and blood bank data were performed for confirmation. All patients underwent a standard weight-adjusted protocol for catheter-directed thrombolysis. Thrombolytic therapy with rt-PA (0.2 mg/mL) was defined as low-dose when 0.02 mg/kg/h rt-PA was used and high-dose when 0.04 mg/kg/h of rt-PA was used. Low-dose heparin therapy was used. Total infusion time, total dose, and hourly rate of dose were calculated. Technical success, defined as complete removal of all clot without surgical intervention, complications, and frequency of transfusions were tabulated., Results: A total of 35 patients underwent catheter-directed thrombolysis with rt-PA, including a total of 21 bypass grafts (60%) and 14 native arteries (40%). Mean age was 57 years (+/- 22.5; range, 3 mo to 83 y). Average rate of heparin infusion was 472.8 U/h (+/- 227). Success rates for graft thrombolysis were 90% (18 of 21). Success rates for native vessels were 79% (11 of 14). In patients who underwent only a low-dose protocol, the transfusion rate was 15% and major complications were 10%. In patients with a combined low-dose/high-dose administration, the transfusion rate was 46% and major complications were 13%. Overall success rate and major complication rates were 86% (30 of 35) and 11% (four of 35), respectively. Frequency of transfusions was 37% (13 of 35; mean, 2.8 U)., Conclusion: Although weight-adjusted dosing for rt-PA provides a high efficacy of relieving ischemia, the rate of complications, especially bleeding, seems excessive in comparison to historical experience with urokinase. Administration of short-term high doses of rt-PA did not appear to have any beneficial effect. Further investigation with lower dosing and concentration should be considered.

Purpose: To identify rates of adverse events associated with the use of conscious sedation in interventional radiology., Methods: In a 5-month period, prospective data were collected on patients undergoing conscious sedation for interventional radiology procedures (n = 594). Adverse events were categorized as respiratory, sedative, or major adverse events. Respiratory adverse events were those that required oral airway placement, ambu bag, or jaw thrust. Sedation adverse events were unresponsiveness, oxygen saturation less than 90%, use of flumazenil/naloxone, or agitation. Major adverse events were hypotension, intubation, CPR, or cardiac arrest. The frequency of adverse events for the five most common radiology procedures were determined., Results: The five most common procedures (total n = 541) were biliary tube placement/exchange (n = 182), tunneled catheter placement (n = 135), diagnostic arteriography (n = 125), vascular interventions (n = 52), and other catheter insertions (n = 46). Rates for respiratory, sedation, and major adverse events were 4.7%, 4.2%, and 2.0%, respectively. The most frequent major adverse event was hypotension (2.0%). Biliary procedures had the highest rate of total adverse events (p < .05) and respiratory adverse events (p < .05)., Conclusion: The frequency of adverse events is low with the use of conscious sedation during interventional procedures. The highest rates occurred during biliary interventions.

Objective: To delineate the progression of symptoms in the early and middle stages of Huntington disease (HD)., Design: A survey of individuals with symptomatic HD completed by a first-degree relative., Setting: The National Huntington Disease Research Roster for Patients and Families, Indianapolis, Ind., Participants: The survey included 1238 individuals with a minimum of a 6-year history of symptomatic HD., Measures: Participating families completed a series of surveys, including the Affected Individual Questionnaire, which consists of 19 physical, emotional, and cognitive signs commonly thought to occur during disease progression. The respondent indicates if each of the symptoms occurred and, if so, at what time during the course of the disease: (1) within 1 year, (2) within 2 to 5 years, (3) within 6 to 10 years, (4) after more than 10 years, (5) has not occurred, or (6) "don't know.", Results: The symptoms are categorized into 6 onset periods. Involuntary movements are grouped alone as the earliest reported symptom. The second group is composed entirely of mental and emotional symptoms, including sadness, depression, and difficult to get along with. The third group includes clumsiness, sexual problems, lack of motivation, and suspiciousness/paranoia. As the disease progresses, a variety of motor, emotional/behavioral, and cognitive symptoms are experienced, including unsteadiness, trouble holding onto things, trouble walking, changes in sleeping patterns, delusions and hallucinations, intellectual decline, and memory loss. With the approach of late-stage HD, affected individuals begin to experience speech difficulty and weight loss. In the late stage, patients lose bowel and bladder control., Conclusions: Even though the symptoms of HD are fairly well characterized, their progression, especially in the early and middle stages, remains uncertain. Clarification of the disease progression is vital to improved understanding of the pathogenesis of HD and to the evaluation of therapeutic agents that are designed to slow the progression of disease. The results of this study assist in clarifying HD progression from early involuntary movements and emotional changes to more overt motor symptoms and difficulty with activities of daily living.

Several approaches were taken to identify the loci contributing to the quantitative and qualitative phenotypes in the Genetic Analysis Workshop 12 simulated data set. To identify possible quantitative trait loci (QTL), the quantitative traits were analyzed using SOLAR. The four replicates identified as the "best replicates" by the simulators, 42, 25, 33, and 38, were analyzed separately. Each of the five quantitative phenotypes was analyzed individually in the four replicates. To increase the power to detect QTL with pleiotropic effects, principal component analysis was performed and one new multivariate phenotype was estimated. In each instance, after performing a 10-cM genome screen, fine mapping was completed in the initially identified linked regions to further evaluate the evidence for linkage. This approach of initially performing a coarse marker screen followed by analyses using much higher marker density successfully identified all the QTL playing a role in the quantitative phenotypes. The principal component phenotype did not substantially improve the power of QTL detection or localization. A neural network approach was utilized to identify loci contributing to disease status. The neural network technique identified the strongest gene influencing disease status as well as a locus contributing to quantitative traits 3 and 4; however, the inputs that contributed the greatest information were markers not in QTL regions.

A two-step process was used to find loci contributing to the qualitative disease phenotype in the Genetic Analysis Workshop (GAW) 12 simulated data. The first step used parametric linkage analysis with a limited number of dominant and recessive models to detect linkage to chromosomal regions. Subsequently, a subset of the simulated biallelic sequence polymorphisms was used for transmission/disequilibrium tests and to build haplotypes to fine map the disease-predisposing polymorphism(s). A haplotype, strongly associated with the disease phenotype whose proximal end was within 39 base pairs of the functional allele for simulated major gene 6, was identified in the isolated population.

Objectives: To compare the neurological and psychometric characteristics of presymptomatic gene carriers and non-gene carriers who are at risk for developing Huntington's disease so as to characterise early signs of disease and to identify markers of neurological function that could be used to assess the impact of experimental therapies on the progression of disease, even among those who are clinically presymptomatic., Methods: A sample of people at risk for Huntington's disease was genotyped and evaluated using subscales of the Wechsler adult intelligence scale-revised (WAIS-R), a quantified neurological rating scale, and computerised physiological measures including speed of movement and reaction time., Results: Genotyping and clinical examination determined that 171 participants were presymptomatic gene carriers (PSGCs) and 414 participants were non-gene carriers (NGCs). The PSGCs performed significantly worse when compared with the NGCs on the digit symbol, picture arrangement, and arithmetic subscales of the WAIS-R (p<0.02) and for the physiological measures: button tapping, auditory reaction time, visual reaction time with decision, and movement time with and without decision (p<0.05). Although no PSGCs had sufficient neurological findings to warrant a diagnosis of Huntington's disease on clinical examination, the PSGCs had more frequent possible or definite abnormality for oculomotor function, chorea, muscle stretch reflexes, gait, and station stability, and rapid alternating movements (p

Objective: To confirm that subtle changes in motor function and reaction time are present in presymptomatic individuals carrying the expanded Huntington disease (HD) allele., Design: A case-control, double-blind study comparing presymptomatic HD gene carriers (PSGCs) and nongene carriers (NGCs) at risk for HD., Setting: The Department of Medical and Molecular Genetics at a general clinical research center in a midwestern city., Participants: Two hundred sixteen individuals at risk for HD who were asymptomatic by self-report and who did not have manifest HD on results of clinical examination, including PSGCs (n = 61) and NGCs (n = 155)., Measures: Molecular testing was used to determine the number of CAG repeats in the HD gene. A quantified neurologic examination and a battery of physiological measures of central nervous system function measuring speed of movement and reaction time were administered., Results: On neurologic examination, the PSGCs exhibited significantly more definite or possible abnormalities than NGCs for overall oculomotor function, saccade velocity, optokinetic nystagmus, chorea of the extremities, and dystonia of the extremities (P<.05). The PSGCs also had significantly slower performance for auditory reaction time, visual reaction time, visual reaction time with decision, movement time, movement time with decision, and button-tapping time, compared with the NGCs (P<.05)., Conclusions: Subtle changes in motor function, speed of movement, and reaction time are present in HD gene carriers who do not exhibit definite choreiform movements and who do not have sufficient signs to make a clinical diagnosis of HD. In addition, a trend toward slower speed of movement and reaction time was observed among this population as their neurologic abnormalities increased.

White-matter hyperintensities (WMHI) are frequently associated with cerebrovascular risk factors in the elderly, particularly hypertension, and have been interpreted as a subclinical form of ischemic brain damage. WMHI, clinical stroke and blood pressures show significant genetic influences. The objective of this study was to determine whether a relationship exists between family history of stroke and/or hypertension in first degree relatives and WMHI in the elderly. WMHI and stroke (CVA) volumes were quantified from brain MRI performed on 414 white, male twins born between 1917 and 1927 (average age 72.3 +/- 2.9 years). WMHI, adjusted for age and head size, was significantly correlated with the family history score (r = 0.21, p < 0.001). Dividing the family history scores into quintiles revealed significant differences in WMHI by quintile mean (p < 0.05). Subjects in the highest quintile of family history score had the highest mean WMHI. Recalculation of the family history score, by only counting relatives reported to have had a clinical stroke as a positive event, revealed a nonsignificant correlation with WMHI, but the correlation of the family history score with MRI CVA volume was significant (p < 0.05). Stepwise multivariate analysis including ApoE status, current smoking status, smoking packyear history, Doppler ankle/arm blood pressure ratios, current and long term hypertensive status and current systolic and diastolic pressures indicated that the stroke/hypertension family history score was the single best predictor (p < 0.01) of WMHI volumes. Family history was not an independent predictor of CVA volume.

Cystinuria, a renal tubule disease affecting urinary cystine excretion with or without kidney stone formation, previously was mapped to chromosome region 2p.21. Mutations in the gene SLC3A1 or NBAT, the reported candidate gene for cystinuria at 2p.21, have been demonstrated in individuals with the autosomal recessive Type I cystinuria phenotype. Recently, the Type III cystinuria phenotype was mapped to chromosome region 19q13.1. Here we report a kindred of 39 persons in two families of cystinurics, Types II and III, that support linkage to 19q13.1 and exclude 2p.21. Based on a dominant model of inheritance, two-point analysis of the entire pedigree produced a maximum lod score (Z(max)) of 3.82 at marker D19S425. Multipoint analysis yielded a lod score of 4.96 at this marker, and a resultant lod score of 5.90 using a codominant model of inheritance. Furthermore, a candidate gene interval of 8.9 cM, flanked by markers D19S225 and D19S223, was obtained using multipoint and haplotype analyses. Thus, this kindred demonstrates the linkage of Type II cystinuria to 19q13.1 and confirms the linkage of Type III cystinuria at 19q13.1 while excluding the marker D19S225 that was previously included in the critical interval., (Copyright 1999 Wiley-Liss, Inc.)

Objective: To determine whether longitudinal changes in cognitive and motor function can be detected among clinically presymptomatic individuals carrying the Huntington disease (HD) allele., Design: A longitudinal, case-control, double-blind study comparing presymptomatic gene carriers and non-gene carriers at risk for HD examined an average of 3.7 years apart., Setting: The Department of Medical and Molecular Genetics at a general clinic research center in Indianapolis, Ind., Participants: A sample of 43 at-risk individuals consisting of presymptomatic gene carriers (n = 12) and non-gene carriers (n = 31)., Measures: Huntington disease gene status was determined by molecular testing of the HD gene. Subscales from the Wechsler Adult Intelligence Scale-Revised and a quantified neurologic rating scale were administered., Results: Scores on the digit symbol subscale of the Wechsler Adult Intelligence Scale-Revised (P<.05) and 2 neurologic variables-optokinetic nystagmus (P<.01) and rapid alternating movements (P<.005)-declined more rapidly among presymptomatic gene carriers than among non-gene carriers. At follow-up examination, compared with nongene carriers, presymptomatic gene carriers had significantly lower scores on the digit symbol subscale (P = .02) and for 4 neurologic variables-rapid alternating movements (P<.005), optokinetic nystagmus (P<.001), overall ocular movements (P<.02), and chorea of the trunk (P<.02)., Conclusions: Psychomotor speed, optokinetic nystagmus, and rapid alternating movements demonstrated significant decline early in the pathological process of HD. These results suggest that subtle worsening of psychomotor, oculomotor, and motor functions occurs before the onset of signs sufficient to make a clinical diagnosis in individuals who have inherited the HD allele.

The oxidation of low density lipoprotein (LDL) is believed to be an important process in the development and progression of atherosclerosis. In this study, human subjects were supplemented daily with one of: 6 g raw garlic; 2.4 g aged garlic extract (AGE); or 0.8 g DL-alpha-tocopherol acetate for 7 days to determine the effect on the susceptibility of LDL particles to Cu2+-mediated oxidation. LDL isolated from subjects given either alpha-tocopherol or AGE, but not raw garlic, was significantly more resistant to oxidation than LDL isolated from subjects receiving no supplements. These results suggest that if antioxidants are proven to be antiatherogenic, AGE may be useful in preventing atherosclerotic disease.

To investigate whether differences in metabolic rate are related to differences in muscle mitochondrial morphology and/or to differences in in vitro muscle respiration, we studied 17 healthy Caucasians, covering a wide range of body weight and composition [9 males, 8 females; body wt 96 +/- 37 (SD) kg; body fat = 28 +/- 10%]. Central and peripheral mitochondrial volume density (Vmit c and Vmit p, respectively) and the ratio of mitochondrial outer surface to volume of mitochondria (SVmit c in center and SVmit p at periphery) were determined by stereological analyses of transmission electron micrographs from samples of the vastus lateralis. There was no relationship between mitochondrial morphology or muscle respiration and 24-h energy expenditure, basal metabolic rate, or sleeping energy expenditure adjusted for differences in fat-free mass, fat mass, age, and sex. Although total body fat was not associated with muscle cell morphology, central distribution of body fat [waist-to-thigh circumference ratio (W/T)] correlated negatively with Vmit c (r = -0.58, P = 0.01), SVmit c (r = -0.59, P = 0.01), and SVmit p (r = -0.48, P = 0.05). W/T was also negatively related to muscle respiration (r = -0.59, P = 0.01). Despite the lack of relationship between metabolic rate and muscle mitochondrial morphology, central distribution of body fat is associated with lower mitochondrial density and larger mitochondria in skeletal muscle and is associated with a decreased oxidative capacity of muscle.

The oxidation of UDP-glucose by the enzyme UDP-glucose dehydrogenase (EC 1.1.1.22) from beef liver has been shown to proceed via the enzyme-bound intermediate, UDP-alpha-D-glyco-hexodialdose. The enzyme does not release this aldehyde, nor can it be trapped by reaction with hydroxylamine, thiosemicarbazide, or cyanide. Tight binding of the intermediate aldehyde can be explained by the recent observation that the essential thiol group of the enzyme forms a thiohemiacetal with the aldehyde during the course of the reaction. However, an enzyme preparation with the essential thiol derivatized with cyanide will still not release the aldehyde, indicating an additional as yet unknown binding mechanism. Derivatization ([14C]formaldehyde, followed by NaBH4 reduction) of 6 of the approximately 168 lysine residues per enzyme molecule (of six catalytic subunits) results in destruction of 47% of the enzyme activity, suggesting the involvement of an essential reactive lysine in the mechanism. Preincubation of the enzyme with UDP-glucose decreases both the loss of activity and incorporation of the label, indicating that this lysine is in the vicinity of the active site. Acid hydrolysis of the labeled preparation, followed by paper chromatography, shows that the label has a mobility, in the system used, that is identical with lysine. Elution of this spot followed by chromatography on Aminex A-5 resin showed that it contained the expected mixture of epsilon-N-methyl lysines. When enzyme that has its essential thiol derivatized with cyanide is incubated with UDP-[14C]glucose and NAD+, and then reduced with NaB3H4, a stable enzyme complex is formed which contains both labels. Acid hydrolysis of this preparation, followed by either two-dimensional paper chromatography or separation in an amino acid analyzer, results in both labels appearing in the position of lysine. It is evident that the enzyme oxidizes the UDP-[14C]glucose to the corresponding aldehyde which occurs as the Schiff's base with an essential lysine. This is then reduced by the NaB3H4 to form a secondary amine which is stable toward hydrolysis and migrates with lysine in separation procedures. As would be predicted, the enzyme can be similarly labeled by treatment with UDP-alpha-D-gluco-hexodisidose alone, followed by NaB3H4 reduction. The same hydrolysis product results from this procedure, and it behaves identically with the product formed by treating alpha-N-acetyl lysine with UDP-alpha-D-gluco-hexodialdose, reducing with NaBH4, and then hydrolyzing. This substance appears to be N5-((5-formyl-2-furanyl)methyl)lysine. When chromatographed on Aminex A-5, both the model compound and enzyme hydrolysate gave peaks corresponding to free lysine and the proposed derivative. Evidence is presented that the oxidation of UDP-glucose to the aldehyde is a concerted reaction involving the formation of the Schiff's base, rather than the formation of the aldehyde with the subsequent formation of the Schiff's base...

A method for the large-scale production of a (1 yields 3)-beta-D-glucan glucohydrolase (EC 3.2.1.58) from the culture filtrate of Basidiomycete QM806 is described. The final preparation is homogeneous by disc electrophoresis under non-dissociating and denaturing conditions, by ultracentrifugation, and by isoelectric focusing. Various physical and chemical characteristics of the enzyme have been determined, including terminal amino acid residues, extinction coefficient, and stability to pH extremes. The N-terminal amino acids are leucine and serine (Sanger's method) and the C-terminal amino acids are alanine, serine, and glycine (hydrazinolysis). pH profile studies show that no group titrating in the region 2.5-8 is directly involved with substrate binding and that a single group having a pKa of 6.5 is involved in the catalysis. Photooxidation of the enzyme caused rapid inactivation. The pH-dependence of this photooxidation, and amino acid analysis of the photooxidized enzyme, indicate that decomposition of histidine is probably responsible for the loss of activity. Other chemical modifications performed were: treatment with hydrogen peroxide under acidic conditions, esterification with diphenyldiazomethane, and oxidation with N-bromosuccinimide. Oxidation with N-bromosuccinimide indicated that a tryptophan side-chain is involved in, but not necessary for, the catalytic activity.

Initial velocity and product inhibition studies were carried out on UDP-glucose dehydrogenase (UDPglucose: NAD+ 6-oxidoreductase, EC 1.1.1.22) from beef liver to determine if the kinetics of the reaction are compatible with the established mechanism. An intersecting initial velocity pattern was observed with NAD+ as the variable substrate and UDPG as the changing fixed substrate. UDPglucuronic acid gave competitive inhibition of UDPG and non-competitive inhibition of NAD+. Inhibition by NADH gave complex patterns.Lineweaver-Burk plots of 1/upsilon versus 1/NAD+ at varied levels of NADH gave highly non-linear curves. At levels of NAD+ below 0.05 mM, non-competitive inhibition patterns were observed giving parabolic curves. Extrapolation to saturation with NAD+ showed NADH gave linear uncompetitive inhibition of UDPG if NAD+ was saturating. However, at levels of NAD+ above 0.10 mM, NADH became a competitive inhibitor of NAD+ (parabolic curves) and when NAD+ was saturating NADH gave no inhibition of UDPG. NADH was non-competitive versus UDPG when NAD+ was not saturating. These results are compatible with a mechanism in which UDPG binds first, followed by NAD+, which is reduced and released. A second mol of NAD+ is then bound, reduced, and released. The irreversible step in the reaction must occur after the release of the second mol of NADH but before the release of UDPglucuronic acid. This is apparently caused by the hydrolysis of a thiol ester between UDPglucoronic acid and the essential thiol group of the enzyme. Examination of rate equations indicated that this hydrolysis is the rate-limiting step in the overall reaction. The discontinuity in the velocities observed at high NAD+ concentrations is apparently caused by the binding of NAD+ in the active site after the release of the second mol of NADH, eliminating the NADH inhibition when NAD+ becomes saturating.