Screening for pompe disease using a rapid dried blood spot method: Experience of a clinical diagnostic laboratory

Pompe disease (acid maltase deficiency; glycogen storage disease type II) is caused by deficiency of the lysosomal enzyme acid alpha‐glucosidase (GAA). Our clinical laboratory began to offer a fluorometric dried blood spot (DBS)‐based GAA activity assay for Pompe disease in 2006 after the FDA approved GAA enzyme replacement therapy in April of that year. The purpose of this study was to examine the experience of our clinical laboratory in using this assay. Over a 2‐year period, we received samples for the DBS GAA assay from 891 patients referred for possible Pompe disease, of whom 111 (12.5%) patients across the disease spectrum who had results in the affected range. The majority of the patients were referred by neurologists and geneticists. When available, we correlated the results obtained through DBS GAA activity assay with the results from a second DBS, or a second tissue (cultured skin fibroblasts or muscle biopsy). In our experience, the DBS GAA activity assay provides a robust, rapid, and reliable first tier test for screening patients suspected of having Pompe disease. Muscle Nerve 40: 32–36, 2009     

Associations between betel nut (Areca catechu) and symptoms of schizophrenia among patients in Nepal: A longitudinal study

Betel nut is one of the mostly widely used substances in the world, particularly across Asia. Arecoline, a partial muscarinic agonist, has been hypothesized to have beneficial effects on both positive and negative symptoms of schizophrenia. This study aims to further explore associations between betel use and symptoms of schizophrenia in a 4-month longitudinal study in Nepal. Sixty Nepali patients with schizophrenia were recruited from regional outpatient clinics. The Positive and Negative Syndrome Scale (PANSS) and the Social Adaptation Self-Evaluation Scale were used to assess symptoms and social functioning in regular betel users and non-users. No significant group differences or dose–response relationships were noted on either initial or follow-up assessments. Stratifying by sex also failed to reveal an association between symptoms and betel use, which stands in contrast with previously reported data from Micronesia. There were no differences seen in social functioning other than a significantly higher proportion of betel users holding jobs. It was also noted that significantly fewer betel chewers were taking anti-cholinergic medication, which may tentatively indicate a potentially therapeutic role in the future for partial muscarinic agonists in the treatment of medication-induced movement disorders.     

Eye-pursuit and reafferent head movement signals carried by pursuit neurons in the caudal part of the frontal eye fields during head-free pursuit

Eye and head movements are coordinated during head-free pursuit. To examine whether pursuit neurons in frontal eye fields (FEF) carry gaze-pursuit commands that drive both eye-pursuit and head-pursuit, monkeys whose heads were free to rotate about a vertical axis were trained to pursue a juice feeder with their head and a target with their eyes. Initially the feeder and target moved synchronously with the same visual angle. FEF neurons responding to this gaze-pursuit were tested for eye-pursuit of target motion while the feeder was stationary and for head-pursuit while the target was stationary. The majority of pursuit neurons exhibited modulation during head-pursuit, but their preferred directions during eye-pursuit and head-pursuit were different. Although peak modulation occurred during head movements, the onset of discharge usually was not aligned with the head movement onset. The minority of neurons whose discharge onset was so aligned discharged after the head movement onset. These results do not support the idea that the head-pursuit-related modulation reflects head-pursuit commands. Furthermore, modulation similar to that during head-pursuit was obtained by passive head rotation on stationary trunk. Our results suggest that FEF pursuit neurons issue gaze or eye movement commands during gaze-pursuit and that the head-pursuit-related modulation primarily reflects reafferent signals resulting from head movements.     

Bone Disease in Thalassemia: A Frequent and Still Unresolved Problem

Adults with β thalassemia major frequently have low BMD, fractures, and bone pain. The purpose of this study was to determine the prevalence of low BMD, fractures, and bone pain in all thalassemia syndromes in childhood, adolescence, and adulthood, associations of BMD with fractures and bone pain, and etiology of bone disease in thalassemia. Patients of all thalassemia syndromes in the Thalassemia Clinical Research Network, ≥6 yr of age, with no preexisting medical condition affecting bone mass or requiring steroids, participated. We measured spine and femur BMD and whole body BMC by DXA and assessed vertebral abnormalities by morphometric X‐ray absorptiometry (MXA). Medical history by interview and review of medical records, physical examinations, and blood and urine collections were performed. Three hundred sixty‐one subjects, 49% male, with a mean age of 23.2 yr (range, 6.1–75 yr), were studied. Spine and femur BMD Z‐scores < ?2 occurred in 46% and 25% of participants, respectively. Greater age, lower weight, hypogonadism, and increased bone turnover were strong independent predictors of low bone mass regardless of thalassemia syndrome. Peak bone mass was suboptimal. Thirty‐six percent of patients had a history of fractures, and 34% reported bone pain. BMD was negatively associated with fractures but not with bone pain. Nine percent of participants had uniformly decreased height of several vertebrae by MXA, which was associated with the use of iron chelator deferoxamine before 6 yr of age. In patients with thalassemia, low BMD and fractures occur frequently and independently of the particular syndrome. Peak bone mass is suboptimal. Low BMD is associated with hypogonadism, increased bone turnover, and an increased risk for fractures.     

Idd loci synergize to prolong islet allograft survival induced by costimulation blockade in NOD mice

OBJECTIVE—NOD mice model human type 1 diabetes and are used to investigate tolerance induction protocols for islet transplantation in a setting of autoimmunity. However, costimulation blockade–based tolerance protocols have failed in prolonging islet allograft survival in NOD mice.RESEARCH DESIGN AND METHODS—To investigate the underlying mechanisms, we studied the ability of costimulation blockade to prolong islet allograft survival in congenic NOD mice bearing insulin-dependent diabetes (Idd) loci that reduce the frequency of diabetes.RESULTS—The frequency of diabetes is reduced in NOD.B6 Idd3 mice and is virtually absent in NOD.B6/B10 Idd3 Idd5 mice. Islet allograft survival in NOD.B6 Idd3 mice treated with costimulation blockade is prolonged compared with NOD mice, and in NOD.B6/B10 Idd3 Idd5, mice islet allograft survival is similar to that achieved in C57BL/6 mice. Conversely, some Idd loci were not beneficial for the induction of transplantation tolerance. Alloreactive CD8 T-cell depletion in (NOD × CBA)F1 mice treated with costimulation blockade was impaired compared with similarly treated (C57BL/6.H2^g7 × CBA)F1 mice. Injection of exogenous interleukin (IL)-2 into NOD mice treated with costimulation prolonged islet allograft survival. NOD.B6 Idd3 mice treated with costimulation blockade deleted alloreactive CD8 T-cells and exhibited prolonged islet allograft survival.CONCLUSIONS—Il2 is the Idd3 diabetes susceptibility gene and can influence the outcome of T-cell deletion and islet allograft survival in mice treated with costimulation blockade. These data suggest that Idd loci can facilitate induction of transplantation tolerance by costimulation blockade and that IL-2/Idd3 is a critical component in this process.The NOD mouse is a model of type 1–like autoimmune diabetes and is used to study costimulation blockade–based transplantation tolerance within the context of autoimmunity (1–4). However, costimulation blockade protocols fail in NOD mice. To investigate further the cellular and genetic control of costimulation blockade–induced transplantation tolerance, we used NOD Idd congenic mice that have small introgressed regions of genetic intervals derived from diabetes-resistant C57 stocks. These mice exhibit varying degrees of protection from autoantibodies, insulitis, and diabetes (5). Using Idd congenic NOD mice, we have observed that islet allograft survival is improved by the addition of the diabetes-protective Idd3 locus (6,7).Idd3 modulates infiltration of autoreactive lymphocytes into the islets (8), and there is compelling evidence that Idd3 is the interleukin (IL)-2 gene (9). In vivo stimulated NOD T-cells produce twofold less IL-2 mRNA than cells from NOD congenic mice having protective alleles at Idd3 (9,10). Neutralizing antibodies to IL-2 lead to accelerated disease in NOD mice (11), and targeted genetic disruption of IL-2 accelerates type 1–like autoimmune diabetes (9). Treatment with exogenous IL-2 inhibits diabetes development in NOD mice and improves T regulatory (Treg) function (12). IL-2 is also known to have a nonredundant role in CD8 T-cell activation–induced cell death via the CD95 (Fas) pathway (13), is required for the development of self-tolerance (14), and is essential for the induction of allograft tolerance by costimulation blockade (15). However, IL-2 is a double-edged sword, since administration of IL-2 in vivo can either enhance or depress a cytotoxic T lymphocyte (CTL) response (16).In this study, we show that costimulation blockade fails to delete alloreactive CD8 T-cells in NOD mice. Genetic replacement of IL-2 in NOD.B6 Idd3 mice enhances alloreactive CD8 T-cell deletion and improves islet allograft survival. Finally, we show that Idd3 synergizes with genes within the Idd5 interval, leading to permanent islet allograft survival in a majority of NOD.B6/B10 Idd3 Idd5 mice treated with costimulation blockade.     

The neurophysiological bases of emotion: An fMRI study of the affective circumplex using emotion-denoting words

Objective: We aimed to study the neural processing of emotion‐denoting words based on a circumplex model of affect, which posits that all emotions can be described as a linear combination of two neurophysiological dimensions, valence and arousal. Based on the circumplex model, we predicted a linear relationship between neural activity and incremental changes in these two affective dimensions. Methods: Using functional magnetic resonance imaging, we assessed in 10 subjects the correlations of BOLD (blood oxygen level dependent) signal with ratings of valence and arousal during the presentation of emotion‐denoting words. Results: Valence ratings correlated positively with neural activity in the left insular cortex and inversely with neural activity in the right dorsolateral prefrontal and precuneus cortices. The absolute value of valence ratings (reflecting the positive and negative extremes of valence) correlated positively with neural activity in the left dorsolateral and medial prefrontal cortex (PFC), dorsal anterior cingulate cortex, posterior cingulate cortex, and right dorsal PFC, and inversely with neural activity in the left medial temporal cortex and right amygdala. Arousal ratings and neural activity correlated positively in the left parahippocampus and dorsal anterior cingulate cortex, and inversely in the left dorsolateral PFC and dorsal cerebellum. Conclusion: We found evidence for two neural networks subserving the affective dimensions of valence and arousal. These findings clarify inconsistencies from prior imaging studies of affect by suggesting that two underlying neurophysiological systems, valence and arousal, may subserve the processing of affective stimuli, consistent with the circumplex model of affect. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.     

Do beliefs about HIV treatments affect peer norms and risky sexual behaviour among African-American men who have sex with men?

We examined the association between perceptions about condom use among one's peers, beliefs about new HIV treatments, and HIV sexual risk behaviour among 849 young African-American men who have sex with men (MSM). Participants were randomly recruited from and anonymously interviewed in community venues in Atlanta, Georgia, USA, in cross-sectional samples between 1999 and 2002. Data analyses indicated that 30% of the sample reported unprotected anal intercourse in the past three months; stronger peer condom norms predicted less-frequent risky sexual behaviour. However, the belief in less threat of HIV because of HIV treatments was not associated with either risky sexual behaviour or peer norms, and peer norms did not mediate the association between HIV treatment beliefs and unprotected anal intercourse. These findings suggest that changing peer norms for condom use may reduce HIV risky sex in African-American MSM, regardless of their beliefs about HIV drug treatments.     

The risk of valve surgery for endocarditis in patients with dialysis-dependent renal failure

BACKGROUND AND AIM OF THE STUDY: Valvular endocarditis occurring in patients with dialysis-dependent renal failure increases the risk of mortality following valve surgery, but few specific data are available to guide surgical selection. The study aim was to develop a simple risk scoring system to identify high-risk dialysis patients undergoing valve surgery for endocarditis. METHODS: Using STS data from between January 1994 and December 2003, a total of 1,862 valvular procedures was recorded in dialysis patients with endocarditis. Isolated mitral procedures were performed in 718 patients, isolated aortic in 656, double valves in 386, isolated tricuspid in 55, and triple valves in 47. Logistic regression analysis was performed relating baseline variables to hospital mortality. Points were assigned to each significant risk factor by rounding regression coefficients to integers. An estimate of risk was obtained for each patient by averaging the predicted mortality among all patients having the same number of total points. RESULTS: In the logistic regression, significant variables (all p < 0.001) and effect estimates (odds ratios; points) were: cardiogenic shock or salvage status (2.77; 3), double valve (2.37; 3), age > or = 60 years (2.02; 2), isolated mitral valve (1.89; 2), body surface area > 2.1 m2 (1.86; 2), arrhythmia (1.56; 1), active endocarditis (1.54; 1), and female gender (1.53; 1), with a C-statistic of 0.705. Mortality increased exponentially as a function of points, with operative mortality exceeding 70% at 10 points. CONCLUSION: The risk of mortality for dialysis patients having valve surgery for endocarditis is high, yet depends on a variety of factors. The proposed risk scoring system successfully discriminates between higher and lower risk patients, and could contribute to better decision making.     

Implicit integration in a case of integrative visual agnosia

We present a case (SE) with integrative visual agnosia following ischemic stroke affecting the right dorsal and the left ventral pathways of the visual system. Despite his inability to identify global hierarchical letters [Navon, D. (1977). Forest before trees: The precedence of global features in visual perception. Cognitive Psychology, 9, 353-383], and his dense object agnosia, SE showed normal global-to-local interference when responding to local letters in Navon hierarchical stimuli and significant picture-word identity priming in a semantic decision task for words. Since priming was absent if these features were scrambled, it stands to reason that these effects were not due to priming by distinctive features. The contrast between priming effects induced by coherent and scrambled stimuli is consistent with implicit but not explicit integration of features into a unified whole. We went on to show that possible/impossible object decisions were facilitated by words in a word-picture priming task, suggesting that prompts could activate perceptually integrated images in a backward fashion. We conclude that the absence of SE's ability to identify visual objects except through tedious serial construction reflects a deficit in accessing an integrated visual representation through bottom-up visual processing alone. However, top-down generated images can help activate these visual representations through semantic links.