Web-based training intervention to increase physical activity level and improve health for adults with intellectual disability.

BACKGROUND: Individuals with intellectual disability (ID) are less physically active, have a higher body mass index (BMI) and are at greater risk for cardiovascular diseases (CVDs) than people without ID. The purpose of the study was to explore the effectiveness of a web-based training programme, consisting of 150 min of activity per week, on the health of people with ID. METHOD: Participants with ID living in supported accommodation (n = 28, 48% female, age = 36.4 ± 9.56 years) participated in a web-based training programme, consisting of a combination of exercises (endurance, strength balance and flexibility) of moderate intensity, 50 min, three times per week for 12 weeks. The body composition and waist circumference (WC) were measured, and questionnaires were used to assess enjoyment, quality of life (QoL) and physical activity (PA) level. Descriptive statistics and pairwise comparison pre and post intervention were carried out. RESULTS: A total of 22 out of 28 participants completed the 12-week training intervention with 83% mean attendance of training sessions. The intensity of the PA level increased and a decrease in fat mass of 1.9 ± 2.4 kg, P < 0.001 and WC of 3 ± 5 cm, P = 0.009 were observed. Enjoyment of training sessions was 3.9 out of 5, and no differences in QoL were found. CONCLUSION: A web-based training programme is an effective tool for improving health parameters of people with ID and offers a new way for caregivers to enhance the PA for the target group.

Sitting position affects performance in cross-country sit-skiing.

PURPOSE: In cross-country sit-skiing (XCSS), athletes with reduced trunk control predominantly sit with the knees higher than the hips (KH); a position often associated with large spinal flexion. Therefore, to improve spinal curvature a new sledge with frontal trunk support, where knees are lower than hips (KL) was created. It was hypothesized that the KL position would improve respiratory function and enhance performance in seated double-poling compared to KH. METHODS: Ten female able-bodied cross-country skiers (age 25.5 ± 3.8 years, height 1.65 ± 0.05 m, mass 61.1 ± 6.8 kg) completed a 30 s all-out test (WIN), a submaximal incremental test including 3-7 3 min loads (SUB) and a maximal 3 min time trial (MAX) in both KL and KH positions. During SUB and MAX external power, pole forces, surface electromyography, and kinematics were measured. Metabolic rates were calculated from oxygen consumption and blood lactate concentrations. RESULTS: KL reduced spinal flexion and range of motion at the hip joint and indicated more muscle activation in the triceps. Performance (W kg−1) was impeded in both WIN (KH 1.40 ± 0.30 vs. KL 1.13 ± 0.33, p < 0.01) and MAX (KH 0.88 ± 0.19 vs. KL 0.67 ± 0.14, p < 0.01). KH resulted in lower lactate concentration, anaerobic metabolic rate, and minute ventilation for equal power output [corrected]. CONCLUSIONS: The new KL position can be recommended due to improved respiratory function but may impede performance. Generalization of results to XCSS athletes with reduced trunk muscle control may be limited, but these results can serve as a control for future studies of para-athletes.

Long-term effects of a lumbosacral ventral root avulsion injury on axotomized motor neurons and avulsed ventral roots in a non-human primate model of cauda equina injury.

Here, we have translated from the rat to the non-human primate a unilateral lumbosacral injury as a model for cauda equina injury. In this morphological study, we have investigated retrograde effects of a unilateral L6-S2 ventral root avulsion (VRA) injury as well as the long-term effects of Wallerian degeneration on avulsed ventral roots at 6-10 months post-operatively in four adult male rhesus monkeys. Immunohistochemistry for choline acetyl transferase and glial fibrillary acidic protein demonstrated a significant loss of the majority of the axotomized motoneurons in the affected L6-S2 segments and signs of an associated astrocytic glial response within the ventral horn of the L6 and S1 spinal cord segments. Quantitative analysis of the avulsed ventral roots showed that they exhibited normal size and were populated by a normal number of myelinated axons. However, the myelinated axons in the avulsed ventral roots were markedly smaller in caliber compared to the fibers of the intact contralateral ventral roots, which served as controls. Ultrastructural studies confirmed the presence of small myelinated axons and a population of unmyelinated axons within the avulsed roots. In addition, collagen fibers were readily identified within the endoneurium of the avulsed roots. In summary, a lumbosacral VRA injury resulted in retrograde motoneuron loss and astrocytic glial activation in the ventral horn. Surprisingly, the Wallerian degeneration of motor axons in the avulsed ventral roots was followed by a repopulation of the avulsed roots by small myelinated and unmyelinated fibers. We speculate that the small axons may represent sprouting or axonal regeneration by primary afferents or autonomic fibers.

Myopathies associated with ß-tropomyosin mutations.

Mutations in TPM2, encoding ß-tropomyosin, have recently been found to cause a range of muscle disorders. We review the clinical and morphological expression of the previously reported mutations illustrating the heterogeneity of ß-tropomyosin-associated diseases and describe an additional case with a novel mutation. The manifestations of mutations in TPM2 include non-specific congenital myopathy with type 1 fibre predominance, nemaline myopathy, cap disease and distal arthrogryposis. In addition, Escobar syndrome with nemaline myopathy is a manifestation of homozygous truncating ß-tropomyosin mutation. Cap disease appears to be the most common morphological manifestation. A coarse intermyofibrillar network and jagged Z lines are additional frequent changes. The dominant ß-tropomyosin mutations manifest either as congenital myopathy or distal arthrogryposis. The various congenital myopathies are usually associated with moderate muscle weakness and no congenital joint contractures. The distal arthrogryposis syndromes associated with TPM2 mutations include the less severe forms, with congenital contractures mainly of the hands and feet and mild or no muscle weakness. The dominant TPM2 mutations include amino acid deletions/insertions and missense mutations. There is no clear relation between the type of mutations or the localisation of the mutated residue in the ß-tropomyosin molecule and the clinical and morphological phenotype.

New morphologic and genetic findings in cap disease associated with beta-tropomyosin (TPM2) mutations.

OBJECTIVE: Mutations in the beta-tropomyosin gene (TPM2) are a rare cause of congenital myopathies with features of nemaline myopathy and cap disease and may also cause distal arthrogryposis syndromes without major muscle pathology. We describe the muscle biopsy findings in three patients with cap disease and novel heterozygous mutations in TPM2. METHODS: Three unrelated patients with congenital myopathy were investigated by muscle biopsy and genetic analysis. RESULTS: All three patients had early-onset muscle weakness of variable severity and distribution. Muscle biopsy demonstrated in all three patients near uniformity of type 1 fibers and an unusual irregular and coarse-meshed intermyofibrillar network. By electron microscopy, the myofibrils were broad and partly split, and the Z lines appeared jagged. In one of the patients caps structures were identified only by electron microscopy, and in one patient they were identified only in a second biopsy at adulthood. Three novel, de novo, heterozygous mutations in TPM2 were identified: a three-base pair deletion in-frame (p.Lys49del), a three-base pair duplication in-frame (p.Gly52dup), and a missense mutation (p.Asn202Lys). CONCLUSIONS: Mutations in TPM2 seem to be a frequent cause of cap disease. Because cap structures may be sparse, other prominent features, such as a coarse-meshed intermyofibrillar network and jagged Z lines, may be clues to correct diagnosis and also indicate that the pathogenesis involves defective assembly of myofilaments.

Glial reactions and degeneration of myelinated processes in spinal cord gray matter in chronic experimental autoimmune encephalomyelitis.

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) result in inflammatory white matter lesions in the CNS. However, information is sparse with regard to the effects of autoimmune demyelinating disease on gray matter regions. Therefore, we studied the late effects of chronic EAE in C57BL/6 mice on the spinal cord gray matter using immunohistochemistry. Here, EAE induced marked astrocytic, microglial, and macrophage activation in the ventral horn gray matter, without any motoneuron loss. Activated caspase-3 was also increased in the ventral horn gray matter. Furthermore, activated poly (ADP-ribose) polymerase (PARP), another apoptotic marker, co-localized with myelin basic protein (MBP) of oligodendrocyte processes, but not with the oligodendroglial cell body marker, adenomatous polyposis coli gene clone CC1 (APC-CC1), or with neurofilament marker (RT-97) or synaptophysin of axonal arbors. However, there was no associated increase in the number of terminal deoxynucleotidyl transferase (TdT) mediated-dUTP nick end labeling positive nuclei in the spinal cord gray matter of EAE mice. In addition, co-localization of MBP and the low-affinity neurotrophin receptor, p75, was demonstrated, further supporting the notion of apoptotic oligodendrocyte process degeneration in the gray matter of EAE mice.

Mitochondrial abnormalities in inclusion-body myositis.

Mitochondrial changes are frequently encountered in sporadic inclusion-body myositis (s-IBM). Cytochrome c oxidase (COX)-deficient muscle fibers and large-scale mitochondrial DNA (mtDNA) deletions are more frequent in s-IBM than in age-matched controls. COX deficient muscle fibers are due to clonal expansion of mtDNA deletions and point mutations in segments of muscle fibers. Such segments range from 75 microm to more than 1,000 microm in length. Clonal expansion of the 4977 bp "common deletion" is a frequent cause of COX deficient muscle fiber segments, but many other deletions also occur. The deletion breakpoints cluster in a few regions that are similar to what is found in human mtDNA deletions in general. Analysis in s-IBM patients of three nuclear genes associated with multiple mtDNA deletions, POLG1, ANT1 and C10orf2, failed to demonstrate any mutations. In s-IBM patients with high number of COX-deficient fibers, the impaired mitochondrial function probably contribute to muscle weakness and wasting. Treatment that has positive effects in mitochondrial myopathies may be tried also in s-IBM.

Neuronal survival and glial reactions after recurrent laryngeal nerve resection in the rat.

OBJECTIVES/HYPOTHESIS: Complete axonal injury to the recurrent laryngeal nerve (RLN) leads to permanent loss of coordinated function of the intrinsic muscles of the larynx. The aim of the present study was to investigate retrograde reactions, neuronal survival, and glial reactions in the nucleus ambiguus after a distal resection of the RLN to evaluate the potential need for neuroprotective substances. STUDY DESIGN AND METHODS: A segment of the left RLN was resected in 31 adult rats. Before sacrifice of the animals at 2 to 28 days postlesion, the motor neurons in the nucleus ambiguus were retrogradely traced by the use of Fluorogold. Brainstems were isolated and processed for neuron quantification and immunohistochemical analysis. Neuron counts were performed in the nucleus ambiguus on serial sections. Glial reactions were investigated in the nucleus ambiguus using immunohistochemistry. RESULTS: No decrease in the number of motor neurons in the nucleus ambiguus could be demonstrated up to 1 month postlesion. Astroglia and microglia showed increased immunoreactivity at 7 to 14 days postinjury, followed by a slight decline in glial reaction. Microglia revealed no signs of transformation into macrophages during the study period, further indicating the absence of neuronal loss. CONCLUSIONS: Neuronal death does not occur within 1 month postlesion as a result of resection of the RLN in the adult rat, and neuroprotective substances should therefore be of minor value after RLN injury. Glial reactions appear in a similar fashion as after other peripheral nerve lesions not causing neuronal loss.

Follow-up of nemaline myopathy in two patients with novel mutations in the skeletal muscle alpha-actin gene (ACTA1).

Nemaline myopathy has been associated with mutations in five different genes, which all encode protein components of the sarcomeric thin filaments. We report follow-up studies in two children with mutations not previously described in skeletal muscle alpha-actin (ACTA1). Case 1 was a male patient who after birth suffered from pronounced muscle weakness and hypotonia. Muscle biopsy showed small fibers with numerous rods. He failed to achieve any motor milestones. At the age of 17 he required 24 h ventilator support. He could not lift his arms against gravity, but he could use his hands to control his electric wheelchair. The muscle biopsy showed marked replacement of muscle tissue by fat and connective tissue. Only few fibers showed nemaline rods. He had a de novo, heterozygous mutation, G268D in ACTA1. Case 2 was a female patient with feeding difficulties and mild hypotonia in the neonatal period. Muscle biopsy showed hypoplastic muscle fibers and numerous rods. At 11 years of age she walked and moved unhindered and could run fairly well. She had a de novo, heterozygous mutation, K373E, in ACTA1. These two patients illustrate the marked variability in the clinical features of nemaline myopathy in spite of similar muscle pathology in early childhood. The severe muscle atrophy with replacement of fat and connective tissue in case 1 demonstrates the progressive nature of nemaline myopathy in some cases. The described two mutations add to the previously reported mutations in ACTA1 associated with nemaline myopathy.

CD40, CD154, Bax and Bcl-2 expression in Sjögren's syndrome salivary glands: a putative anti-apoptotic role during its effector phases.

Sjögren's syndrome (SS) is an autoimmune rheumatic disorder characterized by chronic lymphocytic infiltration and decreased secretion in the salivary glands (SGs). For some time, apoptosis has been suggested to constitute the major mechanism for acinar epithelial destruction during the effector phases; however, this is still controversial. We have recently demonstrated that despite the expression of Fas and FasL, the incidence of apoptosis is not increased in SS patients compared with control individuals. Our aim was therefore to further evaluate the expression of the pro- and anti-apoptotic Bax and Bcl-2 proteins. CD40 and CD154 expression was also investigated, as CD40 ligation has been suggested to protect cells from Fas-mediated apoptosis. Immunohistochemical staining was performed on SG tissue from primary and secondary SS patients, a group of patients with non-SS-related degenerative changes as well as on healthy control individuals. The frequency of stained cells in the foci of infiltrating mononuclear cells (IMCs) and in the acinar and ductal epithelium was determined. We found the expression of Bcl-2 but rarely Bax in SS SG IMCs. Bcl-2 in epithelial cells was sparse, while Bax expression occurred frequently and with no significant difference between the patient groups. CD40 and CD154 expression was high among SS IMCs, while CD40 levels were slightly decreased in SS epithelium compared with controls. Elevated CD154 expression was found in SS epithelium, being significantly increased in the ducts. In conclusion, our study further supports the hypothesis about apoptosis resistance among SS focal IMCs and suggests a putative protective role of CD40 ligation in SS SG epithelium.

Subcellular redistribution and surface exposure of the Ro52, Ro60 and La48 autoantigens during apoptosis in human ductal epithelial cells: a possible mechanism in the pathogenesis of Sjögren's syndrome.

The Ro52, Ro60 and La48 autoantigens are associated with Sjögren's syndrome (SS) and systemic lupus erythematosus (SLE). The mechanisms behind tolerance breakdown of these self-peptides remain unclear; however, apoptosis has been proposed to cause their presentation to the immune system. We have examined the localization of transiently expressed enhanced green fluorescent protein (EGFP)-tagged Ro52, Ro60 and La48 autoantigens in a human salivary gland (HSG) cell line by laser confocal microscopy under normal growth conditions and during apoptosis. Surface exposure of Ro52, Ro60 and La48 was demonstrated on nonfixed apoptotic cells with monoclonal antibodies (MoAbs) or with primary SS patient antisera. Laser scanning cytometry determined the apoptotic frequency. EGFP alone was studied as control. We found that Ro52 mainly is cytoplasmic, Ro60 both nuclear and cytoplasmic, while La48 only resides in the nucleus under normal conditions. During early apoptosis, La48 is dramatically redistributed to the cytoplasm, while the localization of Ro52 and Ro60 is maintained. All three autoantigens filled apoptotic blebs and covered TUNEL (terminal-deoxynucleotidyl-transferase-mediated dUTP-digoxigenin nick end labelling)-positive apoptotic bodies. Identical results were obtained in COS-7 cells. We have developed a transfection system to study the intracellular localization of the three autoantigens Ro52, Ro60 and La48, without antibody detection. During apoptosis, there is an intracellular redistribution of endogenous and EGFP-tagged Ro52, Ro60 and La48, leading to surface exposure. These findings may indicate a role for apoptosis in the induction and facilitation of humoral responses to Ro52, Ro60 and La48 in the autoimmune exocrinopathy of SS.

T cell proliferation and apoptosis in HIV-1-infected lymphoid tissue: impact of highly active antiretroviral therapy.

T cell turnover was studied in situ in tonsillar lymphoid tissue (LT) from HIV-1-infected individuals during 48 weeks of highly active antiretroviral therapy (HAART) and compared to that of HIV-1-negative controls. Prior to therapy, CD4 cell proliferation (%CD4+ Ki67+) and apoptosis (%CD4+ TUNEL+) were increased in HIV-1-infected LT and both parameters correlated with tonsillar viral load. CD8 cell proliferation (%CD8+ Ki67+) was increased 4- to 10-fold, mainly in the germinal centers. Apoptotic CD8+ T cell levels (%CD8+ TUNEL+) were raised preferentially in the tonsillar T cell zone. The frequency of CD8+ Ki67+ and CD8+ TUNEL+ T cells correlated with tonsillar viral load and with the fraction of CD8(+) T cells expressing activation markers. During HAART, CD4 cell turnover normalized while CD8 cell turnover was dramatically reduced. However, low level viral replication concomitant with slightly elevated levels of CD8 cell turnover indicated a persistent cellular immune response in LT. In conclusion, enhanced T cell turnover may reflect effector cells related to HIV-1 infection.

The optimal reference population for cardiac normality in myocardial SPET in the detection of coronary artery stenoses: patients with normal coronary angiography or subjects with low likelihood of coronary artery disease?

Both subjects with a low likelihood for coronary artery disease (CAD) and patients with normal findings on coronary angiography have been used as reference populations in non-invasive stress testing, including myocardial perfusion scintigraphy. Both of these criteria of normality--low likelihood of CAD and normal coronary angiography--have been criticised, and consensus on this issue is lacking. The aim of this study was to compare two different reference populations by testing the performance of artificial neural networks designed to interpret myocardial scintigrams. The networks were trained on myocardial perfusion scintigrams from 87 patients with angiographically documented CAD and on studies from one of two different reference groups: 48 patients with no signs of CAD based on angiography or 128 healthy volunteers with a likelihood for CAD <5%. The performance of the two different networks was then tested using scintigrams from a separate test group of 68 patients. Coronary angiography was used as the gold standard in this group. The network trained on patients with no signs of CAD based on angiography showed an area under the receiver operating characteristic (ROC) curve of 93%. The ROC area for the network trained on healthy volunteers was 72%, and this difference was statistically significant (P=0.03). The results of this study using artificial neural networks suggest that normal angiography should be preferred as the reference standard in myocardial scintigraphy when a patient is examined for CAD prior to possible angiography. Whether the same is true for other indications, e.g. in prognostic evaluation, is unknown.

Usefulness of serial electrocardiograms for diagnosis of acute myocardial infarction.

The purpose of this study was to determine whether the automated detection of acute myocardial infarction (AMI) by utilizing artificial neural networks was improved by using a previous electrocardiogram (ECG) in addition to the current ECG. A total of 4,691 ECGs were recorded from patients admitted to an emergency department due to suspected AMI. Of these, 902 ECGs, in which diagnoses of AMI were later confirmed, formed the study group, whereas the remaining 3,789 ECGS comprised the control group. For each ECG recorded, a previous ECG of the same patient was selected from the clinical electrocardiographic database. Artificial neural networks were then programmed to detect AMI based on either the current ECG only or on the combination of the previous and the current ECGs. On this basis, 3 assessors--a neural network, an experienced cardiologist, and an intern--separately classified the ECGs of the test group, with and without access to the previous ECG. The detection performance, as measured by the area under the receiver operating characteristic curve, showed an increase for all assessors with access to previous ECGs. The neural network improved from 0.85 to 0.88 (p = 0.02), the cardiologist from 0.79 to 0.81 (p = 0.36), and the intern from 0.71 to 0.78 (p <0.001). Thus, the performance of a neural network, detecting AMI in an ECG, is improved when a previous ECG is used as an additional input.

Maintained CD40 and loss of polarised CD40 ligand expression in oral squamous cell carcinoma.

BACKGROUND: CD40 and its ligand (CD40L) are involved in immune response and inhibition or induction of apoptosis in different tissues. Little is known about CD40 and CD40L in oral squamous cell carcinomas (OSCC). MATERIALS AND METHODS: CD40 and CD40L were immunohistochemically evaluated in fresh-frozen samples of OSCC (n = 24) and normal oral epithelium (OE, n = 10). RESULTS: A high proportion of OE-cells expressed CD40 (> 80%) and CD40L (> 90%) in the basal compartment compared to less than 1% CD40-positive and 1% CD40L-positive cells in the suprabasal cell layer, reflecting a zonal distribution. In well-differentiated and moderately-differentiated OSCC, there was a less pronounced zonal distribution of CD40 and a marked loss of CD40L compared to OE (p < 0.05). Poorly-differentiated OSCC maintained CD40 and markedly lost CD40L compared to OE (p < 0.05). Double immunostaining for CD40L and laminin in OE showed a basement membrane associated localisation of CD40L. CONCLUSION: In OSCC, loss of polarised expression of CD40L and maintained expression of CD40 might be involved in tumourigenesis and immune evasion.

An independent evaluation of a new method for automated interpretation of lung scintigrams using artificial neural networks.

The purpose of this study was to evaluate a new automated method for the interpretation of lung perfusion scintigrams using patients from a hospital other than that where the method was developed, and then to compare the performance of the technique against that of experienced physicians. A total of 1,087 scintigrams from patients with suspected pulmonary embolism comprised the training group. The test group consisted of scintigrams from 140 patients collected in a hospital different to that from which the training group had been drawn. An artificial neural network was trained using 18 automatically obtained features from each set of perfusion scintigrams. The image processing techniques included alignment to templates, construction of quotient images based on the perfusion/template images, and finally calculation of features describing segmental perfusion defects in the quotient images. The templates represented lungs of normal size and shape without any pathological changes. The performance of the neural network was compared with that of three experienced physicians who read the same test scintigrams according to the modified PIOPED criteria using, in addition to perfusion images, ventilation images when available and chest radiographs for all patients. Performances were measured as area under the receiver operating characteristic curve. The performance of the neural network evaluated in the test group was 0.88 (95% confidence limits 0.81-0.94). The performance of the three experienced experts was in the range 0.87-0.93 when using the perfusion images, chest radiographs and ventilation images when available. Perfusion scintigrams can be interpreted regarding the diagnosis of pulmonary embolism by the use of an automated method also in a hospital other than that where it was developed. The performance of this method is similar to that of experienced physicians even though the physicians, in addition to perfusion images, also had access to ventilation images for most patients and chest radiographs for all patients. These results show the high potential for the method as a clinical decision support system.

Fas-induced apoptosis is a rare event in Sjögren's syndrome.

The aim of this study was to perform a controlled in situ analysis on the incidence of apoptosis, investigate the expression of apoptosis-mediating proteins, and determine the frequency of apoptotic CD4+ and CD8+ T cells in Sjögren's syndrome (SS). The study was extended to patients with atrophy-fibrosis (AF) not related to SS, as well as to a control group. Immunohistochemistry and the terminal deoxynucleotidyl transferase mediated dUTP digoxigenin nick end labeling (TUNEL) method were applied to study the Fas and FasL expression and the incidence of apoptosis in salivary glands (SG) from patients with primary and secondary SS, AF, and controls. These methods were also combined to enable simultaneous detection of apoptotic and CD4+ or CD8+ T cells. Despite abundant expression of Fas and FasL in SS SG, apoptotic cells were not exceeding 1% in the foci of infiltrating mononuclear cells (IMC). Double staining showed that the frequency of apoptosis was low among both CD4+ and CD8+ T cells. Only a few TUNEL+ epithelial cells were found in all patient groups. Fas was expressed predominantly on SS IMC, single SS epithelial cells, and a few normal acinar cells, but not in AF SG. Although FasL was present on SS and AF IMC and epithelial cells, it was rarely detected in normal tissue. Consequently we demonstrate that Fas-induced apoptosis among SS SG is a rare event. Our findings support an earlier hypothesis indicating that IMC seem to be able to escape apoptosis, resulting in foci of inflammatory cells. Notably, however, no obvious correlation can be drawn to previous studies where a high incidence of apoptosis of epithelial cells was proposed as an important mechanism leading to decreased glandular function, which is a hallmark of SS.