Time Of Clinical Onset Research Articles

1555-P: Novel Imaging Platform Highlights the Disconnect between ß-Cell Mass and Glucose Control in the Onset of Type 1 Diabetes

The age of onset of Type 1 Diabetes (T1D) presents considerable variation from patient to patient. Some become insulin dependent in a just few weeks, while others may take months or years. In either, immune system-β-cell interactions conspire to lead to loss of β-cells and insulin secretion. The molecular and cellular events involved have been the focus of intense research efforts, but most longitudinal studies during the onset of T1D have been limited to biomarkers (circulating autoantibodies, C-peptide⋯), without direct β-cell assessment. Despite data indicating that patients can retain functional β-cells years after the onset of the disease, one school of thought is that there is a precipitous loss of β-cells just preceding the time of clinical onset, triggering the hyperglycemia observed in T1D patients. A counter-view supported by recent studies suggests that insulin secretion is reduced even before β-cell loss. These assessments are traditionally performed through histo-morphometry. The process is time-consuming, prone to errors and costly. Using an NOD line with a SfGFP reporter attached to the C-peptide, we have designed a platform allowing the in toto imaging of β-cell mass in a model of T1D. After a 15-minute IPGTT to capture the peak of insulin secretion, pancreata were harvested and imaged on a cohort of animals at a time of early onset of T1D. A comparison of classical histo-morphometry and in toto imaging revealed a tight correlation between both approaches. Using the new platform allowed the rapid classification of large cohorts of animals based on the β-cell mass and glucose response. The results highlighted a significant disconnect between mass and function in a subset of mice: Some animals presenting near-normal mass while being glucose intolerant while others displaying a drastically reduced mass but still responding normally to a glucose challenge. These findings emphasize the role of islet dysfunction during the onset of T1D even before β-cell death. Disclosure C.Cras-méneur: None. R.J.Seeley: Board Member; Fractyl Health, Inc., Consultant; Novo Nordisk, Eli Lilly and Company, Research Support; Novo Nordisk, Fractyl Health, Inc., AstraZeneca, Eli Lilly and Company. P.Arvan: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases (P30DK020572)

Maturation of nucleus accumbens synaptic transmission signals a critical period for the rescue of social deficits in a mouse model of autism spectrum disorder

Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although social deficits are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J and the idiopathic ASD mouse model BTBR T+Itpr3tf/J at postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. BTBR NAc MSNs display increased spontaneous excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs compared to C57BL/6J mice. BTBR mice also show increased optically evoked medial prefrontal cortex-NAc paired pulse ratios at P15 and P30. These early changes in synaptic transmission are consistent with a potential critical period, which could maximize the efficacy of rescue interventions. To test this, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established intervention for ASD-like behavior. Rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but did not affect social interaction in adulthood.

Temporal and sequence-related variability in diffusion-weighted imaging of presumed cerebrovascular accidents in the dog brain.

Diffusion-weighted MRI (DWI) is often used to guide clinical interpretation of intraparenchymal brain lesions when there is suspicion for a cerebrovascular accident (CVA). Despite widespread evidence that imaging and patient parameters can influence diffusion-weighted measurements, such as apparent diffusion coefficient (ADC), there is little published data on such measurements for naturally occurring CVA in clinical cases in dogs. We describe a series of 22 presumed and confirmed spontaneous canine CVA with known time of clinical onset imaged on a single 3T magnet between 2011 and 2021. Median ADC values of < 1.0x10-3 mm2/s were seen in normal control tissues as well as within CVAs. Absolute and relative ADC values in CVAs were well-correlated (R2 = 0.82). Absolute ADC values < 1.0x10-3 mm2/s prevailed within ischemic CVAs, though there were exceptions, including some lesions of < 5 days age. Some lesions showed reduced absolute but not relative ADC values when compared to matched normal contralateral tissue. CVAs with large hemorrhagic components did not show restricted diffusion. Variation in the DWI sequence used impacted the ADC values obtained. Failure to identify a region of ADC < 1.0x10-3 mm2/s should not exclude CVA from the differential list when clinical suspicion is high.

Inflammation and Vascular Injury as the Basis of COVID-19 Skin Changes: Preliminary Analysis of 23 Patients from the Literature.

BackgroundCOVID-19 can affect various organ systems including the skin. Cutaneous manifestations of COVID-19 in infected patients are poorly characterized.ObjectiveTo summarize retrospectively the skin features of COVID-19 infection and to analyze the skin rash incidence rate, clinical onset time, cutaneous manifestations, pathological characteristics and relationship with the novel coronavirus pneumonia severity.MethodsThe literature up to Sep 20, 2020, were searched and analyzed. Information on clinical features including skin manifestations, disease severity, stage and onset day, and cutaneous pathological characteristics was extracted. Data were analyzed using descriptive non-parametric statistics. For categorical data, the number and percentage of patients are presented. A Spearman correlation test was used to analyze the associations between rash type, rash onset and severity of COVID-19. All statistical analysis was performed with IBM SPSS software (version 20) using two-tailed tests. P values <0.05 were considered statistically significant.ResultsTwenty-three cases of COVID-19 patients with cutaneous manifestations from seven reports were collected. Inflammatory dermatosis, skin vasculitis and vascular dermatosis were the main lesion types of COVID-19 patients. Microvascular and endothelial cell injury, perivascular lymphocytic infiltrate, thrombosis, extremely dilated vessels and prominent deposits of C5b-9 were the main dermatologic pathological changes. The onset day analysis showed that out of 19 patients, 63.2% of cutaneous manifestations were within 10 days, 21.1% in 10–20 days and 15.8% were 20 days after the time the patient presented with COVID-19 main symptoms. Spearman rho analysis found no correlation between skin rash type, onset day and COVID-19 severity.ConclusionCOVID-19 induced skin changes are one of the manifestations of immune responses to the novel coronavirus. Clinical and pathological characteristics were identified as dermal inflammatory reactions and/or skin vascular injury. External or systematic use of anti-inflammatories, protection of blood vessels and circulation-improving medicines should be considered in the skin treatments for novel coronavirus pneumonia patients.

Role of myocardial inflammation and fibrosis in the development of ventricular arrythmias in patients with inflammatory cardiomyopathy (results of 1-year follow-up)

Abstract Background Myocardial inflammatory and fibrotic changes are the most frequent and significant causes of ventricular rhythm disorders that could result in development of life threatening arrythmias and increase the risk of sudden cardiac death, especially in young patients with inflammatory cardiomyopathy (ICM). The purpose – to estimate association of myocardial inflammation and fibrosis with development of ventricular arrythmias in patients with ICM during 12-months of follow-up. Material and methods The study was performed on 70 patients with ICM, average age was (35,2±2,7) years. Initially all patients had cardiomegaly with reduced left ventricular (LV) ejection fraction - &amp;lt;40% and absolute value of longitudinal global systolic strain &amp;lt;9,0%. By 24-hour ECG monitoring we studied frequency of ventricular premature beats (VPB) and incidence of non-sustained ventricular tachycardia (NSVT) paroxysms. All patients underwent for cardiac MRI with evaluation of early T1- and T2-weighted images for the detection of inflammatory changes and T1-weighted delayed images for detection of myocardial fibrosis. Results of cardiac MRI were estimated by Lake Louise criteria and also we performed quantification of segments involved according to standard 17-segment LV model. Initial examination was carried out within the 1st month from the clinical onset of disease and subsequent evaluation of studied parameters was performed after 12 months of follow-up. Results After 12 months of follow-up average frequency of VPB reduced to (1,42±0,14) % from (2,32±0,27) % on initial examination (p&amp;lt;0,01), similarly reduced the incidence of NSVT paroxysms – to 11,4% after 12 months from 28,6% initially. Mean quantity of LV segments, affected by inflammatory process and characterized by presence of edema and/or hyperemia, reduced to (2,12±0,22) segm. after 12 months of follow up from (6,12±0,71) segm. on the 1st month (p&amp;lt;0,01). Also we observed increase of LV segments amount with the presence of delayed enhancement which indicates myocardial fibrosis – from (2,04±0,21) segm. on initial examination to (4,79±0,38) segm. after 12 months (p&amp;lt;0,01). Using binary regression analysis we defined that initial presence of inflammatory lesions in ≥5,0 LV segments was associated with frequent VPB (≥1,0%) and NSVT paroxysms. Wherein, after 12 months presence of inflammatory lesions had no association with ventricular rhythm disorders but the same relation was observed between the presence of delayed enhancement in ≥4,0 LV segments and frequent VPB (≥1,0%) as also with NSVT paroxysms. Conclusion At the time of clinical onset of inflammatory cardiomyopathy ventricular rhythm disorders (particularly VPB and NSVT paroxysms) were associated with larger quantity of LV segments involved into inflammatory process. After 12 months of follow-up ventricular rhythm disorders were associated predominantly with the presence of fibrotic lesions in several (≥4,0) segments of LV. Funding Acknowledgement Type of funding source: None

IL-11 Induces Encephalitogenic Th17 Cells in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

IL-11+CD4+ cells accumulate in the cerebrospinal fluid of patients with early relapsing-remitting multiple sclerosis (MS) and in active brain MS lesions. Mouse studies have confirmed a causal role of IL-11 in the exacerbation of relapsing-remitting experimental autoimmune encephalomyelitis (RREAE). Administration of IL-11 at the time of clinical onset of RREAE induced an acute exacerbation and increased clinical scores, which persisted during the entire course of the disease. IL-11 increased the numbers of spinal cord inflammatory foci, as well as the numbers of peripheral and CNS-infiltrating IL-17+CD4+ cells and IL-17A serum levels. Ag recall assays revealed that IL-11 induces IL-17A+, GM-CSF+, and IL-21+CD4+ myelin Ag-reactive cells. Passive transfer of these encephalitogenic CD4+ T cells induced severe RREAE with IL-17A+CCR6+ CD4+ and B cell accumulation within the CNS. Furthermore, passive transfer of nonmanipulated CNS-derived mononuclear cells from mice with RREAE after a single dose of IL-11 induced severe RREAE with increased accumulation of IL-17A+ and CCR6+ CD4+ cells within the CNS. These results suggest that IL-11 might serve as a biomarker of early autoimmune response and a selective therapeutic target for patients with early relapsing-remitting MS.

Simultaneous scalp EEG improves seizure lateralization during unilateral intracranial EEG evaluation in temporal lobe epilepsy

PurposeTo determine if simultaneous bilateral scalp EEG (scEEG) can accurately detect a contralateral seizure onset in patients with unilateral intracranial EEG (IEEG) implantation. MethodsWe evaluated 39 seizures from 9 patients with bitemporal epilepsy who underwent simultaneous scEEG and IEEG (SSIEEG). To simulate conditions of unilateral IEEG implantation with a missed contralateral seizure onset, we analyzed the IEEG recording contralateral to the seizure onset (CL- IEEG), in conjunction with simultaneous scEEG. The following criteria were evaluated between scEEG and CL- IEEG (1) latency: the time to onset of EEG seizure (2) location: concordance of ictal onset zones and (3) pattern: congruence of EEG morphology and frequency. ResultsSSIEEG correctly lateralized 36/39 (92.3%) seizures compared to 13/39 (33.3%) seizures using CL- IEEG alone (OR = 24.0, p < 0.01), 33 (84.6%) seizures using scEEG alone (OR = 2.2, p = 0.29) and 26 (66.9%) seizures using time of clinical onset alone (OR = 6.0, p = 0.01). For the three criteria evaluated, (1) 22/39 (56.4%) seizures had an earlier onset on the scEEG, compared to CL- IEEG; (2) lack of congruence of location of seizure onset was noted in 33/39 (84.6%) of the seizures; and (3) 22/39 (56.4%) seizures did not have a congruent ictal pattern. ConclusionsThe chronological, topographic and morphologic features of SSIEEG can accurately detect the hemisphere of seizure onset in most cases with unilateral IEEG implantation. SSIEEG is significantly better than, IEEG, scEEG or clinical onset alone in this scenario. We propose that SSIEEG should be considered in all cases of intractable focal epilepsy undergoing unilateral IEEG evaluation.

Rheumatic immune-related adverse events from cancer immunotherapy

Immunotherapy has revolutionized the treatment of cancer, but a rapid rise in the use of the family of therapeutic agents known as checkpoint inhibitors (CPIs) is associated with a new group of immune-related adverse events (irAEs) in almost any organ system. Among these irAEs, rheumatic complications are common and seem to have features that are distinct from irAEs in other organ systems, including a highly variable time of clinical onset and the capacity to persist, possibly indefinitely, even after cessation of CPI therapy. In this Review, mechanisms of action of CPIs and how they might cause rheumatic irAEs are described. Also covered are epidemiology and clinical descriptions of rheumatic irAEs, plus guiding principles for managing irAEs. Finally, we outline future directions that must be taken in response to a series of unanswered questions and unmet needs that now confront rheumatologists who are, or will be, engaged in this new area of rheumatology.

Vitamin D status, enterovirus infection, and type 1 diabetes in Italian children/adolescents.

At the time of the clinical onset of type 1 diabetes (T1D), we investigated 82 pediatric cases in parallel with 117 non-diabetic controls matched by age, geographic area, and time of collection. The occurrence of an enteroviral infection was evaluated in peripheral blood using a sensitive method capable of detecting virtually all human enterovirus (EV) types. While non-diabetic controls were consistently EV-negative, 65% of T1D cases carried EVs in blood. The vitamin D status was assessed by measuring the concentration of 25-hydroxyvitamin D [25(OH)D] in serum. Levels of 25(OH)D were interpreted as deficiency (≤50 nmol/L), insufficiency (52.5-72.5 nmol/L), and sufficiency (75-250 nmol/L). In T1D cases, the median serum concentration of 25(OH)D was 54.4 ± 27.3 nmol/L vs 74.1 ± 28.5 nmol/L in controls (P = .0001). Diabetic children/adolescents showed deficient levels of vitamin D 25(OH)D (ie, 72.5 nmol/L) in 48.8% cases vs 17.9% in non-diabetic controls (P = .0001). Unexpectedly, the median vitamin D concentration was significantly reduced in virus-positive vs virus-negative diabetics (48.2 ± 22.5 vs 61.8 ± 31.2 nmol/L; P = .015), with deficient levels in 58.5% vs 31.0%, respectively. Thus, at the time of clinical onset, EV-positive cases had reduced vitamin D levels compared with EV-negative cases. This could indicate either that the virus-negative children/adolescents had been hit by a non-infectious T1D-triggering event, or that children/adolescents with proper levels of vitamin D had been able to rapidly clear the virus. Thus, it would be important to assess whether adequate vitamin D supplementation before or during the prediabetic phase of T1D may counteract the diabetogenic potential of infectious pathogens.

CD15 as a marker of fetoplacental endothelial immaturity in IUGR placentas

Background: Structural or functional defects in the placenta, are the primary cause of growth restriction of the fetus. Morphological examination of such placentas from intrauterine growth restricted (IUGR) fetuses often appears deceptively normal. Evaluation of angiogenesis and fetoplacental vasculature is critical to understand the underlying pathogenesis of fetal growth restriction in both idiopathic as well as cases where it is thought to be secondary to complications like preeclampsia (PE). We analyzed the immaturity of fetoplacental vasculature using CD15, which is a stage specific embryonic antigen known to be expressed in immature endothelium.Material and methods: One hundred and twelve placentas (81 from IUGR and 31 from gestationally appropriate samples (appropriate for gestational age (AGA)) were collected based on stringent inclusion criteria, and subjected to detailed examination of morphology and microscopy along with immunostaining for CD15. IUGR placentas known to have villous immaturity such as those associated with gestational diabetes, Rh negative pregnancies and anemia were excluded. The time of clinical onset of IUGR, associated complications like PE and oligohydramnios along with clinical variables were recorded. CD15 expression was scored in both distal and proximal vasculature and the values in IUGR and AGA pregnancies were compared and correlated with clinical variables.Results: The mean CD 15 scores in both proximal vasculature (PV) as well as distal (DV) vasculature were significantly higher in the IUGR group compared to AGA (17.7 versus 5.16 in PV and 50.8 versus 23.7 in distal vasculature (DV)). Gestational age had no influence on CD15 staining in PV or DV in IUGR group, whereas preterm AGAs expressed higher CD15 only in the distal vessels. PE, oligohydramnios and the time of onset of IUGR did not influence the fetal vascular immaturity, as measured by CD15 scores. Although none of the clinical or obstetric factors influenced CD15 staining in AGA, fetal vessel immaturity in the IUGR group remained high even after adjusting for confounding variables like maternal age, gestational age and birth weight. Histological features suggestive of chronic hypoxia were significantly higher in IUGR placentas, compared to AGA and correlated positively with CD15 expression.Conclusion: Fetoplacental endothelium in both PV and DV is immature in IUGR irrespective of the gestational age or any other associated factors and CD15 immunodetection is a valuable marker for assessment of immaturity.

Small-area distribution of multiple sclerosis incidence in western France: in search of environmental triggers

BackgroundDespite intensive research over several decades, the etiology of multiple sclerosis (MS) remains poorly understood, although environmental factors are supposedly implicated. Our goal was to identify spatial clusters of MS incident cases at the small-area level to provide clues to local environmental risk factors that might cause or trigger the disease.MethodsA population-based and multi-stage study was performed in the French Brittany region to accurately ascertain the clinical onset of disease during the 2000–2004 period. The municipality of residence at the time of clinical onset was geocoded. To test for the presence of MS incidence clusters and to identify their approximate locations, we used a spatial scan statistic. We adjusted for socioeconomic deprivation, known to be strongly associated with increased MS incident rates, and scanned simultaneously for areas with either high or low rates. Sensitivity analyses (focusing on relapsing-remitting forms and/or places of residence available within the year following clinical onset) were performed.ResultsA total of 848 incident cases of MS were registered in Brittany, corresponding to a crude annual incidence rate of 5.8 per 100,000 inhabitants. The spatial scan statistic did not find a significant cluster of MS incidence in either the primary analysis (p value ≥ 0.56) or in the sensitivity analyses (p value ≥ 0.16).ConclusionThe findings of this study indicate that MS incidence is not markedly affected across space, suggesting that in the years preceding the first clinical expression of the disease, no environmental trigger is operative at the small-area population level in the French Brittany region.

Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset.

Type 1 diabetes is characterized by the loss of insulin production caused by β-cell dysfunction and/or destruction. The hypothesis that β-cell loss occurs early during the prediabetic phase has recently been challenged. Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and β-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that β-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in β-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of β-cells per islet. Our data indicate that β-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when β-cell mass is still intact, could be a successful therapeutic strategy.

The streetlight effect--is there light at the end of the tunnel?

Autoimmune type 1 diabetes research and treatment are seemingly plagued with problems. Large and small, mostly well-thought out clinical studies and trials since the early 1980s have basically been negative. None of the treatments tested have reached clinical routine to replace current lifesaving insulin replacement therapy. A combination type of therapy to diminish the requirement for insulin is yet to be found. The chronic autoimmune disease at the time of clinical onset of type 1 diabetes has been the “winner” in all attempts made so far to stifle the disease process. The disease is also the “winner” over islet transplantation, a potential cure for diabetes. Islet transplantation research was drastically reduced after it was found that the so-called Edmonton protocol did not yield sustainable insulin independence despite short-term restoration of endogenous insulin production and glycemic stability (1). The Diabetes Control and Complications Trial (DCCT) study, well known to all, continues to underscore the importance of glucose control. The reduction in the risk of complications resulting from intensive therapy in patients with type 1 diabetes persisted at least for 4 years after the study was completed, despite increasing hyperglycemia (2). Notwithstanding progress in the overall diabetes management, we were all recently reminded of the fact that type 1 diabetes remains a deadly disease (3). Although mortality was the highest in patients with poorly controlled diabetes, it was reported that patients with type 1 diabetes with A1C of 6.9% or lower had a risk of death from any cause that was twice as high as the risk for matched control subjects (3). Against this background of an uphill battle, the current issue of Diabetes contains a Perspective by Battaglia and Atkinson entitled “The Streetlight Effect in Type 1 Diabetes” (4). In their Perspective, the authors put forward several remedies to …

Biomarkers to the Rescue in a Lung Nodule Epidemic

Biomarkers to the Rescue in a Lung Nodule Epidemic

Therapeutic effect of peripheral administration of an anti‐prion protein antibody on mice infected with prions

It is generally thought that effective treatments for prion diseases need to inhibit prion propagation, protect neuronal tissues and promote functional recovery of degenerated nerve tissues. In addition, such treatments should be effective even when given after clinical onset of the disease and administered via a peripheral route. In this study, the effect of peripheral administration of an anti-PrP antibody on disease progression in prion-infected mice was examined. mAb 31C6 was administered via the tail veins of prion-infected mice at the time of clinical onset (120 days post-inoculation with the Chandler prion strain) and the distribution of this mAb in the brain and its effect on mouse survival assessed. The antibody was distributed to the cerebellums and thalami of the infected mice and more than half these mice survived longer than mice that had been given a negative control mAb. The level of PrP(Sc) in the mAb 31C6-treated mice was lower than that in mice treated with the negative control mAb and progression of neuropathological lesions in the cerebellum, where the mAb 31C6 was well distributed, appeared to be mitigated. These results suggest that administration of an anti-PrP mAb through a peripheral route is a candidate for the treatment of prion diseases.

Long-term remission of diabetes in NOD mice is induced by nondepleting anti-CD4 and anti-CD8 antibodies.

Residual β-cells found at the time of clinical onset of type 1 diabetes are sufficient to control hyperglycemia if rescued from ongoing autoimmune destruction. The challenge, however, is to develop an immunotherapy that not only selectively suppresses the diabetogenic response and efficiently reverses diabetes, but also establishes long-term β-cell–specific tolerance to maintain remission. In the current study, we show that a short course of nondepleting antibodies (Abs) specific for the CD4 and CD8 coreceptors rapidly reversed clinical disease in recent-onset diabetic NOD mice. Once established, remission was maintained indefinitely and immunity to foreign antigens unimpaired. Induction of remission involved selective T-cell purging of the pancreas and draining pancreatic lymph nodes and upregulation of transforming growth factor (TGF)-β1 by pancreas-resident antigen-presenting cells. Neutralization of TGF-β blocked the induction of remission. In contrast, maintenance of remission was associated with tissue-specific immunoregulatory T cells. These findings demonstrate that the use of nondepleting Ab specific for CD4 and CD8 is a robust approach to establish long-term β-cell–specific T-cell tolerance at the onset of clinical diabetes.

G.P.117 Clinical implications of the proposal that sarcolemma properties of actively growing myofibres differ to those of mature adult myofibres

Abstract The new hypothesise that ‘the sarcolemma of an actively growing myofibre has different properties to the sarcolemma of a mature adult myofibre’ (Grounds & Shavlakadze, 2011, Bioessays) is supported by data showing that elevated IGF-1 triggers a signalling response in growing, but not adult, myofibres. Differences in sarcolemmal properties between growing and adult myofibres are also indicated by the time of clinical onset of various inherited genetic myopathies involving proteins associated with the sarcolemma e.g. Duchenne muscular dystrophy (due to defects in dystrophin) is a paediatric disease and the dystropathology appears to be exacerbated by growth. In striking contrast, young patients with defective dysferlin (another membrane-associated protein) appear to be pre-symptomatic during growth and adolescence and they are often very active in sports, with clinical manifestation usually very shortly after cessation of the main growth phase: thus the reliance on dysferlin seems to be very different between growing and mature adult myofibres. If this hypothesis is true, then the need to use ‘mature muscle’ experimental models (isolated myofibres in culture or adult animals in vivo) for these post-growth myopathies, rather than immature myofibres (e.g. cultured myotubes) is emphasised, in order to define the molecular basis, and identify the best targets for therapies, for dysferlinopathies. During growth, multinucleated myofibres increase enormously in size and volume with dramatic increases in length (up to ∼600 mm): this differs markedly to most mononucleated cells, e.g. fibroblasts, that remain at a relatively small size (∼10–20 μm diameter). In addition, myofibres are long-lived and probably persist throughout the life of an individual (in the absence of severe injury that results in myonecrosis). The consequences of a dynamic expanding sarcolemma during growth, compared with an adult myofibre of a fixed length, have many scientific and clinical implications.

Enfermedad de Erdheim-Chester: estudio de 12 casos

Background and objectiveErdheim-Chester disease (EC) is a rare form of non-Langerhans’ cell histiocytosis. It is characterized by the xanthomatous infiltration of tissues with foamy CD68+/CD1a- histiocytes. We report a series of 12 patients diagnosed with EC. Patients and methodsWe reviewed the clinical, pathological and therapeutic aspects of 12 cases diagnosed with EC at 7 tertiary teaching hospitals in Spain. Patients were included if tissue infiltration by histiocytes CD68+/CD1a- could be demonstrated in an appropriate clinical setting. ResultsTwelve patients (7 male) were included. Median follow-up was 36 months (IQR: 20-84). The median age at the time of clinical onset and pathological diagnosis was 49 (IQR: 28-61) and 56 years (IQR: 37-62), respectively. In 6 cases multiples biopsies were performed (skin, muscle, testicular) previous to diagnosis, which was confirmed in 3 cases after a carefully review of pathological tissues. Neurological involvement was independently associated with mortality (P<.05). Characteristic long bone osteosclerosis was detected in 9 patients. ConclusionEC is a multisystemic and heterogeneous clinicopathological condition. A high index of suspicion and fluent communication between clinicians and pathologists is necessary to achieve a correct diagnosis.

Low risk HLA-DQ and increased body mass index in newly diagnosed type 1 diabetes children in the Better Diabetes Diagnosis study in Sweden

ObjectiveType 1 diabetes and obesity has increased in childhood. We therefore tested the hypothesis that type 1 diabetes HLA-DQ risk genotypes may be associated with an increased body mass index (BMI).DesignThe type 1 diabetes high risk HLA-DQ A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype along with lower risk DQ genotypes were determined at the time of clinical onset by PCR and hybridization with allele-specific probes. Body mass index was determined after diabetes was stabilized.SubjectsA total of 2403 incident type 1 diabetes children below 18 years of age were ascertained in the Swedish national Better Diabetes Diagnosis (BDD) studybetween May 2005 to September 2009. All children classified with type 1 diabetes including positivity for at least one islet autoantibody were investigated.ResultsOverall, type 1 diabetes HLA-DQ risk was negatively associated with BMI (p<0.0008). The proportion of the highest risk A1*05:01-B1*02:01/A1*03:01-B1*03:02 genotype decreased with increasing BMI (p<0.0004). However, lower risk type 1 diabetes DQ genotypes were associated with an increased proportion of patients who were overweight or obese (p<0.0001). Indeed, the proportion of patients with the low risk A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype increased with increasing body mass index (p<0.003). The magnitude of association on the multiplicative scale between the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and increased body mass index was significant (p<0.006). The odds ratio in patients with this genotype of being obese was 1.80 (95% CI 1.21–2.61; p<0.006). The increased proportion of overweight type 1 diabetes children with the A1*05:01-B1*02:01 haplotype was most pronounced in children diagnosed between 5 and 9 years of age.ConclusionsSusceptibility for childhood type 1 diabetes was unexpectedly found to be associated with the A1*05:01-B1*02:01/A1*05:01-B1*02:01 genotype and an increased BMI. These results support the hypothesis that overweight may contribute to the risk of type 1 diabetes in children positive for HLA-DQ A1*05:01-B1*02:01.

Vaccination against type 1 diabetes

The clinical onset of type 1 diabetes or autoimmune diabetes occurs after a prodrome of islet autoimmunity. The warning signals for the ensuing loss of pancreatic islet beta cells are autoantibodies against insulin, GAD65, IA-2 and ZnT8, alone or in combinations. Autoantibodies against, for example, insulin alone have only a minor risk of type 1 diabetes. However, progression to clinical onset is increased by the induction of multiple islet autoantibodies. At the time of clinical onset, insulitis may be manifest, which seems to reduce the efficacy of immunosuppression. Autoantigen-specific immunotherapy with alum-formulated GAD65 (Diamyd(®)) shows promise to reduce the loss of beta-cell function after the clinical onset of type 1 diabetes. The mechanisms are unclear but may involve the induction of T regulatory cells, which may suppress islet autoantigen reactivity. Past and ongoing clinical trials have been safe. Future clinical trials, perhaps as combination autoantigen-specific immunotherapy, may increase the efficacy in preventing the clinical onset in subjects with islet autoantibodies or preserve residual beta-cell function in patients newly diagnosed with type 1 diabetes.