Vitamin D Deficiency in Obese Children and Its Relationship to Insulin Resistance and Adipokines

Low-serum concentrations of 25-hydroxyvitamin D [25(OH)D] are associated with insulin resistance in adults. Less data are available in pediatric populations. Serum 25(OH)D serum concentrations were assessed in 125 obese and 31 nonobese children (age 11.9 ± 2.7 y, range 6–16 y, 49% male) living in Bonn, Germany. The relationship between 25(OH)D, measured by liquid chromatography-tandem mass spectrometry, and measures of insulin sensitivity and adipokines adiponectin and resistin were analyzed. Seventy-six % of subjects were 25(OH)D deficient (<20 ng/mL). Higher insulin, homeostasis model assessment-insulin resistance (HOMA-IR r = −0.269, P = 0.023), and hemoglobin A1c (HbA1c) as well as lower quantitative insulin-sensitivity check index (QUICKI r = 0.264, P = 0.030) values were found in obese children with lower 25(OH)D concentrations even after adjustment for gender, age, and body mass index. Furthermore, 25(OH)D correlated significantly with adiponectin, but not with resistin. Our results suggest that hypovitaminosis D is a risk factor for developing insulin resistance independent of adiposity

Diagnostic errors in paediatric cardiac intensive care

AbstractIntroductionDiagnostic errors cause significant patient harm and increase costs. Data characterising such errors in the paediatric cardiac intensive care population are limited. We sought to understand the perceived frequency and types of diagnostic errors in the paediatric cardiac ICU.MethodsPaediatric cardiac ICU practitioners including attending and trainee physicians, nurse practitioners, physician assistants, and registered nurses at three North American tertiary cardiac centres were surveyed between October 2014 and January 2015.ResultsThe response rate was 46% (N=200). Most respondents (81%) perceived that diagnostic errors harm patients more than five times per year. More than half (65%) reported that errors permanently harm patients, and up to 18% perceived that diagnostic errors contributed to death or severe permanent harm more than five times per year. Medication side effects and psychiatric conditions were thought to be most commonly misdiagnosed. Physician groups also ranked pulmonary overcirculation and viral illness to be commonly misdiagnosed as bacterial illness. Inadequate care coordination, data assessment, and high clinician workload were cited as contributory factors. Delayed diagnostic studies and interventions related to the severity of the patient’s condition were thought to be the most commonly reported process breakdowns. All surveyed groups ranked improving teamwork and feedback pathways as strategies to explore for preventing future diagnostic errors.ConclusionsPaediatric cardiac intensive care practitioners perceive that diagnostic errors causing permanent harm are common and associated more with systematic and process breakdowns than with cognitive limitations.</jats:sec

Early and rapid prediction of patency of the infarct-related coronary artery by using left ventricular wall thickness as measured by two-dimensional echocardiography

AbstractObjectives. The aim of this study was to determine whether echocardiography can distinguish between persistent coronary occlusion and reperfusion.Background. There are no adequate clinical or noninvasive laboratory markers to accurately predict successful reperfusion in an acute myocardial infarction.Methods. In a closed chest swine model, the effect of reperfusion on myocardial wall thickness was studied by comparing a 150-min total coronary artery occlusion (group 1) with 120 min of occlusion followed by 30 min of reperfusion (group 2) in the area of risk as measured by echocardiography. Wall thickness was measured at baseline and at 90 and 150 min.Results. In group 1 (n = 4), there was no appreciable change in mean wall thickness from 90 min to 150 min of occlusion at either end-diastole or end-systole (0.54 ± 0.02 to 0.52 ± 0.03 cm, 0.55 ± 0.03 to 0.54 ± 0.03 cm, respectively; p = NS). In contrast, in group 2 (n = 6), an increase in mean wall thickness from 0.53 ± 0.02 to 0.97 ± 0.05 cm at end-diastole and from 0.56 ± 0.04 to 1.04 ± 0.07 cm at end-systole was found from 90 min of occlusion to 30 min of reperfusion (p < 0.001). Reperfusion resulted. in an increase in wall thickness of 83 ± 11% at end-diastole and 92 ± 17% at end-systole. In contrast, persistent coronary occlusion showed minimal changes of −3.0 ± 5% at end-diastole and −2.0 ± 6% at end-systole.Conclusions. This study confirms the hypothesis that an increase in wall thickness can accurately distinguish between reperfusion and permanent coronary occlusion

A metaproteomic approach to study human-microbial ecosystems at the mucosal luminal interface

Aberrant interactions between the host and the intestinal bacteria are thought to contribute to the pathogenesis of many digestive diseases. However, studying the complex ecosystem at the human mucosal-luminal interface (MLI) is challenging and requires an integrative systems biology approach. Therefore, we developed a novel method integrating lavage sampling of the human mucosal surface, high-throughput proteomics, and a unique suite of bioinformatic and statistical analyses. Shotgun proteomic analysis of secreted proteins recovered from the MLI confirmed the presence of both human and bacterial components. To profile the MLI metaproteome, we collected 205 mucosal lavage samples from 38 healthy subjects, and subjected them to high-throughput proteomics. The spectral data were subjected to a rigorous data processing pipeline to optimize suitability for quantitation and analysis, and then were evaluated using a set of biostatistical tools. Compared to the mucosal transcriptome, the MLI metaproteome was enriched for extracellular proteins involved in response to stimulus and immune system processes. Analysis of the metaproteome revealed significant individual-related as well as anatomic region-related (biogeographic) features. Quantitative shotgun proteomics established the identity and confirmed the biogeographic association of 49 proteins (including 3 functional protein networks) demarcating the proximal and distal colon. This robust and integrated proteomic approach is thus effective for identifying functional features of the human mucosal ecosystem, and a fresh understanding of the basic biology and disease processes at the MLI. © 2011 Li et al

Impaired β-glucocerebrosidase activity and processing in frontotemporal dementia due to progranulin mutations.

Loss-of-function mutations in progranulin (GRN) are a major autosomal dominant cause of frontotemporal dementia. Most pathogenic GRN mutations result in progranulin haploinsufficiency, which is thought to cause frontotemporal dementia in GRN mutation carriers. Progranulin haploinsufficiency may drive frontotemporal dementia pathogenesis by disrupting lysosomal function, as patients with GRN mutations on both alleles develop the lysosomal storage disorder neuronal ceroid lipofuscinosis, and frontotemporal dementia patients with GRN mutations (FTD-GRN) also accumulate lipofuscin. The specific lysosomal deficits caused by progranulin insufficiency remain unclear, but emerging data indicate that progranulin insufficiency may impair lysosomal sphingolipid-metabolizing enzymes. We investigated the effects of progranulin insufficiency on sphingolipid-metabolizing enzymes in the inferior frontal gyrus of FTD-GRN patients using fluorogenic activity assays, biochemical profiling of enzyme levels and posttranslational modifications, and quantitative neuropathology. Of the enzymes studied, only β-glucocerebrosidase exhibited impairment in FTD-GRN patients. Brains from FTD-GRN patients had lower activity than controls, which was associated with lower levels of mature β-glucocerebrosidase protein and accumulation of insoluble, incompletely glycosylated β-glucocerebrosidase. Immunostaining revealed loss of neuronal β-glucocerebrosidase in FTD-GRN patients. To investigate the effects of progranulin insufficiency on β-glucocerebrosidase outside of the context of neurodegeneration, we investigated β-glucocerebrosidase activity in progranulin-insufficient mice. Brains from Grn-/- mice had lower β-glucocerebrosidase activity than wild-type littermates, which was corrected by AAV-progranulin gene therapy. These data show that progranulin insufficiency impairs β-glucocerebrosidase activity in the brain. This effect is strongest in neurons and may be caused by impaired β-glucocerebrosidase processing

Characteristics of patients misdiagnosed with Alzheimer’s disease and their medication use: an analysis of the NACC-UDS database

BACKGROUND: This study compared individuals whose clinical diagnosis of Alzheimer’s disease (AD) matched or did not match neuropathologic results at autopsy on clinical and functional outcomes (cognitive impairment, functional status and neuropsychiatric symptoms). The study also assessed the extent of potentially inappropriate medication use (using potentially unnecessary medications or potentially inappropriate prescribing) among misdiagnosed patients. METHODS: Longitudinal data from the National Alzheimer’s Coordinating Center Uniform Data Set (NACC-UDS, 2005–2010) and corresponding NACC neuropathological data were utilized to compare 88 misdiagnosed and 438 accurately diagnosed patients. RESULTS: Following adjustment of sociodemographic characteristics, the misdiagnosed were found to have less severe cognitive and functional impairment. However, after statistical adjustment for sociodemographics, dementia severity level, time since onset of cognitive decline and probable AD diagnosis at baseline, the groups significantly differed on only one outcome: the misdiagnosed were less likely to be depressed/dysphoric. Among the misdiagnosed, 18.18% were treated with potentially inappropriate medication. An additional analysis noted this rate could be as high as 67.10%. CONCLUSIONS: Findings highlight the importance of making an accurate AD diagnosis to help reduce unnecessary treatment and increase appropriate therapy. Additional research is needed to demonstrate the link between potentially inappropriate treatment and adverse health outcomes in misdiagnosed AD patients

TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes.

A diverse environment challenges skin to maintain temperature, hydration, and electrolyte balance while also maintaining normal immunological function. Rosacea is a common skin disease that manifests unique inflammatory responses to normal environmental stimuli. We hypothesized that abnormal function of innate immune pattern recognition could explain the enhanced sensitivity of patients with rosacea, and observed that the epidermis of patients with rosacea expressed higher amounts of Toll-like receptor 2 (TLR2) than normal patients. Increased expression of TLR2 was not seen in other inflammatory skin disorders such as atopic dermatitis or psoriasis. Overexpression of TLR2 on keratinocytes, treatment with TLR2 ligands, and analysis of TLR2-deficient mice resulted in a calcium-dependent release of kallikrein 5 from keratinocytes, a critical protease involved in the pathogenesis of rosacea. These observations show that abnormal TLR2 function may explain enhanced inflammatory responses to environmental stimuli and can act as a critical element in the pathogenesis of rosacea

Increased Matrix Metalloproteinase (MMPs) Levels Do Not Predict Disease Severity or Progression in Emphysema

Rationale: Though matrix metalloproteinases (MMPs) are critical in the pathogenesis of COPD, their utility as a disease biomarker remains uncertain. This study aimed to determine whether bronchoalveolar lavage (BALF) or plasma MMP measurements correlated with disease severity or functional decline in emphysema. Methods: Enzyme-linked immunosorbent assay and luminex assays measured MMP-1, -9, -12 and tissue inhibitor of matrix metalloproteinase-1 in the BALF and plasma of non-smokers, smokers with normal lung function and moderate-to-severe emphysema subjects. In the cohort of 101 emphysema subjects correlative analyses were done to determine if MMP or TIMP-1 levels were associated with key disease parameters or change in lung function over an 18-month time period. Main Results: Compared to non-smoking controls, MMP and TIMP-1 BALF levels were significantly elevated in the emphysema cohort. Though MMP-1 was elevated in both the normal smoker and emphysema groups, collagenase activity was only increased in the emphysema subjects. In contrast to BALF, plasma MMP-9 and TIMP-1 levels were actually decreased in the emphysema cohort compared to the control groups. Both in the BALF and plasma, MMP and TIMP-1 measurements in the emphysema subjects did not correlate with important disease parameters and were not predictive of subsequent functional decline. Conclusions: MMPs are altered in the BALF and plasma of emphysema; however, the changes in MMPs correlate poorly with parameters of disease intensity or progression. Though MMPs are pivotal in the pathogenesis of COPD, these findings suggest that measuring MMPs will have limited utility as a prognostic marker in this disease. © 2013 D'Armiento et al