Association between p.Leu54Met polymorphism at the paraoxonase-1 gene and plantar fascia thickness in young subjects with type 1 diabetes

OBJECTIVE— In type 1 diabetes, plantar fascia, a collagen-rich tissue, is susceptible to glycation and oxidation. Paraoxonase-1 (PON1) is an HDL-bound antioxidant enzyme. PON1 polymorphisms have been associated with susceptibility to macro- and microvascular complications. We investigated the relationship between plantar fascia thickness (PFT) and PON1 gene variants, p.Leu54Met, p.Gln192Arg, and c.-107C>T, in type 1 diabetes.RESEARCH DESIGN AND METHODS—This was a cross-sectional study of 331 adolescents with type 1 diabetes (162 male and 169 female). PFT was assessed by ultrasound, PON1 was assessed by genotyping with PCR and restriction fragment–length polymorphism, and serum PON1 activity was assessed by rates of hydrolysis of paraoxon and phenylacetate.RESULTS—Median (interquartile range) age was 15.4 (13.5–17.3) years, and diabetes duration was 7.6 (4.9–10.6) years. The distribution of p.Leu54Met genotypes was LL 135 (40.8%), ML 149 (45%), and MM 47 (14.2%). PFT was abnormal (>1.7 mm) in 159 adolescents (48%). In multivariate analysis, predictors of abnormal PFT were ML/LL versus MM p.Leu54Met polymorphism (odds ratio 3.84 [95% CI 1.49–9.82], P = 0.005); BMI (percentile) (1.02 [1.01–1.03], P = 0.007); systolic blood pressure (percentile) (1.01 [1.00–1.02], P = 0.03); and male sex (3.29 [1.98–5.46], P < 0.001).CONCLUSIONS—Thickening of the plantar aponeurosis occurs predominantly in overweight and male adolescents with type 1 diabetes. The MM genotype at PON1 p.Leu54Met is associated with a reduced risk of abnormal PFT.Paraoxonase-1 (PON1) is a calcium-dependent HDL-associated enzyme that protects LDLs from oxidation. In type 1 diabetic patients, the serum paraoxonase concentration is lower and HDL is a less efficient antioxidant than in healthy individuals (1). Oxidized LDL is implicated in the pathogenesis of atherosclerosis, diabetic retinopathy, and nephropathy (2). Variations in lipoprotein-related enzymes and genotypes may also promote diabetic microvascular damage (3).Soft-tissue thickening is associated with chronic hyperglycemia and is hypothesized to be due to collagen glycation (4). With use of ultrasound techniques to measure plantar aponeurosis, a collagen-rich tissue, researchers demonstrated previously that people with diabetes have increased plantar fascia thickness (PFT) (5). Recently, this group reported that increased PFT predicted the development of microvascular complications in adolescents with type 1 diabetes and proposed abnormal PFT as a putative marker of soft-tissue glycation (6).The PON gene cluster maps to chromosome 7q21-22 and influences gene expression and serum activity. There is an established link between PON1 and macrovascular disease (7) and emerging evidence linking PON1 to microvascular complications (8,9). In this study we investigated whether the variants c.-107C>T at the promoter region and p.Leu54Met and p.Gln192Arg at the coding regions of PON1 are associated with PFT in type 1 diabetes.     

Imaging of amyloid beta in Alzheimer's disease with 18F-BAY94-9172, a novel PET tracer: proof of mechanism

BACKGROUND: Amyloid-beta (Abeta) plaque formation is a hallmark of Alzheimer's disease (AD) and precedes the onset of dementia. Abeta imaging should allow earlier diagnosis, but clinical application is hindered by the short decay half-life of current Abeta-specific ligands. (18)F-BAY94-9172 is an Abeta ligand that, due to the half-life of (18)F, is suitable for clinical use. We thus studied the effectiveness of this ligand in identifying patients with AD. METHODS: 15 patients with mild AD, 15 healthy elderly controls, and five individuals with frontotemporal lobar degeneration (FTLD) were studied. (18)F-BAY94-9172 binding was quantified by use of the standardised uptake value ratio (SUVR), which was calculated for the neocortex by use of the cerebellum as reference region. SUVR images were visually rated as normal or AD. FINDINGS: (18)F-BAY94-9172 binding matched the reported post-mortem distribution of Abeta plaques. All AD patients showed widespread neocortical binding, which was greater in the precuneus/posterior cingulate and frontal cortex than in the lateral temporal and parietal cortex. There was relative sparing of sensorimotor, occipital, and medial temporal cortex. Healthy controls and FTLD patients showed only white-matter binding, although three controls and one FTLD patient had mild uptake in frontal and precuneus cortex. At 90-120 min after injection, higher neocortical SUVR was observed in AD patients (2.0 [SD 0.3]) than in healthy controls (1.3 [SD 0.2]; p<0.0001) or FTLD patients (1.2 [SD 0.2]; p=0.009). Visual interpretation was 100% sensitive and 90% specific for detection of AD. INTERPRETATION: (18)F-BAY94-9172 PET discriminates between AD and FTLD or healthy controls and might facilitate integration of Abeta imaging into clinical practice.     

Motor inhibition in trichotillomania and obsessive-compulsive disorder

We investigated motor inhibition abilities in trichotillomania (TTM) and obsessive-compulsive disorder (OCD), two disorders characterized by repetitive, intentionally performed behaviors. Performance in a GoNogo experiment of 25 TTM and 21 OCD participants was compared to the performance of 26 HC participants. In contrast to OCD and HC participants, TTM participants tended to perform either 'fast and inaccurate' (indicating poor motor inhibition) or 'slow and accurate'. TTM participants with poor motor inhibition reported a significantly earlier age of TTM onset than those TTM participants who performed well. There was no evidence for motor inhibition deficits in OCD. Based on our data, a subgroup of TTM sufferers seems to be characterized by motor inhibition deficits.     

Collaboration in outpatient antipsychotic drug treatment: analysis of potentially influencing factors

Knowledge of factors relevant for medication adherence and patient collaboration is still limited. Our study aims at exploring the contribution of a variety of factors to collaboration in outpatients with schizophrenia and schizoaffective disorder. We obtained self-rated and observer-rated data from 108 outpatients during an interview 6 months after hospital discharge. The compliance rating scale (CRS) classified 76% of the patients as collaborative. Factors related to the patient, illness, treatment, and social environment were analysed in two-step explorative correlation and regression analyses in order to determine their relative contribution to collaboration. Only trust in medication and lack of insight were associated with collaboration, and they accounted for 38% of the variance. Neither medication side effects nor neuropsychological functioning correlated with collaboration. The conceptualisation of medication adherence is complex, and there are a number of unresolved methodological problems. The data indicate that illness and treatment-related subjective attitudes may be more relevant than side effects, cognitive functioning or any sociodemographic variable.     

Autoimmune lymphoproliferative syndrome (ALPS) caused by Fas (CD95) mutation mimicking sarcoidosis

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in apoptosis, characterized by childhood onset of lymphadenopathy, splenomegaly, hyperimmunoglobulinemia, and autoimmune disease. ALPS is most frequently associated with a mutation in the cell death receptor Fas (CD95). Very rarely a mutation in caspase 10 is present. An increase of CD4/CD8 double negative T cells in the peripheral blood and lymph nodes is a feature characteristic of ALPS. Additionally, histiocytic proliferations resembling sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) were reported recently in patients with ALPS. In the rare cases with a caspase 10 mutation an accumulation of dendritic cells in lymphoid organs was noted. We describe a different, sarcoidosislike, histiocytic infiltration of lymph nodes that persisted for years in a girl, that was initially supposed to suffer from sarcoidosis, but was eventually diagnosed as ALPS, associated with a missense mutation in the intracellular death domain of Fas. This sarcoidosislike histologic picture extends the spectrum of histiocytic lymph node alterations observed in ALPS and alerts of a potential diagnostic pitfall.     

Reorganization of the interdisciplinary emergency unit at the university clinic of Göttingen

Configuration of the interdisciplinary emergency unit within the university clinic of G?ttingen was successfully reorganized during the past two years. All emergencies except traumatologic, gynecologic and pediatric emergencies are treated within this functional unit which is guided by the center of internal medicine. It is organized in a three shift operation manner over a period of 24 hours. Due to a close interdisciplinary collaboration between different departments patients receive optimal diagnostic and therapeutic treatment within a short period of time. To improve processes within the emergency department a series of measures were taken including the -establishment of an intermediate care unit for unstable patients, setting up of special diagnostic and therapeutic units for the acute coronary syndrome as well as stroke, implementation of standardized clinical pathways, establishment of an electronic data processing network in close communication with all diagnostic entities, introduction of a quality assurance system and reduction of medical costs. Reorganization measures lead to a substantial optimization and acceleration of emergency proceedings and thus, provides optimal patient care around the clock. In addition, medical costs could clearly be reduced at the interface between preclinical and clinical emergency medicine.     

Growth of Mycobacterium tuberculosis at acidic pH depends on lipid assimilation and is accompanied by reduced GAPDH activity

Acidic pH arrests the growth of Mycobacterium tuberculosis in vitro (pH < 5.8) and is thought to significantly contribute to the ability of macrophages to control M. tuberculosis replication. However, this pathogen has been shown to survive and even slowly replicate within macrophage phagolysosomes (pH 4.5 to 5) [M. S. Gomes et al., Infect. Immun. 67, 3199–3206 (1999)] [S. Levitte et al., Cell Host Microbe 20, 250–258 (2016)]. Here, we demonstrate that M. tuberculosis can grow at acidic pH, as low as pH 4.5, in the presence of host-relevant lipids. We show that lack of phosphoenolpyruvate carboxykinase and isocitrate lyase, two enzymes necessary for lipid assimilation, is cidal to M. tuberculosis in the presence of oleic acid at acidic pH. Metabolomic analysis revealed that M. tuberculosis responds to acidic pH by altering its metabolism to preferentially assimilate lipids such as oleic acid over carbohydrates such as glycerol. We show that the activity of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is impaired in acid-exposed M. tuberculosis likely contributing to a reduction in glycolytic flux. The generation of endogenous reactive oxygen species at acidic pH is consistent with the inhibition of GAPDH, an enzyme well-known to be sensitive to oxidation. This work shows that M. tuberculosis alters its carbon diet in response to pH and provides a greater understanding of the physiology of this pathogen during acid stress.

Tuberculosis (TB) is a chronic disease mostly affecting the lungs and, despite the availability of a vaccine and antibiotic therapy, remains the leading cause of death due to a single bacterium. An estimated 2 billion people are thought to be infected with Mycobacterium tuberculosis, the causative agent of TB, with 10 million new infections each year and 1 million deaths (1). M. tuberculosis success as a pathogen can be attributed to its ability to adapt and persist within the host. This intracellular pathogen replicates within macrophages and must be able to withstand host-imposed stresses as well as gain access to nutrients to survive and proliferate. M. tuberculosis has been observed inside lipid-rich lesions during infection in humans and in animal models of TB (2, 3). Its genome contains an extensive number of redundant genes dedicated to β-oxidation necessary for lipid breakdown, indicating the importance of lipid catabolism (4). In addition to β-oxidation, lipid utilization depends on two key enzymes, isocitrate lyase (ICL) required for the glyoxylate shunt and phosphoenolpyruvate carboxykinase (PEPCK) catalyzing the first committed step of gluconeogenesis. Mutants lacking either ICL or PEPCK cannot grow with lipids as a sole carbon source and are severely attenuated in the TB mouse model (5–7). While M. tuberculosis can simultaneously use several different carbon sources to grow in vitro (8), lipids seem to be the primary source of carbon during infection (5, 7, 9–11). Whether this is because glycolytic carbon sources are scarce or inaccessible or because M. tuberculosis requires lipids to grow during infection is unknown.Despite its ability to block phagosome–lysosome fusion, a notable fraction of phagocytosed M. tuberculosis is rapidly trafficked toward acidified compartments, and this proportion increases upon macrophage activation by T cell produced interferon-γ (IFN-γ) (12–14). Moreover, lung tissues from TB patients were found to have a median pH of pH 5.5 (15) supporting that M. tuberculosis faces acid stress during its infectious cycle in humans. M. tuberculosis can survive at a pH as low as pH 4.5 by maintaining its intracellular pH close to neutral at least in part through sustained peptidoglycan hydrolysis (16, 17). While the identification of mechanisms that enable M. tuberculosis to survive at acidic pH has taken much attention, how the pathogen adapts to an acidified environment to grow and promote disease remains ill defined. At acidity lower than pH 5.8, M. tuberculosis enters a nonreplicating state in vitro (18). This growth arrest at mildly acidic pH is surprising considering that the bacterium likely replicates in more acidic environments during infection.The media used to culture mycobacteria contain glycerol and glucose as main carbon sources. Previous work demonstrated that growth of M. tuberculosis at acidic pH is improved by changing the carbon source (18, 19). Pyruvate promoted growth of M. tuberculosis at pH 5.7 (19) indicating that growth at acidic pH is regulated by available carbon sources. Because lipids appear to be the primary carbon source M. tuberculosis utilizes to grow in vivo (5, 7, 9–11), we hypothesized that providing host-relevant carbon sources to M. tuberculosis, such as lipids, would serve as a more physiologically relevant model to examine how M. tuberculosis responds to acidic pH. Here, we demonstrate that providing oleic acid (OA) (and other host-relevant lipids) as a carbon source to M. tuberculosis, resulted in sustained growth in acidic cultures at pH 5.5 and below. We applied metabolomics, genetic, and biochemical approaches to investigate this pH-driven use of lipids to support growth. Our work helps explain the dependence of M. tuberculosis on lipids as a primary carbon source during infection and demonstrates that M. tuberculosis is well adapted to the acidic environments it encounters during infection; in fact, it is not only able to maintain its neutral intrabacterial pH, as previously reported, but can replicate in acidic conditions similar to those within phagolysosomes.     

Intrauterine growth and infant temperamental difficulties: the Generation R Study

OBJECTIVE: To determine whether intrauterine growth trajectories are associated with temperamental difficulties in infancy. METHOD: The Generation R Study is a population-based cohort study from fetal life onward. Size at different time points during gestation and growth trajectories, calculated on the basis of repeatedly measured fetal growth characteristics, were related to temperamental dimensions, assessed with the Infant Behavior Questionnaire-Revised, in 3,792 infants age 6 months. RESULTS: Birth weight, adjusted for gestational age, was negatively associated with activity level and duration of orienting. These associations disappeared after additional adjustment for maternal height, age, educational level, and national origin. Similarly, the negative associations between intrauterine total body weight gain and falling reactivity and activity level diminished after correction for maternal and child characteristics. After full adjustment, reduced fetal weight gain was only related to prolonged duration of orienting. Children scored 0.38 (95% confidence interval 0.09-0.68) points higher on duration of orienting per SD decrease in total body weight gain from mid-pregnancy to birth. CONCLUSIONS: After controlling for several genetic and socioeconomic status related factors, we found little indication of an association between intrauterine growth trajectories and temperamental difficulties in infants.