Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination

Myelin/oligodendrocyte glycoprotein (MOG) is a target antigen for myelin-destructive Abs in autoimmune central nervous system demyelinating disorders. Little is known about the molecular and structural basis of these pathogenic Ab responses. Here, we have characterized anti-MOG Ab specificities in the marmoset model of experimental allergic encephalomyelitis, by means of a combinatorial IgG-Fab library. We found that a diverse population of Ig genes encodes for auto-Abs that exclusively recognize conformation-dependent antigenic targets on MOG. These antigenic domains correspond to exposed epitopes in vivo, as the Fab fragments recognize native MOG in situ in marmoset brain tissue. The Ab fragments described here represent Ab specificities that are common constituents of the humoral immune repertoire against MOG in outbred populations, as demonstrated by their ability to displace native anti-MOG Abs present in sera from MOG-immune marmosets and patients with multiple sclerosis. Furthermore, neuropathological analysis and characterization of Ab epitope specificities in animals immunized with MOG or MOG-derived peptides revealed that only conformation-dependent Abs are associated with demyelinating activity, suggesting that epitope recognition is an important factor for Ab pathogenicity. Our findings provide novel and unexpected knowledge on the diversity of anti-MOG Ab responses in nonhuman primates and humans, and will permit the dissection of pathogenic auto-Ab properties in multiple sclerosis.     

Autonomic hypoactivity in boys with attention-deficit/hyperactivity disorder and the influence of methylphenidate

Objectives. This study investigates an overall autonomic hypoactivity reflecting hypoarousal as important aetiological factor in ADHD at baseline during rest and in response towards stimuli. In addition, effects of methylphenidate (MPH) are examined. We further assessed whether this hypoarousal is a stable characteristic or ameliorated by arousing emotional stimuli. Methods. Boys with ADHD were examined with (n = 35) or without MPH (n = 45) and compared with healthy boys (n = 22) regarding skin conductance level (SCL) during rest and skin conductance responses (SCRs) as well as valence and arousal ratings in response to positive, neutral, and negative pictures. Results. ADHD children without MPH were characterized by reduced baseline SCL and overall reduced SCRs. ADHD children with MPH never differed from control children. All groups displayed normal valence and arousal ratings of the stimuli and enhanced SCRs to emotional in comparison to neutral pictures. Conclusions. This is the first study to unravel (1) a general autonomic hypoactivity in ADHD children at baseline and in response to low arousing neutral and highly arousing emotional stimuli, and (2) hints that MPH normalizes this hypoactivity. Results contribute to the understanding of ADHD aetiology and MPH functionality, and are consistent with the cognitive-energetic model of ADHD.     

Nationwide analysis on surgical procedures for patients with endometrial cancer in Germany: Results of the AGO pattern of care studies from the years 2013, 2009, and 2006

Purpose

In 2013, 2009, and 2006, the Arbeitsgemeinschaft Gynäkologische Onkologie evaluated the therapeutic approaches and the adherence to their guidelines for endometrial carcinoma (EC) in Germany. Here, we present the results concerning the surgical procedures.

Methods

A questionnaire was developed and sent to 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006). The results were compared with the recommendations of the guideline and with each other.

Results

Responses were available in 40.0 % in 2013, 33.3 % in 2009, and 35.8 % in 2006, respectively. Pelvic lymphadenectomy (LAN) was performed in accordance with the guidelines with some exceptions in 2013, 2009, and 2006, whereas paraaortic LAN was performed in accordance with the guideline only in 2009. Histological high-risk subtypes of EC received pelvic and paraaortic LAN in 2013, 2009, and 2006 in accordance with the guidelines with small exceptions. LAN for Patients, who were postoperatively upstaged or upgraded, was not conducted in accordance with the guidelines in 2013, 2009, and 2006. In 2013, 84.6 % of the participants offered the laparoscopic approach (LSA) for hysterectomy and bilateral salpingo-oophorectomy, 63.3 % for pelvic LAN, and 49.1 % for paraaortic LAN, respectively. More participants offered the LSA in 2013 compared to 2009 and 2006 (p values <0.014).

Conclusions

The paraaortic LAN was the second operation on patients, who are postoperatively upstaged, and the LSA was not conducted in accordance with the guideline. Improvements concerning surgical treatment are possible and might lead to higher survival rates and a reduction of morbidity in patients with EC in Germany.     

The one year exercise and lifestyle intervention program KLAKS: Effects on anthropometric parameters,cardiometabolic risk factors and glycemic control in childhood obesity

Objective

Regular physical exercise within structured lifestyle programs may improve weight status and minimize metabolic risk factors in childhood obesity. The aim of this study was to evaluate the effect of the one-year combined physical exercise/lifestyle program KLAKS on anthropometric and metabolic parameters and glycemic control in childhood obesity.

Materials and Methods

142 overweight/obese (BMI > 90th percentile) candidates (7–18 years) were enrolled, 115 participants completed the program. Anthropometrics and biochemical parameters were obtained at beginning and completion. An oral glucose tolerance test (OGTT) was performed in a subgroup of participants. Course of glucose and insulin levels within OGTT was correlated with several parameters and is reported here for those who completed the program.

Results

The mean standard deviation scores (SDS) decreased significantly for BMI, waist circumference, waist-to-height ratio (WHtR) and percentage body fat (all p ≤ 0.01). Improved metabolic risk markers included mean glucose levels within an OGTT at follow-up compared to baseline (p < 0.0001) and HbA1c (p = 0.05) as well as indications of improvement for gamma-glutamyl-transferase and free fatty acids.

Conclusions

The one-year combined exercise/lifestyle program KLAKS significantly improves markers of obesity and glycemic control. Impaired cardiometabolic risk markers, even subclinical, are also favorably influenced by program participation.     

PROTEIN DISULFIDE ISOMERASE LIKE 5-1 is a susceptibility factor to plant viruses

Protein disulfide isomerases (PDIs) catalyze the correct folding of proteins and prevent the aggregation of unfolded or partially folded precursors. Whereas suppression of members of the PDI gene family can delay replication of several human and animal viruses (e.g., HIV), their role in interactions with plant viruses is largely unknown. Here, using a positional cloning strategy we identified variants of PROTEIN DISULFIDE ISOMERASE LIKE 5–1 (HvPDIL5-1) as the cause of naturally occurring resistance to multiple strains of Bymoviruses. The role of wild-type HvPDIL5-1 in conferring susceptibility was confirmed by targeting induced local lesions in genomes for induced mutant alleles, transgene-induced complementation, and allelism tests using different natural resistance alleles. The geographical distribution of natural genetic variants of HvPDIL5-1 revealed the origin of resistance conferring alleles in domesticated barley in Eastern Asia. Higher sequence diversity was correlated with areas with increased pathogen diversity suggesting adaptive selection for bymovirus resistance. HvPDIL5-1 homologs are highly conserved across species of the plant and animal kingdoms implying that orthologs of HvPDIL5-1 or other closely related members of the PDI gene family may be potential susceptibility factors to viruses in other eukaryotic species.Infectious diseases caused by plant viruses threaten agricultural productivity and reduce globally attainable agricultural production by about 3% (1). In specific pathosystems, plant viruses can result in the loss of the entire crop. For example, the devastation of cassava production by cassava mosaic geminiviruses (CMGs) in Uganda during the 1990s led to widespread food shortages and famine-related deaths (2). Unfortunately protecting plants against viruses (especially soil-borne viruses) by using agrochemicals to control virus vectors is seldom efficient from economic or ecological perspectives. Therefore, crop protection based on naturally occurring virus resistance is key to minimizing losses and achieving sustainable crop yields.Positive-strand RNA viruses represent the largest group of plant viruses (3). They cause a very high proportion of the important infectious virus diseases in agriculture (4, 5). Such plant viruses carry a reduced genome that encodes a limited set of functional proteins (4–10 viral proteins)—insufficient to complete the entire virus replication and proliferation cycle (6). Instead, over evolutionary time, viruses recruited host factors to perform the infectious life cycle (7). This dependence on host factors establishes a possibility that plants can evolve escape, tolerance, or resistance mechanisms to ameliorate the consequences of viral infection. The absence of essential host factors could interfere with the infection process or restrict proliferation (8) leading to either mono- or polygenic recessive resistance (5). Prominent examples of such susceptibility factors that are conserved in multiple plant–virus systems are the EUKARYOTIC TRANSLATION INITIATION FACTORS (EIF)4E, iso4E, 4G, and iso4G (9). Translation initiation factors may interact directly with viral RNA where they catalyze the initiation of translation of viral polyproteins (10, 11). In addition, to establish replication and assembly complexes during infection, viruses typically create membrane-bound environments, referred to as “virus factories” (12). There, cellular chaperones such as HSP70 and DNAJ-like proteins likely contribute to the correct folding and translocation of substrates (12, 13). However, only a few such host factors are known (7, 9, 14).Barley yellow mosaic virus disease caused by barley yellow mosaic virus (BaYMV) and barley mild mosaic virus (BaMMV) (both belong to Bymoviruses) seriously threatens winter barley production in Europe and East Asia (4). Infection leads to yellow discoloration and stunted growth and may result in yield loss of up to 50% (15). Soil-borne transmission via the plasmodiophorid Polymyxa graminis prohibits plant protection by chemical measures, and breeding for resistant cultivars is therefore the only practicable way to prevent yield loss. The naturally occurring recessive resistance locus rym11 confers complete broad-spectrum resistance to all known European isolates of BaMMV and BaYMV (16–19). In the present study, we used a positional cloning strategy to identify the gene underlying rym11-based resistance. We show that it is a susceptibility factor belonging to a gene family of PROTEIN DISULFIDE ISOMERASES (PDIs), and is highly conserved across eukaryotic species. We observe a strong correlation between natural allelic variation and geographic distribution, suggesting that both the origin and subsequent adaptive selection for rym11-based resistance in winter barley occurred in East Asia.     

The combination of daily breakfast consumption and optimal breakfast choices in childhood is an important public health message

The aim of this study was to investigate the association of breakfast consumption with children’s diet quality and cardiometabolic risk factors. Study sample consisted of 1558 children aged 4–8 years from Cyprus. Breakfast frequency was assessed through a parental questionnaire. Body mass index (BMI), BMI z-scores, waist circumference, blood lipid profile and blood pressure were examined in relation to breakfast frequency consumption. Habitual breakfast consumers’ daily nutrient intake was assessed through a 24-Hour Dietary Recall, according to their breakfast choices. Girls who have breakfast on a daily basis had lower mean BMI and BMI z-score; they were also less likely of having abnormal levels of serum triglycerides, atheromatic index (total cholesterol to high density lipoprotein-cholesterol ratio) and diastolic blood pressure after controlling for several confounding factors. Within regular breakfast consumers, of both boys and girls, those having ready to eat cereals had a superior nutrient intake profile. Daily breakfast consumption along with good breakfast choices is an important public health message for Cypriot children.