Anti glutamate-decarboxylase antibodies: A liaison between localisation related epilepsy, stiff-person syndrome and type-1 diabetes mellitus

We present two patients with partial epilepsy, type-1 diabetes and stiff person syndrome associated with high serum autoantibody levels to glutamate-decarboxylase (anti-GAD). Both patients were or have suffered from additional autoimmune conditions. The presence of stiff person syndrome and elevated anti-GAD levels have to make clinicians look for additional autoimmune conditions including type-1 diabetes. On the other hand, the co-morbidity of partial epilepsy with autoimmune conditions in patients with elevated serum anti-GAD suggests an autoimmune mechanism of partial epilepsy in these cases

LADA type diabetes, celiac diasease, cerebellar ataxia and stiff person syndrome. A rare association of autoimmune disorders.

Celiac disease--in its typical form--is a chronic immune-mediated enteropathy with typical clinical symptoms that develops against gliadin content of cereal grains, and is often associated with other autoimmune diseases. In cases of atypical manifestation classic symptoms may be absent or mild, and extra-intestinal symptoms or associated syndromes dominate clinical picture. The authors present a longitudinal follow-up of such a case. A 63-years old woman was diagnosed with epilepsy at the age of 19, and with progressive limb ataxia at the age of 36, which was initially thought to be caused by cerebellar atrophy, later probably by stiff person syndrome. At the age 59, her diabetes mellitus manifested with type 2 diabetic phenotype, but based on GAD positivity later was reclassified as type 1 diabetes. Only the last check-up discovered the celiac disease, retrospectively explaining the entire disease course and neurological symptoms. By presenting this case, the authors would like to draw attention to the fact that one should think of the possibility of celiac disease when cerebellar ataxia, progressive neurological symptoms and diabetes are present at the same time. An early diagnosis may help to delay the progression of disease and help better treatment

Disappearing scales in carps: Re-visiting Kirpichnikov's model on the genetics of scale pattern formation

The body of most fishes is fully covered by scales that typically form tight, partially overlapping rows. While some of the genes controlling the formation and growth of fish scales have been studied, very little is known about the genetic mechanisms regulating scale pattern formation. Although the existence of two genes with two pairs of alleles (S&s and N&n) regulating scale coverage in cyprinids has been predicted by Kirpichnikov and colleagues nearly eighty years ago, their identity was unknown until recently. In 2009, the ‘S’ gene was found to be a paralog of fibroblast growth factor receptor 1, fgfr1a1, while the second gene called ‘N’ has not yet been identified. We re-visited the original model of Kirpichnikov that proposed four major scale pattern types and observed a high degree of variation within the so-called scattered phenotype due to which this group was divided into two sub-types: classical mirror and irregular. We also analyzed the survival rates of offspring groups and found a distinct difference between Asian and European crosses. Whereas nude × nude crosses involving at least one parent of Asian origin or hybrid with Asian parent(s) showed the 25% early lethality predicted by Kirpichnikov (due to the lethality of the NN genotype), those with two Hungarian nude parents did not. We further extended Kirpichnikov's work by correlating changes in phenotype (scale-pattern) to the deformations of fins and losses of pharyngeal teeth. We observed phenotypic changes which were not restricted to nudes, as described by Kirpichnikov, but were also present in mirrors (and presumably in linears as well; not analyzed in detail here). We propose that the gradation of phenotypes observed within the scattered group is caused by a gradually decreasing level of signaling (a dose-dependent effect) probably due to a concerted action of multiple pathways involved in scale formation

Physical similarity or numerical representation counts in same-different, numerical comparison, physical comparison, and priming tasks?

Recent studies have highlighted the fact that some tasks used to study symbolic number representations are confounded by judgments about physical similarity. Here, we investigated whether the contribution of physical similarity and numerical representation differed in the often-used symbolic same-different, numerical comparison, physical comparison, and priming tasks. Experiment 1 showed that subjective physical similarity was the best predictor of participants' performance in the same-different task, regardless of simultaneous or sequential presentation. Furthermore, the contribution of subjective physical similarity was larger in a simultaneous presentation than in a sequential presentation. Experiment 2 showed that only numerical representation was involved in numerical comparison. Experiment 3 showed that both subjective physical similarity and numerical representation contributed to participants' physical comparison performance. Finally, only numerical representation contributed to participants' performance in a priming task as revealed by Experiment 4. Taken together, the contribution of physical similarity and numerical representation depends on task demands. Performance primarily seems to rely on numerical properties in tasks that require explicit quantitative comparison judgments (physical or numerical), while physical stimulus properties exert an effect in the same-different task.This study was funded by the National Natural Science Foundation of China [grant no. 31470996]; and Major Project of the National Social Science Foundation of China [grant no. 14ZDB160]

Effects of photo and thermo cycles on flowering time in barley: a genetical phenomics approach

The effects of synchronous photo (16 h daylength) and thermo (2 °C daily fluctuation) cycles on flowering time were compared with constant light and temperature treatments using two barley mapping populations derived from the facultative cultivar ‘Dicktoo’. The ‘Dicktoo’בMorex’ (spring) population (DM) segregates for functional differences in alleles of candidate genes for VRN-H1, VRN-H3, PPD-H1, and PPD-H2. The first two loci are associated with the vernalization response and the latter two with photoperiod sensitivity. The ‘Dicktoo’בKompolti korai’ (winter) population (DK) has a known functional polymorphism only at VRN-H2, a locus associated with vernalization sensitivity. Flowering time in both populations was accelerated when there was no fluctuating factor in the environment and was delayed to the greatest extent with the application of synchronous photo and thermo cycles. Alleles at VRN-H1, VRN-H2, PPD-H1, and PPD-H2—and their interactions—were found to be significant determinants of the increase/decrease in days to flower. Under synchronous photo and thermo cycles, plants with the Dicktoo (recessive) VRN-H1 allele flowered significantly later than those with the Kompolti korai (recessive) or Morex (dominant) VRN-H1 alleles. The Dicktoo VRN-H1 allele, together with the late-flowering allele at PPD-H1 and PPD-H2, led to the greatest delay. The application of synchronous photo and thermo cycles changed the epistatic interaction between VRN-H2 and VRN-H1: plants with Dicktoo type VRN-H1 flowered late, regardless of the allele phase at VRN-H2. Our results are novel in demonstrating the large effects of minor variations in environmental signals on flowering time: for example, a 2 °C thermo cycle caused a delay in flowering time of 70 d as compared to a constant temperature

Opposite prognostic roles of HIF1alpha and HIF2alpha expressions in bone metastatic clear cell renal cell cancer

BACKGROUND: Prognostic markers of bone metastatic clear cell renal cell cancer (ccRCC) are poorly established. We tested prognostic value of HIF1alpha/HIF2alpha and their selected target genes in primary tumors and corresponding bone metastases. RESULTS: Expression of HIF2alpha was lower in mRCC both at mRNA and protein levels (p/mRNA/=0.011, p/protein/=0.001) while HIF1alpha was similar to nmRCC. At the protein level, CAIX, GAPDH and GLUT1 were increased in mRCC. In all primary RCCs, low HIF2alpha and high HIF1alpha as well as CAIX, GAPDH and GLUT1 expressions correlated with adverse prognosis, while VEGFR2 and EPOR gene expressions were associated with favorable prognosis. Multivariate analysis confirmed high HIF2alpha protein expression as an independent risk factor. Prognostic validation of HIFs, LDH, EPOR and VEGFR2 in RNA-Seq data confirmed higher HIF1alpha gene expression in primary RCC as an adverse (p=0.07), whereas higher HIF2alpha and VEGFR2 expressions as favorable prognostic factors. HIF1alpha/HIF2alpha-index (HIF-index) proved to be an independent prognostic factor in both the discovery and the TCGA cohort. PATIENTS AND METHODS: Expressions of HIF1alpha and HIF2alpha as well as their 7 target genes were analysed on the mRNA and protein level in 59 non-metastatic ccRCCs (nmRCC), 40 bone metastatic primary ccRCCs (mRCC) and 55 corresponding bone metastases. Results were validated in 399 ccRCCs from the TCGA project. CONCLUSIONS: We identified HIF2alpha protein as an independent marker of the metastatic potential of ccRCC, however, unlike HIF1alpha, increased HIF2alpha expression is a favorable prognostic factor. The HIF-index incorporated these two markers into a strong prognostic biomarker of ccRCC

Restoration of energy level in the early phase of acute pediatric pancreatitis

Acute pancreatitis (AP) is a serious inflammatory disease with rising incidence both in the adult and pediatric populations. It has been shown that mitochondrial injury and energy depletion are the earliest intracellular events in the early phase of AP. Moreover, it has been revealed that restoration of intracellular ATP level restores cellular functions and defends the cells from death. We have recently shown in a systematic review and meta-analysis that early enteral feeding is beneficial in adults; however, no reviews are available concerning the effect of early enteral feeding in pediatric AP. In this minireview, our aim was to systematically analyse the literature on the treatment of acute pediatric pancreatitis. The preferred reporting items for systematic review (PRISMA-P) were followed, and the question was drafted based on participants, intervention, comparison and outcomes: P: patients under the age of twenty-one suffering from acute pancreatitis; I: early enteral nutrition (per os and nasogastric- or nasojejunal tube started within 48 h); C: nil per os therapy; O: length of hospitalization, need for treatment at an intensive care unit, development of severe AP, lung injury (including lung oedema and pleural effusion), white blood cell count and pain score on admission. Altogether, 632 articles (PubMed: 131; EMBASE: 501) were found. After detailed screening of eligible papers, five of them met inclusion criteria. Only retrospective clinical trials were available. Due to insufficient information from the authors, it was only possible to address length of hospitalization as an outcome of the study. Our mini-meta-analysis showed that early enteral nutrition significantly (SD = 0.806, P = 0.034) decreases length of hospitalization compared with nil per os diet in acute pediatric pancreatitis. In this minireview, we clearly show that early enteral nutrition, started within 24-48 h, is beneficial in acute pediatric pancreatitis. Prospective studies and better presentation of research are crucially needed to achieve a higher level of evidence

Interactions of pathological hallmark proteins: Tubulin polymerization promoting protein/p25, {beta}-amyloid and {alpha}-synuclein

The disordered tubulin polymerization promoting protein (TPPP/p25) was found to be co-enriched in neuronal and glial inclusions with α-synuclein in Parkinson disease and multiple system atrophy, respectively; however, co-occurrence of α-synuclein with β-amyloid (Aβ) in human brain inclusions has been recently reported, suggesting the existence of mixed type pathologies that could result in obstacles in the correct diagnosis and treatment. Here we identified TPPP/p25 as an interacting partner of the soluble Aβ oligomers as major risk factors for Alzheimer disease using ProtoArray human protein microarray. The interactions of oligomeric Aβ with proteins involved in the etiology of neurological disorders were characterized by ELISA, surface plasmon resonance, pelleting experiments, and tubulin polymerization assay. We showed that the Aβ(42) tightly bound to TPPP/p25 (K(d) = 85 nm) and caused aberrant protein aggregation by inhibiting the physiologically relevant TPPP/p25-derived microtubule assembly. The pair-wise interactions of Aβ(42), α-synuclein, and tubulin were found to be relatively weak; however, these three components formed soluble ternary complex exclusively in the absence of TPPP/p25. The aggregation-facilitating activity of TPPP/p25 and its interaction with Aβ was monitored by electron microscopy with purified proteins by pelleting experiments with cell-free extracts as well as by confocal microscopy with CHO cells expressing TPPP/p25 or amyloid. The finding that the interaction of TPPP/p25 with Aβ can produce pathological-like aggregates is tightly coupled with unusual pathology of the Alzheimer disease revealed previously; that is, partial co-localization of Aβ and TPPP/p25 in the case of diffuse Lewy body disease with Alzheimer disease

Mechanisms and Modulation of Oxidative/Nitrative Stress in Type 4 Cardio-Renal Syndrome and Renal Sarcopenia

Chronic kidney disease (CKD) is a public health problem and a recognized risk factor for cardiovascular diseases (CVD). CKD could amplify the progression of chronic heart failure leading to the development of type 4 cardio-renal syndrome (T4CRS). The severity and persistence of heart failure are strongly associated with mortality risk in T4CRS. CKD is also a catabolic state leading to renal sarcopenia which is characterized by the loss of skeletal muscle strength and physical function. Renal sarcopenia also promotes the development of CVD and increases the mortality in CKD patients. In turn, heart failure developed in T4CRS could result in chronic muscle hypoperfusion and metabolic disturbances leading to or aggravating the renal sarcopenia. The interplay of multiple factors (e.g., comorbidities, over-activated renin-angiotensin-aldosterone system [RAAS], sympathetic nervous system [SNS], oxidative/nitrative stress, inflammation, etc.) may result in the progression of T4CRS and renal sarcopenia. Among these factors, oxidative/nitrative stress plays a crucial role in the complex pathomechanism and interrelationship between T4CRS and renal sarcopenia. In the heart and skeletal muscle, mitochondria, nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, uncoupled nitric oxide synthase (NOS) and xanthine oxidase are major ROS sources producing superoxide anion (O2·−) and/or hydrogen peroxide (H2O2). O2·− reacts with nitric oxide (NO) forming peroxynitrite (ONOO−) which is a highly reactive nitrogen species (RNS). High levels of ROS/RNS cause lipid peroxidation, DNA damage, interacts with both DNA repair enzymes and transcription factors, leads to the oxidation/nitration of key proteins involved in contractility, calcium handling, metabolism, antioxidant defense mechanisms, etc. It also activates the inflammatory response, stress signals inducing cardiac hypertrophy, fibrosis, or cell death via different mechanisms (e.g., apoptosis, necrosis) and dysregulates autophagy. Therefore, the thorough understanding of the mechanisms which lead to perturbations in oxidative/nitrative metabolism and its relationship with pro-inflammatory, hypertrophic, fibrotic, cell death and other pathways would help to develop strategies to counteract systemic and tissue oxidative/nitrative stress in T4CRS and renal sarcopenia. In this review, we also focus on the effects of some well-known and novel pharmaceuticals, nutraceuticals, and physical exercise on cardiac and skeletal muscle oxidative/nitrative stress in T4CRS and renal sarcopenia