Genetic Factors Associated with the Development of Neuropathy in Type 2 Diabetes.

Neuropathy is a serious and frequent complication of type 2 diabetes (T2DM). This study was carried out to search for genetic factors associated with the development of diabetic neuropathy by whole exome sequencing. For this study, 24 patients with long-term type 2 diabetes with neuropathy and 24 without underwent detailed neurological assessment and whole exome sequencing. Cardiovascular autonomic function was evaluated by cardiovascular reflex tests. Heart rate variability was measured by the triangle index. Sensory nerve function was estimated by Neurometer and Medoc devices. Neuropathic symptoms were characterized by the neuropathy total symptom score (NTSS). Whole exome sequencing (WES) was performed on a Thermo Ion GeneStudio S5 system determining the coding sequences of approximately 32,000 genes comprising 50 million base pairs. Variants were detected by Ion Reporter software and annotated using ANNOVAR, integrating database information from dbSNP, ClinVar, gnomAD, and OMIM. Integrative genomics viewer (IGV) was used for visualization of the mapped reads. We have identified genetic variants that were significantly associated with increased (22-49-fold) risk of neuropathy (rs2032930 and rs2032931 of recQ-mediated genome instability protein 2 (RMI2) gene), rs604349 of myosin binding protein H like (MYBPHL) gene and with reduced (0.07-0.08-fold) risk (rs917778 of multivesicular body subunit 12B (MVB12B) and rs2234753 of retinoic acid X receptor alpha (RXRA) genes). The rs2032930 showed a significant correlation with current perception thresholds measured at 5 Hz and 250 Hz for n. medianus (p = 0.042 and p = 0.003, respectively) and at 5 Hz for n. peroneus (p = 0.037), as well as the deep breath test (p = 0.022) and the NTSS (p = 0.023). The rs2032931 was associated with current perception thresholds (p = 0.003 and p = 0.037, respectively), deep breath test (p = 0.022), and NTSS (p = 0.023). The rs604349 correlated with values measured at 2000 (p = 0.049), 250 (p = 0.018), and 5 Hz (p = 0.005) for n. medianus, as well as warm perception threshold measured by Medoc device (p = 0.042). The rs2234753 showed correlations with a current perception threshold measured at 2000 Hz for n. medianus (p = 0.020), deep breath test (p = 0.040), and NTSS (p = 0.003). There was a significant relationship between rs91778 and cold perception threshold (p = 0.013). In our study, genetic variants have been identified that may have an impact on the risk of neuropathy developing in type 2 diabetic patients. These results could open up new opportunities for early preventive measures and might provide targets for new drug developments in the future.

Saving Energy Using the Modified Heuristic Algorithm for Energy Saving (MHAES) in Software-Defined Networks.

Energy consumption is a significant concern in daily life, often neglected in terms of cost and environmental impact. Since IT networks play an essential role in our daily routines, energy-saving in this area is crucial. However, the implementation of energy efficiency solutions in this field have to ensure that the network performance is minimally affected. Traditional networks encounter difficulties in achieving this goal. Software-Defined Networks (SDN), which have gained popularity in the past decade, offer easy-to-use opportunities to increase energy efficiency. Features like central controllability and quick programmability can help to reduce energy consumption. In this article, a new algorithm named the Modified Heuristic Algorithm for Energy Saving (MHAES) is presented, which was compared to eight commonly used methods in different topologies for energy efficiency. The results indicate that by maintaining an appropriate load balance, one can save more energy than in case of using some other well-known procedures by applying a threshold value based on forecast, keeping only a minimal number of nodes in an active state, and ensuring that nodes not participating in packet transmission remain in sleep mode.

The burden of mental disorders, substance use disorders and self-harm among young people in Europe, 1990-2019: Findings from the Global Burden of Disease Study 2019.

Background: Mental health is a public health issue for European young people, with great heterogeneity in resource allocation. Representative population-based studies are needed. The Global Burden of Disease (GBD) Study 2019 provides internationally comparable information on trends in the health status of populations and changes in the leading causes of disease burden over time. Methods: Prevalence, incidence, Years Lived with Disability (YLDs) and Years of Life Lost (YLLs) from mental disorders (MDs), substance use disorders (SUDs) and self-harm were estimated for young people aged 10-24 years in 31 European countries. Rates per 100,000 population, percentage changes in 1990-2019, 95% Uncertainty Intervals (UIs), and correlations with Sociodemographic Index (SDI), were estimated. Findings: In 2019, rates per 100,000 population were 16,983 (95% UI 12,823 - 21,630) for MDs, 3,891 (3,020 - 4,905) for SUDs, and 89·1 (63·8 - 123·1) for self-harm. In terms of disability, anxiety contributed to 647·3 (432-912·3) YLDs, while in terms of premature death, self-harm contributed to 319·6 (248·9-412·8) YLLs, per 100,000 population. Over the 30 years studied, YLDs increased in eating disorders (14·9%;9·4-20·1) and drug use disorders (16·9%;8·9-26·3), and decreased in idiopathic developmental intellectual disability (-29·1%;23·8-38·5). YLLs decreased in self-harm (-27·9%;38·3-18·7). Variations were found by sex, age-group and country. The burden of SUDs and self-harm was higher in countries with lower SDI, MDs were associated with SUDs. Interpretation: Mental health conditions represent an important burden among young people living in Europe. National policies should strengthen mental health, with a specific focus on young people. Funding: The Bill and Melinda Gates Foundation.

Familiarity with images affects how dogs ( Canis familiaris) process life-size video projections of humans.

A central problem of behavioural studies providing artificial visual stimuli for non-human animals is to determine how subjects perceive and process these stimuli. Especially in the case of videos, it is important to ascertain that animals perceive the actual content of the images and are not just reacting to the motion cues in the presentation. In this study, we set out to investigate how dogs process life-sized videos. We aimed to find out whether dogs perceive the actual content of video images or whether they only react to the videos as a set of dynamic visual elements. For this purpose, dogs were presented with an object search task where a life-sized projected human was hiding a target object. The videos were either normally oriented or displayed upside down, and we analysed dogs' reactions towards the projector screen after the video presentations, and their performance in the search task. Results indicated that in the case of the normally oriented videos, dogs spontaneously perceived the actual content of the images. However, the 'Inverted' videos were first processed as a set of unrelated visual elements, and only after some exposure to these videos did the dogs show signs of perceiving the unusual configuration of the depicted scene. Our most important conclusion was that dogs process the same type of artificial visual stimuli in different ways, depending on the familiarity of the depicted scene, and that the processing mode can change with exposure to unfamiliar stimuli.

Do you see what I see? The difference between dog and human visual perception may affect the outcome of experiments.

The visual sense of dogs is in many aspects different than that of humans. Unfortunately, authors do not explicitly take into consideration dog-human differences in visual perception when designing their experiments. With an image manipulation program we altered stationary images, according to the present knowledge about dog-vision. Besides the effect of dogs' dichromatic vision, the software shows the effect of the lower visual acuity and brightness discrimination, too. Fifty adult humans were tested with pictures showing a female experimenter pointing, gazing or glancing to the left or right side. Half of the pictures were shown after they were altered to a setting that approximated dog vision. Participants had difficulty to find out the direction of glancing when the pictures were in dog-vision mode. Glances in dog-vision setting were followed less correctly and with a slower response time than other cues. Our results are the first that show the visual performance of humans under circumstances that model how dogs' weaker vision would affect their responses in an ethological experiment. We urge researchers to take into consideration the differences between perceptual abilities of dogs and humans, by developing visual stimuli that fit more appropriately to dogs' visual capabilities.

[Vitamin D metabolism and signaling in human hepatocellular carcinoma and surrounding non-tumorous liver]. / A D-vitamin metabolizmusa humán hepatocellularis carcinomában és az azt körülvevo tumormentes májszövetben.

INTRODUCTION: 1,25-Dihydroxy vitamin D3 mediates antitumor effects in hepatocellular carcinoma. AIM: We examined mRNA and protein expression differences in 1,25-Dihydroxy vitamin D3-inactivating CYP24A1, mRNA of activating CYP27B1 enzymes, and that of VDR between human hepatocellular carcinoma and surrounding non-tumorous liver. METHODS: Snap-frozen tissues from 13 patients were studied for mRNA and protein expression of CYP24A1. Paraffin-embedded tissues from 36 patients were used to study mRNA of VDR and CYP27B1. mRNA expression was measured by RT-PCR, CYP24A1 protein was detected by immunohistochemistry. RESULTS: Expression of VDR and CYP27B1 was significantly lower in hepatocellular carcinoma compared with non-tumorous liver (p<0.05). The majority of the HCC samples expressed CYP24A1 mRNA, but neither of the non-tumorous liver. The gene activation was followed by CYP24A1 protein synthesis. CONCLUSIONS: The presence of CYP24A1 mRNA and the reduced expression of VDR and CYP27B1 mRNA in human hepatocellular carcinoma samples indicate decreased bioavailability of 1,25-Dihydroxy vitamin D3, providing an escape mechanism from the anti-tumor effect. Orv. Hetil., 2016, 157(48), 1910-1918.

I saw where you have been--The topography of human demonstration affects dogs' search patterns and perseverative errors.

Performance in object search tasks is not only influenced by the subjects' object permanence ability. For example, ostensive cues of the human manipulating the target markedly affect dogs' choices. However, the interference between the target's location and the spatial cues of the human hiding the object is still unknown. In a five-location visible displacement task, the experimental groups differed in the hiding route of the experimenter. In the 'direct' condition he moved straight towards the actual location, hid the object and returned to the dog. In the 'indirect' conditions, he additionally walked behind each screen before returning. The two 'indirect' conditions differed from each other in that the human either visited the previously baited locations before (proactive interference) or after (retroactive interference) hiding the object. In the 'indirect' groups, dogs' performance was significantly lower than in the 'direct' group, demonstrating that for dogs, in an ostensive context, spatial cues of the hider are as important as the observed location of the target. Based on their incorrect choices, dogs were most attracted to the previously baited locations that the human visited after hiding the object in the actual trial. This underlines the importance of retroactive interference in multiple choice tasks.

Clinical Use of Next-Generation Sequencing in the Diagnosis of Wilson's Disease.

Objective. Wilson's disease is a disorder of copper metabolism which is fatal without treatment. The great number of disease-causing ATP7B gene mutations and the variable clinical presentation of WD may cause a real diagnostic challenge. The emergence of next-generation sequencing provides a time-saving, cost-effective method for full sequencing of the whole ATP7B gene compared to the traditional Sanger sequencing. This is the first report on the clinical use of NGS to examine ATP7B gene. Materials and Methods. We used Ion Torrent Personal Genome Machine in four heterozygous patients for the identification of the other mutations and also in two patients with no known mutation. One patient with acute on chronic liver failure was a candidate for acute liver transplantation. The results were validated by Sanger sequencing. Results. In each case, the diagnosis of Wilson's disease was confirmed by identifying the mutations in both alleles within 48 hours. One novel mutation (p.Ala1270Ile) was found beyond the eight other known ones. The rapid detection of the mutations made possible the prompt diagnosis of WD in a patient with acute liver failure. Conclusions. According to our results we found next-generation sequencing a very useful, reliable, time-saving, and cost-effective method for diagnosing Wilson's disease in selected cases.

A simple but powerful test of perseverative search in dogs and toddlers.

Perseverative (A-not-B) errors during the search of a hidden object were recently described in both dogs and 10-month-old infants. It was found that ostensive cues indicating a communicative intent of the person who hides the object played a major role in eliciting perseverative errors in both species. However, the employed experimental set-up gave rise to several alternative explanations regarding the source of these errors. Here we present a simplified protocol that eliminates the ambiguities present in the original design. Using five consecutive object hiding events to one of two locations in a fixed order ("AABBA"), we tested adult companion dogs and human children (24 months old). The experimenter performed the hiding actions while giving ostensive cues in each trial and moved the target object to the given location in a straight line. Our results show that in the B trials, both 24-month-old children and dogs could not reliably find the hidden object, and their performance in the first B trials was significantly below that of any of the A trials. These results are the first to show that the tendency for perseverative errors in an ostensive-communicative context is a robust phenomenon among 2-year-old children and dogs, and not the by-product of a topographically elaborate hiding event.

Test sensitivity is important for detecting variability in pointing comprehension in canines.

Several articles have been recently published on dogs' (Canis familiaris) performance in two-way object choice experiments in which subjects had to find hidden food by utilizing human pointing. The interpretation of results has led to a vivid theoretical debate about the cognitive background of human gestural signal understanding in dogs, despite the fact that many important details of the testing method have not yet been standardized. We report three experiments that aim to reveal how some procedural differences influence adult companion dogs' performance in these tests. Utilizing a large sample in Experiment 1, we provide evidence that neither the keeping conditions (garden/house) nor the location of the testing (outdoor/indoor) affect a dogs' performance. In Experiment 2, we compare dogs' performance using three different types of pointing gestures. Dogs' performance varied between momentary distal and momentary cross-pointing but "low" and "high" performer dogs chose uniformly better than chance level if they responded to sustained pointing gestures with reinforcement (food reward and a clicking sound; "clicker pointing"). In Experiment 3, we show that single features of the aforementioned "clicker pointing" method can slightly improve dogs' success rate if they were added one by one to the momentary distal pointing method. These results provide evidence that although companion dogs show a robust performance at different testing locations regardless of their keeping conditions, the exact execution of the human gesture and additional reinforcement techniques have substantial effect on the outcomes. Consequently, researchers should standardize their methodology before engaging in debates on the comparative aspects of socio-cognitive skills because the procedures they utilize may differ in sensitivity for detecting differences.