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Methods to assess neuronal receptor functions are needed in toxicology and for drug development. Human-based test systems that allow studies on glutamate signalling are still scarce. To address this issue, we developed and characterized pluripotent stem cell (PSC)-based neural cultures capable of forming a functional network. Starting from a stably proliferating neuroepithelial stem cell (NESC) population, we generate “mixed cortical cultures” (MCC) within 24 days. Characterization by immunocytochemistry, gene expression profiling and functional tests (multi-electrode arrays) showed that MCC contain various functional neurotransmitter receptors, and in particular, the N-methyl-d-aspartate subtype of ionotropic glutamate receptors (NMDA-R). As this important receptor is found neither on conventional neural cell lines nor on most stem cell-derived neurons, we focused here on the characterization of rapid glutamate-triggered Ca2+ signalling. Changes of the intracellular free calcium ion concentration ([Ca2+]i) were measured by fluorescent imaging as the main endpoint, and a method to evaluate and quantify signals in hundreds of cells at the same time was developed. We observed responses to glutamate in the low µM range. MCC responded to kainate and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and a subpopulation of 50% had functional NMDA-R. The receptor was modulated by Mg2+, Zn2+ and Pb2+ in the expected ways, and various toxicologically relevant agonists (quinolinic acid, ibotenic acid, domoic acid) triggered [Ca2+]i responses in MCC. Antagonists, such as phencyclidine, ketamine and dextromethorphan, were also readily identified. Thus, the MCC developed here may fill an important gap in the panel of test systems available to characterize the effects of chemicals on neurotransmitter receptors.

Antibiotic resistance is an urgent public health threat that has received substantial attention from the world’s leading health agencies and national governmental bodies alike. However, despite increasing rates of antibiotic resistance, pharmaceutical companies are reluctant to develop new antibiotics due to scientific, regulatory, and financial barriers. Nonetheless, only a handful of countries have addressed this by implementing or proposing financial incentive models to promote antibiotic innovation. This study is comprised of a systematic review that aimed to understand which antibiotic incentive strategies are most recommended within the literature and subsequently analyzed these incentives to determine which are most likely to sustainably revitalize the antibiotic pipeline. Through a case study of Canada, we apply our incentive analysis to the Canadian landscape to provide decision-makers with a possible path forward. Based on our findings, we propose that Canada support the ongoing efforts of other countries by implementing a fully delinked subscription-based market entry reward. This paper seeks to spark action in Canada by shifting the national paradigm to one where antibiotic research and development is prioritized as a key element to addressing antibiotic resistance.

Inhibition of complex I of the mitochondrial respiratory chain (cI) by rotenone and methyl-phenylpyridinium (MPP +) leads to the degeneration of dopaminergic neurons in man and rodents. To formally describe this mechanism of toxicity, an adverse outcome pathway (AOP:3) has been developed that implies that any inhibitor of cI, or possibly of other parts of the respiratory chain, would have the potential to trigger parkinsonian motor deficits. We used here 21 pesticides, all of which are described in the literature as mitochondrial inhibitors, to study the general applicability of AOP:3 or of in vitro assays that are assessing its activation. Five cI, three complex II (cII), and five complex III (cIII) inhibitors were characterized in detail in human dopaminergic neuronal cell cultures. The NeuriTox assay, examining neurite damage in LUHMES cells, was used as in vitro proxy of the adverse outcome (AO), i.e., of dopaminergic neurodegeneration. This test provided data on whether test compounds were unspecific cytotoxicants or specifically neurotoxic, and it yielded potency data with respect to neurite degeneration. The pesticide panel was also examined in assays for the sequential key events (KE) leading to the AO, i.e., mitochondrial respiratory chain inhibition, mitochondrial dysfunction, and disturbed proteostasis. Data from KE assays were compared to the NeuriTox data (AO). The cII-inhibitory pesticides tested here did not appear to trigger the AOP:3 at all. Some of the cI/cIII inhibitors showed a consistent AOP activation response in all assays, while others did not. In general, there was a clear hierarchy of assay sensitivity: changes of gene expression (biomarker of neuronal stress) correlated well with NeuriTox data; mitochondrial failure (measured both by a mitochondrial membrane potential-sensitive dye and a respirometric assay) was about 10–260 times more sensitive than neurite damage (AO); cI/cIII activity was sometimes affected at > 1000 times lower concentrations than the neurites. These data suggest that the use of AOP:3 for hazard assessment has a number of caveats: (i) specific parkinsonian neurodegeneration cannot be easily predicted from assays of mitochondrial dysfunction; (ii) deriving a point-of-departure for risk assessment from early KE assays may overestimate toxicant potency. Supplementary Information The online version contains supplementary material available at 10.1007/s00204-020-02970-5., Article highlights Comparison of 21 data-rich mitochondrial toxicants for neurotoxicityQuantitative comparison of key event triggering thresholds for AOP:3Comparison of two cell models and two exposure times for neurotoxicityComparison of transcriptome changes and classical key event measures for sensitivity Supplementary Information The online version contains supplementary material available at 10.1007/s00204-020-02970-5.

Purpose:Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses.Experimental Design:We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers.Results:We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17).Conclusions:In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.

"Background. In an attempt to find genetic explanations for the heterogeneous characteristics of autistic patients, research has shown that parents of autistic children are more likely than parents of neurotypical children to exhibit autistic-like characteristics, meeting the criteria for the so-called “broad autism phenotype” . Subclinical autistic traits have been identified in the families of children with ASD, in both fathers and mothers, but the way in which specific parental phenotypes influence the child’s pathology remains unclear. Methods. This study aimed to analyse the progress that a group of children with Autism Spectrum Disorders (ASD) have made during a behavioural therapy programme and the way their evolution has been influenced by the parents’ systemizing level. 52 participants (aged 2 to 5 years old) diagnosed with an Autism Spectrum Disorder and both of their parents were included in the study. The severity of ASD symptomatology was assessed using the ADOS-G instrument, at the beginning of the study (T0) and after one year of behavioural therapy as well (T1), while the parents’ systemizing level was evaluated using the self-report Systemizing Quotient (SQ). Results. The ADOS-G scores showed a significant improvement after one year of therapy in both Communication and Social Interaction domains. Only the fathers` systemizing level (SQF) had a significant effect on the ADOS-G scores after one year of therapy, with greater improvements reported for children having fathers with higher SQF scores. Conclusion. The significance of these findings is discussed in relation to the empathizing-systemizing (E-S) theory. We consider that it’s particularly important to continue investigating the way that specific parents’ traits, including their systemizing level or their possible broad autism phenotype, can influence the severity of their children’s ASD or the outcome of the behavioural intervention."

A loss of GABA signaling is a prevailing hypothesis for the pathogenesis of schizophrenia. Preclinical studies indicate that blockade of the α5 subtype of the GABA receptor (α5-GABAARs) leads to behavioral phenotypes associated with schizophrenia, and postmortem evidence indicates lower hippocampal α5-GABAARs protein and mRNA levels in schizophrenia. However, it is unclear if α5-GABAARs are altered in vivo or related to symptoms. We investigated α5-GABAARs availability in antipsychotic-free schizophrenia patients and antipsychotic-medicated schizophrenia patients using [11C]Ro15-4513 PET imaging in a cross-sectional, case–control study design. Thirty-one schizophrenia patients (n = 10 antipsychotic free) and twenty-nine matched healthy controls underwent a [11C]Ro15-4513 PET scan and MRI. The α5 subtype GABA-A receptor availability was indexed using [11C]Ro15-4513 PET imaging. Dynamic PET data were analyzed using the two-tissue compartment model with an arterial plasma input function and total volume of distribution (VT) as the outcome measure. Symptom severity was assessed using the PANSS scale. There was significantly lower [11C]Ro15-4513 VT in the hippocampus of antipsychotic-free patients, but not in medicated patients (p = 0.64), relative to healthy controls (p 11C]Ro15-4513 VT and total PANSS score in antipsychotic-free patients (r = 0.72; p = 0.044). The results suggest that antipsychotic-free patients with schizophrenia have lower α5-GABAARs levels in the hippocampus, consistent with the hypothesis that GABA hypofunction underlies the pathophysiology of the disorder.

New generation sequencing (NGS) genetic testing is a powerful diagnostic tool and is increasingly used in the clinical workup of patients, especially in unusual presentations or where a positive family history suggests heritable disease. This review addresses the NGS technologies Targeted sequencing (TS), Whole exome sequencing (WES), Whole genome sequencing (WGS), and the use of gene panels or gene lists for clinical diagnostic purposes. These methods primarily assess nucleotide sequence but can also detect copy number variants and many tandem repeat expansions, greatly simplifying diagnostic algorithms for movement disorders. Studies evaluating the efficacy of NGS in diagnosing movement disorders have reported a diagnostic yield of up to 10.1% for familial and 15.7% for early-onset PD, 11.7–37.5% for dystonia, 12.1–61.8% for ataxia/spastic paraplegia and 11.3–28% for combined movement disorders. Patient selection and stringency in the interpretation of the detected variants and genotypes affect diagnostic yield. Careful comparison of the patient's or family's disease features with the previously reported phenotype associated with the same variant or gene can avoid false-positive diagnoses, although some genes are implicated in various phenotypes. Moving from TS to WES and WGS increases the number of patients correctly diagnosed, but for many patients, a genetic cause cannot be identified today. However, new genetically defined entities are discovered at rapid pace, and genetic databases and our knowledge of genotype-phenotype correlations expand steadily. We discuss the need for clear communication of genetic results and suggest a list of aspects to consider when reporting neurogenetic disorders using NGS testing.

Background The risk of outbreaks escalating into pandemics has soared with globalization. Therefore, understanding transmission mechanisms of infectious diseases has become critical to formulating global public health policy. This systematic review assessed evidence in the medical and public health literature for the military as a disease vector. Methods We searched 3 electronic databases without temporal restrictions. Two researchers independently extracted study data using a standardized form. Through team discussions, studies were grouped according to their type of transmission mechanism and direct quotes were extracted to generate themes and sub-themes. A content analysis was later performed and frequency distributions for each theme were generated. Results Of 6477 studies, 210 met our inclusion criteria and provided evidence, spanning over two centuries (1810–2020), for the military as a pathogen transmitter, within itself or between it and civilians. Biological mechanisms driving transmission included person-to-person transmission, contaminated food and water, vector-borne, and airborne routes. Contaminated food and/or water were the most common biological transmission route. Social mechanisms facilitating transmission included crowded living spaces, unhygienic conditions, strenuous working, training conditions, absent or inadequate vaccination programs, pressure from military leadership, poor compliance with public health advice, contractor mismanagement, high-risk behaviours, and occupation-specific freedom of movement. Living conditions were the most common social transmission mechanism, with young, low ranking military personnel repeatedly reported as the most affected group. Selected social mechanisms, such as employment-related freedom of movement, were unique to the military as a social institution. While few studies explicitly studied civilian populations, considerably more contained information that implied that civilians were likely impacted by outbreaks described in the military. Conclusions This study identified features of the military that pose a significant threat to global health, especially to civilian health in countries with substantial military presence or underdeveloped health systems. While biological transmission mechanisms are shared by other social groups, selected social transmission mechanisms are unique to the military. As an increasingly interconnected world faces the challenges of COVID-19 and future infectious diseases, the identified features of the military may exacerbate current and similar challenges and impair attempts to implement successful and equitable global public health policies.

ObjectiveTo determine the contribution of common genetic variants to risk of early onset ischemic stroke (IS).MethodsWe performed a meta-analysis of genome-wide association studies of early onset IS, ages 18-59, using individual level data or summary statistics in 16,927 cases and 576,353 non-stroke controls from 48 different studies across North America, Europe, and Asia. We further compared effect sizes at our most genome-wide significant loci between early and late onset IS and compared polygenic risk scores for venous thromboembolism between early versus later onset IS.ResultsWe observed an association between early onset IS and ABO, a known stroke locus. The effect size of the peak ABO SNP, rs8176685, was significantly larger in early compared to late onset IS (OR 1.17 (95% C.I.: 1.11-1.22) vs 1.05 (0.99-1.12); p for interaction = 0.008). Analysis of genetically determined ABO blood groups revealed that early onset IS cases were more likely to have blood group A and less likely to have blood group O compared to both non-stroke controls and to late onset IS cases. Using polygenic risk scores, we observed that greater genetic risk for venous thromboembolism, another prothrombotic condition, was more strongly associated with early, compared to late, onset IS (p=0.008).ConclusionThe ABO locus, genetically predicted blood group A, and higher genetic propensity for venous thrombosis are more strongly associated with early onset IS, compared with late onset IS, supporting a stronger role of prothrombotic factors in early onset IS.

Introduction: At present, the researchers are targeted to improve and increase the biocompatibility of dental materials that are in direct contact with biological tissues. The biocompatibility of the dental materials that contact the tissues of the oral cavity present relevance for the patient, clinician, dental technician, and manufacturer. Aim of the study: The aim of this study was represented by the comparative research regarding the comfort of the patients wearing removable partial prostheses with clasps made of wire and flexible polymers. Material and Methods. Patients wearing partial dentures from Meliodent heat-cured acrylic resins with wipla wire clasps, flexible partial dentures made from Valplast and dentures with clasps of CuSil silicone rubber participated in this study. The research was performed on 3 groups, of 8 patients each, in which comfort levels (according to 5 criteria) were determined, after 6, 12, 18, respectively 24 months of the partial removable prostheses insertion in the oral cavity. Results. Presence of decubitus lesions of the oral mucosa in the clasps areas was noticed mostly in the Valplast polyamide dentures (37.5%), existence of color changes at the base of prostheses and of clasps area appeared in 37.5% of the third group (CuSil PAD) patients, no patient included in the study presented allergic reactions and at the third and fourth recall, only 1 patient of all groups complained of unpleasant taste in the oral cavity. Conclusion. The removable prosthetic restorations with clasps made of flexible polymers and CuSil gaskets of silicone rubber, although initially much more comfortable and therefore much better accepted by patients, after two years were no longer active, could not be activated and necessited technical restorations, compared to those made of wipla wire clasps, which were activated with pliers, or, in the case of fracture, were replaced by the technician in the dental laboratory.

It is estimated that, with the increase of the life expectancy of the population, one in two people at the age of 85 years old will have a form of dementia. This will represent a real burden for medical systems, and an increasing responsibility for their families and for society. The behavioral and psychological symptoms of dementia continue to receive insufficient attention. These symptoms can be observed some years before an adequate diagnosis of dementia, and they can be the first signs of alarm before the development of specific cognitive pathology. Patients suffering from dementia can benefit from integrated medical services, specialized care at home or at the hospital, day care services, specialized health services, memory assessment services, psychological and home care therapies, together with a specific drug therapy. Taking into account all of these aspects presented above, the aim of the paper is to analyze if an earlier diagnosis of dementia can be done in clinical practice, because the initiation of earlier treatment, in the mild-to-moderate phase, can lead to a considerable improvement of cognitive functions. In this context, as dementia is diagnosed earlier, an appropriate treatment can also improve the behavioral symptomatology. Also, a multidisciplinary approach can be of real help in assessing, anticipating and managing all these issues.

Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VWFpp/VWF:Ag negatively correlated with FVIII half-life in patients with non-O blood type, but no correlation was observed for type O patients, suggesting that von Willebrand factor (VWF) half-life, as modified by the ABO blood group, is a strong regulator of FVIII PK. The FVIII-binding activity of VWF positively correlated with FVIII half-life, and the rare or low-frequency nonsynonymous VWF variants p.(Arg826Lys) and p.(Arg852Glu) were identified in patients with reduced VWF:FVIIIB but not VWF:Ag. Common variants at the VWF, CLEC4M, and STAB2 loci, which have been previously associated with plasma levels of VWF and FVIII, were associated with the FVIII PK profile. Together, these studies characterize the mechanistic basis by which VWF clearance and ABO glycosylation modify FVIII PK in a pediatric population. Moreover, this study is the first to identify non-VWF and non-ABO variants that modify FVIII PK in pediatric hemophilia A patients.

Motivation/Background: We aim at presenting a case that would circumscribe to the concept of schizo-obsessive disorder, in which the onset at the end of adolescence was with OC phenomenology, the negative symptoms appearing subsequently, while the productive perceptual and ideational area (auditory hallucinations and pseudohallucinations, next to the reference delusional ideation and Kandinsky Clerambault syndrome) developed at about one year and a half after social insulation. To be noticed that in residual phases, OC phenomenology acquires other connotations than those prior to schizophrenia onset, the patient never acquiring again a total insight on the disorder. Method: Computed EEG, psychiatric interview, psychodynamic interview, psychiatric and psychological monitoring of daily evolution under treatment, life map, heteroanamnesis, psychological tests, psychodynamic interpretations. Results: According to Poyurovsky’s guide, the case circumscribes to the diagnostic of schizo-obsessive disorder. When obsessions and compulsions were related to the content of delusional ideas and hallucinations, other typical rituals of obsessive-compulsive disorders appeared too, the patient considered sometimes irrational and excessive. Conclusions: Social degradation of the patient is dictated mainly by the negative dimension of schizophrenia, secondly by energy consumption in fulfilling the rituals and compulsions and last but not least by the mood change in depressive sense.

Suicide is one of the leading causes of death in the world, and depression is among the top causes of morbidity and mortality at international level. The main complication of any depression is precisely suicidal behavior, with all its facets. The present work is a succinct study aimed at highlighting the main categories of motivations that lead to suicidal behaviors in the spectrum of depression. The group of patients selected for this study presents all possible variants of diagnoses in the spectrum of endogenous depressions. The research reveals data on psychotic motivation, motivations in the socio-familial and professional sphere, as well as the correlation between the present suicidal behavior and the clinical form of depression. The findings emphasize once again the imperative need not to neglect any of the symptoms of depression, from anxiety to delusional hallucinatory phenomena, in correlation with the patient's entire bio-psycho-social context, to support the prevention of any form of suicidal behavior.

Delineating the gross tumor volume (GTV) is a core task within radiation treatment planning. GTVs must be precisely defined irrespective of the region involved, but even more so in a sensitive area such as the brain. As precision medicine cannot exist without precision imaging, the current article aims to discuss the various imaging modalities employed in the radiation treatment planning of brain tumors.Gliomas, meningiomas, and paragangliomas are some of the most challenging tumors and the advancement in diagnostic imaging can significantly contribute to their delineation. For gliomas, irradiation based on multiparametric magnetic resonance imaging (MRI) and amino-acid positron emission tomography (PET)/computed tomography (CT) may have a higher sensitivity and specificity, which could lead to a better sparing of organs at risk and help distinguish between tumor, edema, and radiogenic alterations. Meningiomas and paragangliomas are often associated with a good prognosis. Therefore, GTV delineation according to MRI and somatostatin receptor ligand-PET/CT plays an essential role in sparing sensitive structures and maintaining a good quality of life for these patients.The combination of multiparametric MRI and PET/CT (possibly in the form of PET/MRI) presently appears to be the optimal approach for target volume delineation. The comparative efficacy of these imaging modalities has to be further evaluated in prospective trials.

Background In 2002, Zambia withdrew chloroquine as first-line treatment for Plasmodium falciparum malaria due to increased treatment failure and worldwide spread of chloroquine resistance. The artemisinin combination regimen, artemether–lumefantrine, replaced chloroquine (CQ) as first choice malaria treatment. The present study determined the prevalence of CQ resistance molecular markers in the Pfcrt and Pfmdr1 genes in Eastern Zambia at 9 and 13 years after the removal of drug pressure. Methods Samples collected from Katete District during the drug therapeutic efficacy assessments conducted in 2012 and 2016 were assayed by polymerase chain reaction (PCR) and restriction fragment length polymorphisms (RFLP) to determine the prevalence of genetic mutations, K76T on the Pfcrt gene and N86Y on the Pfmdr1 gene. A total of 204 P. falciparum-positive DBS samples collected at these two time points were further analysed. Results Among the samples analysed for Pfcrt K76T and Pfmdr1 N86Y in the present study, 112 (82.4%) P. falciparum-infected samples collected in 2012 were successfully amplified for Pfcrt and 94 (69.1%) for Pfmdr1, while 69 (65.7%) and 72 (68.6%) samples from 2016 were successfully amplified for Pfcrt and Pfmdr1, respectively. In 2012, the prevalence of Pfcrt 76K (sensitive) was 97.3%, 76T (resistant) was 1.8%, and 0.8% had both 76K and 76T codons (mixed). Similarly in 2012, the prevalence of Pfmdr1 86N (sensitive) was 97.9% and 86Y (resistant) was 2.1%. In the 2016 samples, the prevalence of the respective samples was 100% Pfcrt 76K and Pfmdr1 86N. Conclusion This study shows that there was a complete recovery of chloroquine-sensitive parasites by 2016 in Katete District, Eastern Zambia, 13 years following the withdrawal of CQ in the country. These findings add to the body of evidence for a fitness cost in CQ-resistant P. falciparum in Zambia and elsewhere. Further studies are recommended to monitor resistance countrywide and explore the feasibility of integration of the former best anti-malarial in combination therapy in the future.

The interaction of reactive oxygen species (ROS) with lipids, proteins, nucleic acids and hydrocarbonates promotes acute and chronic tissue damage, mediates immunomodulation and triggers autoimmunity in systemic lupus erythematous (SLE) patients. The aim of the study was to determine the pathophysiological mechanisms of the oxidative stress-related damage and molecular mechanisms to counteract oxidative stimuli in lupus nephritis. Our study included 38 SLE patients with lupus nephritis (LN group), 44 SLE patients without renal impairment (non-LN group) and 40 healthy volunteers as control group. In the present paper, we evaluated serum lipid peroxidation, DNA oxidation, oxidized proteins, carbohydrate oxidation, and endogenous protective systems. We detected defective DNA repair mechanisms via 8-oxoguanine-DNA-glycosylase (OGG1), the reduced regulatory effect of soluble receptor for advanced glycation end products (sRAGE) in the activation of AGE-RAGE axis, low levels of thiols, disulphide bonds formation and high nitrotyrosination in lupus nephritis. All these data help us to identify more molecular mechanisms to counteract oxidative stress in LN that could permit a more precise assessment of disease prognosis, as well as developing new therapeutic targets.

The aim of the study was to assess the oral health related quality of life (OHRQoL) of elderly in care homes, one of Romania’s most vulnerable social categories, to correlate it to sociodemographic, oral health parameters, and prosthodontic status. Therefore, a cross-sectional study was performed on 58 geriatrics divided into 3 age groups, who were clinically examined and answered the oral health impact profile (OHIP-14) questionnaire. Very high rates of complete edentulism in the oldest-old subgroup (bimaxillary in 64.3%, mandibular in 64.3%, maxillary in 85.7%), and alarming frequencies in the other subgroups (middle-old and youngest-old), statistically significant differences between age groups being determined. The OHIP-14 mean score was 14.5. Although not statistically significant, females had higher OHIP-14 scores, also middle-old with single maxillary arch, single mandibular arch, and bimaxillary complete edentulism, whether they wore dentures or not, but especially those without dental prosthetic treatment in the maxilla. A worse OHRQoL was also observed in wearers of bimaxillary complete dentures, in correlation with periodontal disease-related edentulism, in those with tertiary education degree, and those who came from rural areas. There were no statistically significant correlations of OHRQoL with age, total number of edentulous spaces or edentulous spaces with no prosthetic treatment. In conclusion, despite poor oral health and prosthetic status of the institutionalized elderly around Bucharest, the impact on their wellbeing is comparatively moderate.

Abnormalities in glutamate neurotransmission are linked to psychotic symptoms and cognitive dysfunction in schizophrenia. magnetic resonance spectroscopy (MRS) provides an acceptable means of measuring glutamate in the human brain but findings from patient studies at conventional magnetic field strength show considerable heterogeneity. Ultra-high-field MRS offers greater precision in glutamate measurement, particularly in delineation of glutamate from its precursor and metabolite, glutamine. This study aimed to use high-field (7 T) MRS to measure concentrations of glutamate and glutamine in three brain regions, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (DLPFC) and putamen (PUT), in young men with early psychosis. MRS was performed in 17 male participants with early psychosis and 18 healthy age-matched controls. Neurometabolite levels were calculated with unsuppressed water signal as the reference and corrected for individual grey matter, white matter and cerebrospinal fluid concentration. Cognitive function was measured with the Brief Assessment of Cognition in Schizophrenia (BACS). Compared to controls, patients with early psychosis had lower concentrations of glutamate and glutamine in ACC. No differences were apparent in the DLPFC and PUT. In patients with early psychosis, there was a highly significant correlation between glutamate concentration in ACC and performance on the BACS, though the numbers available for this analysis were small. Our finding of lower glutamate levels in ACC in patients with schizophrenia is consistent with a recent meta-analysis of 7 T studies and suggests that this abnormality is present in both patients with early psychosis and those with longer-established illness. The possible link between ACC glutamate and cognitive performance requires replication in larger studies.

Lichen planus (LP) is a chronic, immune-mediated inflammatory skin condition that mainly affects the skin (cutaneous LP, CLP) and oral mucosa (oral LP, OLP). However, the mechanisms involved in the pathogenesis of the disease are not fully elucidated. Over time, several theories that could explain the appearance of LP lesions have been postulated. The key players in LP pathogenesis are the inflammatory infiltrate consisting of T cells and the proinflammatory cytokines. The cytokines stimulate the production of reactive oxygen species that induce cell apoptosis, a defining element encountered in LP. The lead inquiry triggered by this revolves around the role of oxidative stress in LP development. There are currently numerous studies showing the involvement of oxidative stress in OLP, but in terms of CLP, data are scarce. In this review, we analyze for the first time the currently existing studies on oxidative stress in CLP and summarize the results in order to assess the role of oxidative stress in skin lesions offering a fresher updated perspective.

Basal cell carcinoma (BCC) is the most common skin malignancy, which rarely metastasizes but has a great ability to infiltrate and invade the surrounding tissues. One of the molecular players involved in the metastatic process are matrix metalloproteinases (MMPs). MMPs are enzymes that can degrade various components of the extracellular matrix. In the skin, the expression of MMPs is increased in response to various stimuli, including ultraviolet (UV) radiation, one of the main factors involved in the development of BCC. By modulating various processes that are linked to tumor growth, such as invasion and angiogenesis, MMPs have been associated with UV-related carcinogenesis. The sources of MMPs are multiple, as they can be released by both neoplastic and tumor microenvironment cells. Inhibiting the action of MMPs could be a useful therapeutic option in BCC management. In this review that reunites the latest advances in this domain, we discuss the role of MMPs in the pathogenesis and evolution of BCC, as molecules involved in tumor aggressiveness and risk of recurrence, in order to offer a fresh and updated perspective on this field.

All social and economic systems worldwide, including the educational one have been disrupted by escalating the global COVID-19 pandemic. One of the most impacted areas were the medical and dental education fields, due to the forced break from clinical practice during the lockdown, which affected both the educational part, as well as the patients. Thus, the main goal of our research was to investigate the impact of the COVID-19 pandemic on the dental students’ education as related to their perceptions and evaluations, in Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. A cross-sectional study was conducted on 878 dental students who reported their perception of the psychological and educational impact of this period by completing a Google Forms questionnaire. Collected data were statistically analyzed using Stata/IC 16. There was a severe psychological impact among the respondents, the levels of stress being perceived as high and very high (33.83%, n = 297, 28.59%, n = 251), similar to high and very high anxiety feelings (26.54%, n = 233, 24.26%, n = 213). Very high educational impact from the point of view of the acquisition of practical skills (48.52%, n = 426) and future professional perspectives (38.95%, n = 342) were recorded. While online theoretical learning ability was principally low (37.93%, n = 333) despite consistently modified time allocated to the individual study (44.35%, n = 389), most of the students evaluated the efficiency of lecturers in online courses as neutral (41.12%, n = 361). New dentistry teaching programs will have to be adopted taking into account the dynamics of the pandemic and its strong impact on our students, in order to improve both their wellbeing and the sustainability of dental education.

We have investigated glycoconjugates sialization profile, endogen synthesis rate of antiganglioside antibodies (AGA), IL-6 signaling pathways correlated with activity disease in systemic lupus erythematous (SLE) and lupus nephritis (LN). Material and methods. A case-control study was developed and included 109 patients with SLE with or without renal impairment, 32 patients with IgA nephropathy and 60 healthy volunteers, clinically and paraclinically monitored. The following parameters were evaluated in volunteers serum: total sialic acid (TSA), orosomucoids, lipid bound sialic acid (LSA), interleukin-6 (IL-6), soluble factors IL-6R, gp130, anti –GM1, -GM2, -GM3, -GD1a, -GD1b, -GT1b, -GQ1b antigangliosides antibodies of IgG and IgM type. Results. Experimental data analysis showed: increase in synthesis rhythm of sialoglyco-conjugated in SLE (TSA increased in SLE and LN compared to control), accelerated catabolism of LSA in LN (LSA/TSA ratio was higher in SLE and LN than in control group), overexpression of IL-6 mediated trans-signaling (sIL-6R/sgp 130 ratio was subunit in SLE and IgA nephropathy and superunit in LN), large AGA profile synthesis of IgM isotype (over 45.1% in SLE and over 20.7% in LN). Conclusions. Hypersialization, accelerated glycosphingolipids degradation, IL-6 trans-signaling amplify and AGA pattern could represent essential mechanisms in LN pathogenesis.

Dental pulp vitality is a desideratum for preserving the health and functionality of the tooth. In certain clinical situations that lead to pulp exposure, bioactive agents are used in direct pulp-capping procedures to stimulate the dentin-pulp complex and activate reparative dentinogenesis. Hydraulic calcium-silicate cements, derived from Portland cement, can induce the formation of a new dentin bridge at the interface between the biomaterial and the dental pulp. Odontoblasts are molecularly activated, and, if necessary, undifferentiated stem cells in the dental pulp can differentiate into odontoblasts. An extensive review of literature was conducted on MedLine/PubMed database to evaluate the histological outcomes of direct pulp capping with hydraulic calcium-silicate cements performed on animal models. Overall, irrespective of their physico-chemical properties and the molecular mechanisms involved in pulp healing, the effects of cements on tertiary dentin formation and pulp vitality preservation were positive. Histological examinations showed different degrees of dental pulp inflammatory response and complete/incomplete dentin bridge formation during the pulp healing process at different follow-up periods. Calcium silicate materials have the ability to induce reparative dentinogenesis when applied over exposed pulps, with different behaviors, as related to the animal model used, pulpal inflammatory responses, and quality of dentin bridges.

Background In the current context of a global pandemic it is imperative for fertility clinics to consider the necessity of individual tests and eliminate those that have limited utility and may impose unnecessary risk of exposure. The purpose of this study was to implement and evaluate a multi-modal quality improvement (QI) strategy to promote resource stewardship by reducing routine day 3 (d3) bloodwork and transvaginal ultrasound (TVUS) for patients undergoing intrauterine insemination (IUI) and timed intercourse (IC) treatment cycles. Methods After literature review, clinic stakeholders at an academic fertility centre met to discuss d3 testing utility and factors contributing to d3 bloodwork/TVUS in IC/IUI treatment cycles. Consensus was reached that it was unnecessary in patients taking oral/no medications. The primary intervention changed the default setting on the electronic order set to exclude d3 testing for IC/IUI cycles with oral/no medications. Exceptions required active test selection. Protocols were updated and education sessions were held. The main outcome measure was the proportion of cycles receiving d3 bloodwork/TVUS during the 8-week post-intervention period compared with the 8-week pre-intervention period. Balancing measures included provider satisfaction, pregnancy rates, and incidence of cycle cancellation. Results A significant reduction in the proportion of cycles receiving d3 TVUS (57.2% vs 20.8%, p p = 0.86). Treatment with medications, cyst history, prescribing physician, and treatment centre were associated with receiving d3 bloodwork/TVUS. 74% of providers were satisfied with the intervention. Conclusion A significant reduction in IC/IUI treatment cycles that received d3 bloodwork/TVUS was achieved without measured negative treatment impacts. During a pandemic, eliminating routine d3 bloodwork/TVUS represents a safe way to reduce monitoring appointments and exposure.

Migrants are at an increased risk of HIV acquisition. We aimed to use phylogenetics to characterize transmission clusters among newly-diagnosed asylum seekers and to understand the role of networks in local HIV transmission. Retrospective chart reviews of asylum seekers linked to HIV care between 1 June 2017 and 31 December 2018 at the McGill University Health Centre and the Jewish General Hospital in Montreal were performed. HIV-1 partial pol sequences were analyzed among study participants and individuals in the provincial genotyping database. Trees were reconstructed using MEGA10 neighbor-joining analysis. Clustering of linked viral sequences was based on a strong bootstrap support (&gt, 97%) and a short genetic distance (&lt, 0.01). Overall, 10,645 provincial sequences and 105 asylum seekers were included. A total of 13/105 participant sequences (12%, n = 7 males) formed part of eight clusters. Four clusters (two to three people) included only study participants (n = 9) and four clusters (two to three people) included four study participants clustered with six individuals from the provincial genotyping database. Six (75%) clusters were HIV subtype B. We identified the presence of HIV-1 phylogenetic clusters among asylum seekers and at a population-level. Our findings highlight the complementary role of cohort data and population-level genotypic surveillance to better characterize transmission clusters in Quebec.

ObjectiveTo describe a possible novel genetic mechanism for cerebral small vessel disease (cSVD) and stroke.MethodsWe studied a Swedish kindred with ischemic stroke and intracerebral hemorrhage, tremor, dysautonomia, and mild cognitive decline. Members were examined clinically, radiologically, and by histopathology. Genetic workup included whole-exome sequencing (WES) and whole-genome sequencing (WGS) and intrafamilial cosegregation analyses.ResultsFifteen family members were examined clinically. Twelve affected individuals had white matter hyperintensities and 1 or more of (1) stroke episodes, (2) clinically silent lacunar ischemic lesions, and (3) cognitive dysfunction. All affected individuals had tremor and/or atactic gait disturbance. Mild symmetric basal ganglia calcifications were seen in 3 affected members. Postmortem examination of 1 affected member showed pathologic alterations in both small and large arteries the brain. Skin biopsies of 3 affected members showed extracellular amorphous deposits within the subepidermal zone, which may represent degenerated arterioles. WES or WGS did not reveal any potentially disease-causing variants in known genes for cSVDs or idiopathic basal ganglia calcification, but identified 1 heterozygous variant, NM_004672.4 MAP3K6 c.322G>A p.(Asp108Asn), that cosegregated with the disease in this large family. MAP3K6 has known functions in angiogenesis and affects vascular endothelial growth factor expression, which may be implicated in cerebrovascular disease.ConclusionsOur data strongly suggest the MAP3K6 variant to be causative for this novel disease phenotype, but the absence of functional data and the present lack of additional families with this disease and MAP3K6 mutations still limit the formal evidence for the variant's pathogenicity.

An author correction to this article published in December 2020 is available at https://doi.org/10.1038/s41588-020-00760-4. Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.

BACKGROUND: Depression and anxiety are the most prevalent mental health difficulties in the workplace, costing the global economy $1 trillion each year. Evidence indicates that symptoms may be reduced by interventions in the workplace. This paper is the first to systematically review psychosocial interventions for depression, anxiety, and suicidal ideation and behaviours in small-to medium-size enterprises (SMEs). METHODS: A systematic search following PRISMA guidelines, registered in PROSPERO (CRD42020156275), was conducted for psychosocial interventions targeting depression, anxiety, and suicidal ideation/behaviour in SMEs. The PubMed, PsycINFO, Scopus, and two specific occupational health databases were searched, as well as four databases for grey literature, without time limit until 2nd December 2019. RESULTS: In total, 1283 records were identified, 70 were retained for full-text screening, and seven met the inclusion criteria: three randomised controlled trials (RCTs), three before and after designs and one non-randomised trial, comprising 5111 participants. Study quality was low to moderate according to the Quality Assessment Tool for Quantitative Studies. Five studies showed a reduction in depression and anxiety symptoms using techniques based on cognitive behavioural therapy (CBT), two reported no significant change. LIMITATIONS: Low number and high heterogeneity of interventions and outcomes, high attrition and lack of rigorous RCTs. CONCLUSIONS: Preliminary evidence indicates CBT-based interventions can be effective in targeting symptoms of depression and anxiety in SME employees. There may be unique challenges to implementing programmes in SMEs. Further research is needed in this important area. ispartof: JOURNAL OF AFFECTIVE DISORDERS vol:290 pages:378-386 ispartof: location:Netherlands status: published

Neonicotinoid pesticides, originally developed to target the insect nervous system, have been reported to interact with human receptors and to activate rodent neurons. Therefore, we evaluated in how far these compounds may trigger signaling in human neurons, and thus, affect the human adult or developing nervous system. We used SH-SY5Y neuroblastoma cells as established model of nicotinic acetylcholine receptor (nAChR) signaling. In parallel, we profiled dopaminergic neurons, generated from LUHMES neuronal precursor cells, as novel system to study nAChR activation in human post-mitotic neurons. Changes of the free intracellular Ca2+ concentration ([Ca2+]i) were used as readout, and key findings were confirmed by patch clamp recordings. Nicotine triggered typical neuronal signaling responses that were blocked by antagonists, such as tubocurarine and mecamylamine. Pharmacological approaches suggested a functional expression of α7 and non-α7 nAChRs on LUHMES cells. In this novel test system, the neonicotinoids acetamiprid, imidacloprid, clothianidin and thiacloprid, but not thiamethoxam and dinotefuran, triggered [Ca2+]i signaling at 10–100 µM. Strong synergy of the active neonicotinoids (at low micromolar concentrations) with the α7 nAChR-positive allosteric modulator PNU-120596 was observed in LUHMES and SH-SY5Y cells, and specific antagonists fully inhibited such signaling. To provide a third line of evidence for neonicotinoid signaling via nAChR, we studied cross-desensitization: pretreatment of LUHMES and SH-SY5Y cells with active neonicotinoids (at 1–10 µM) blunted the signaling response of nicotine. The pesticides (at 3–30 µM) also blunted the response to the non-α7 agonist ABT 594 in LUHMES cells. These data show that human neuronal cells are functionally affected by low micromolar concentrations of several neonicotinoids. An effect of such signals on nervous system development is a toxicological concern.

Posttranslational modifications are dynamic enzymatic-mediated processes, regulated in time and space, associated with cancer development. We aimed to evaluate the significance of posttranslational modifications in the pathogenesis of clear cell renal cell carcinoma. The authors developed a prospective, observational study during a period of three years and included 55 patients with localized renal cell carcinoma and 30 heathy subjects. Glycosylation, nitration and carbonylation, thiol-disulfide homeostasis, methylation, phosphorylation and proteolytic cleavage were evaluated in the serum of the evaluated subjects in the present study. Our results showed some characteristics for early ccRCC: high production of cytokines, substrate hypersialylation, induced nitrosative and carbonylic stress, arginine hypermethylation, thiol/disulfide homeostasis (TDH) alteration, the regulatory role of soluble receptors (sRAGE—soluble receptor for advanced glycation end products, sIL-6R—soluble receptor for Interleukin 6) in RAGE and IL-6 signaling, the modulatory effect of TK1—thymidine kinase 1 and TuM2-PK—tumoral pyruvate-kinase 2 in controlling the level of phosphometabolites in neoplastic cells. These data could be the initial point for development of a panel of biomarkers such as total sialic acid, orosomucoids, nitrotyrosine, carbonylic metabolites, Asymmetric Dimethylarginines (ADMA), Symmetric Dimethylarginines (SDMA), and thiol-disulfide equilibrium for early diagnosis of ccRCC. Moreover, they could be considered a specific disease posttranslational modification signature which underlines the transition from early to advanced stages in this neoplasia, and of a therapeutic target in kidney oncogenesis.

The urgent public health threat of antimicrobial resistance (AMR) has received much attention from the world’s most important health agencies and national governmental organizations. However, despite large investments being allocated to strategizing national and international plans for addressing this public health problem, the incidence of untreatable, antimicrobial-resistant diseases continues to rise in many nations. To avoid returning to a society in which common infections once again become deadly, one must consider the often-ignored root causes driving inappropriate behaviors relating to antimicrobial use, such as the history of antimicrobial drug development, the effects of commodifying health-related services, and the rise in social inequalities. By employing the lens of political economy to analyze the phenomenon of AMR on national and international scales, it is found that the acceptance of neoliberalism as a governing ideology by authorities is hindering our ability to globally combat AMR through the depoliticization of issues that require political intervention to stimulate change. Differences in level of AMR and approaches to pharmaceutical governance between social democratic and liberal welfare states provide validity to this hypothesis.

Paraphilic disorders are diagnosed largely in forensic settings and it is both a social and a public health issue. In this paper we discuss about the differences between paraphilias and paraphilic disorders and we emphasize clinical features regarding voyeuristic disorder, pedophilia, necrophilia and rape.

Objective: This study extends prior findings by looking at the relationship between hearing acuity and cognitive difficulties in 51 nations. Methods: We draw on data from the Integrated Public Use Microdata International Series available at the Institute for Social Research and Data Innovation at the University of Minnesota. For all countries where data are available, bivariate relationships between hearing and cognitive problems are examined using correlation coefficients ( Rs) and multivariate relationships using linear regression techniques (betas), controlling for age, gender, marital status, and education. Results: For all 51 countries, the R between hearing problems and cognitive problems is 0.334 ( p < .001); the multivariate beta is 0.316 ( p < .001). Regional results are also statistically significant. Discussion: The relationship between hearing and memory appears to be universal, and practitioners must carefully assess and treat their client’s hearing disabilities before they can expect them to remember any information.

Hysteroscopy has known an increasing use in Romania over the last decade, succeeding to mark an impact on lowering the costs of medical services. The strategy of this study was to present the experience of two Romanian medical units with different experiences using inpatient regimen hysteroscopy, and to further compare it with current worldwide tendencies. Strong points in our practice were sought, as well as components that require improvement. Overall, abnormal uterine bleeding stands for most hospital case presentations in our study group, hysteroscopy had the highest accuracy and positive predictive value in identifying uterine myomas: 91.03% and 100%, respectively, for endometrial polyps, statistical analysis showed the highest sensitivity: 100%, with 83.89% specificity and a 77.64% positive predictive value. The applicability of hysteroscopy was further described for infertility cases and isthmocele repair.

Context Oxytocin has been investigated as a potential medication for psychiatric disorders. Objective and design This study prospectively investigates correlations between oxytocin and other neuropeptides plasma levels in patients with autism spectrum disorders (ASD) according to severity and treatment, as compared to controls. Subjects and methods Thirty-one children (6 neurotypical as control) participated in this study. The patients were classified into mildly and severely-affected, according to Autism Diagnostic Observation Schedule (ADOS) scores. Oxytocin, orexin A and B, α-MSH, β-endorphins, neurotensin and substance P were investigated using a quantitative multiplex assay or a competitive-ELISA method. Results Plasma oxytocin levels differed between the groups (F (2, 24) =6.48, p=0.006, η2=0.35, observed power=86%): patients with the mild ASD had higher values of plasma oxytocin than those with the severe form (average difference=74.56±20.74pg/mL, p=0.004). Conclusions These results show a negative correlation between plasma levels of oxytocin and the severity of ASD and support the involvement of oxytocinergic mechanisms in ASD.

Despite ongoing malaria control efforts implemented throughout sub-Saharan Africa, malaria remains an enormous public health concern. Current interventions such as indoor residual spraying with insecticides and use of insecticide-treated bed nets are aimed at targeting the key malaria vectors that are primarily endophagic and endophilic. Anopheles coustani s.l., an understudied vector of malaria, is a species previously thought to exhibit mostly zoophilic behavior. Like many of these understudied species, An. coustani has greater anthropophilic tendencies than previously appreciated, is often both endophagic and exophagic, and carries Plasmodium falciparum sporozoites. The aim of this study was to explore genetic variation of An. coustani mosquitoes and the potential of this species to contribute to malaria parasite transmission in high transmission settings in Zambia and the Democratic Republic of the Congo (DRC). Morphologically identified An. coustani specimens that were trapped outdoors in these study sites were analyzed by PCR and sequencing for species identification and bloodmeal sources, and malaria parasite infection was determined by ELISA and qPCR. Fifty An. coustani s.s. specimens were confirmed by analysis of mitochondrial DNA cytochrome c oxidase subunit I (COI) and ribosomal internal transcribed spacer region 2 (ITS2). Maximum likelihood phylogenetic analysis of COI and ITS2 sequences revealed two distinct phylogenetic groups within this relatively small regional collection. Our findings indicate that both An. coustani groups have anthropophilic and exophagic habits and come into frequent contact with P. falciparum, suggesting that this potential alternative malaria vector might elude current vector control measures in northern Zambia and southern DRC.

Despite ongoing malaria control efforts implemented throughout sub-Saharan Africa, malaria remains an enormous public health concern. Current interventions such as indoor residual spraying with insecticides and use of insecticide-treated bed nets are aimed at targeting the key malaria vectors that are primarily endophagic and endophilic. While these control measures have resulted in a substantial decline in malaria cases and continue to impact indoor transmission, the importance of alternative vectors for malaria transmission has been largely neglected. Anopheles coustani, an understudied vector of malaria, is a species previously thought to exhibit mostly zoophilic behavior. However, recent studies from across Africa bring to light the contribution of this and ecologically similar anopheline species to human malaria transmission. Like many of these understudied species, An. coustani has greater anthropophilic tendencies than previously appreciated, is often both endophagic and exophagic, and carries Plasmodium falciparum sporozoites. These recent developments highlight the need for more studies throughout the geographic range of this species and the potential need to control this vector. The aim of this study was to explore the genetic variation of An. coustani mosquitoes and the potential of this Anopheles species to contribute to malaria parasite transmission in high transmission settings in Nchelenge District, Zambia, and the Kashobwe and Kilwa Health Zones in Haut-Katanga Province, the Democratic Republic of the Congo (DRC). Morphologically identified An. coustani specimens that were trapped outdoors in these study sites were analyzed by PCR and sequencing for species identification and blood meal sources, and malaria parasite infection was determined by ELISA and qPCR. Fifty specimens were confirmed to be An. coustani by the analysis of mitochondrial DNA cytochrome c oxidase subunit I (COI) and ribosomal internal transcribed spacer region 2 (ITS2). Further, maximum likelihood phylogenetic analysis of COI and ITS2 sequences revealed two distinct phylogenetic groups within this relatively small regional collection. Our findings indicate that both An. coustani groups have anthropophilic and exophagic habits and come into frequent contact with P. falciparum, suggesting that this potential alternative malaria vector might elude current vector controls in Northern Zambia and Southern DRC. This study sets the groundwork for more thorough investigations of bionomic characteristics and genetic diversity of An. coustani and its contribution to malaria transmission in these regions.

Cutaneous squamous cell carcinoma (cSCC) is a common form of skin cancer with a complex but not fully understood pathogenesis. Recent research suggests the role of beta human papillomavirus (HPV) types and HPV-associated inflammatory processes in cSCC development. Beta HPV types are components of the normal flora; however, under the influence of certain cofactors, the virus may trigger a malignant process. Dysregulation of the immune system (chronic inflammation and immunosuppression), environmental factors (ultraviolet radiation), and genetic factors are the most important cofactors involved in beta HPV-related carcinogenesis. In addition, the oncoproteins E6 and E7 of beta HPV types differ biochemically from their counterparts in the structure of alpha HPV types, resulting in different mechanisms of action in carcinogenesis. The aim of our manuscript is to present an updated point of view on the involvement of beta HPV types in cSCC pathogenesis.

Backgrounds and Purpose— Although new methods for genetic analyses are rapidly evolving, there are currently knowledge gaps in how to detect Mendelian forms of stroke. Methods— We performed whole-exome sequencing in 22 probands, under 56 years at their first ischemic stroke episode, from multi-incident stroke families. With the use of a comprehensive stroke-gene panel, we searched for variants in stroke-related genes. The probands’ clinical stroke subtype was related to clinical characteristics previously associated with pathogenic variants in these genes. Relatives were genotyped in 7 families to evaluate stroke-gene variants of unknown significance. In 2 larger families with embolic stroke of unknown source, whole-exome sequencing was performed in additional members to examine the possibility of identifying new stroke genes. Results— Six of 22 probands carried pathogenic or possibly pathogenic variants in genes reported to be associated with their stroke subtype. A known pathogenic variant in NOTCH3 and a possibly pathogenic variant in ACAD9 gene were identified. A novel JAK2 :c.3188G>A (p.Arg1063His) mutation was seen in a proband with embolic stroke of undetermined source and prothrombotic status. However, penetrance in the family was incomplete. COL4A2: c.3368A>G (p.Glu1123Gly) was detected in 2 probands but did not cosegregate with the disease in their families. Whole-exome sequencing in multiple members of 2 pedigrees with embolic stroke of undetermined source revealed possibly pathogenic variants in genes not previously associated with stroke, GPR142: c.148C>G (p.Leu50Val), and PTPRN2 :c.2416A>G (p.Ile806Val); LRRC1 c.808A>G (p.Ile270Val), SLC7A10 c.1294dupG (p.Val432fs), IKBKB : c.1070C>T (p.Ala357Val), and OXGR1 c.392G>A (p.Arg131His), respectively. Conclusions— Screening with whole-exome sequencing using a comprehensive stroke-gene panel may identify rare monogenic forms of stroke, but careful evaluation of clinical characteristics and potential pathogenicity of novel variants remain important. In our study, the majority of individuals with familial aggregation of stroke lacked any identified genetic causes.

The presence of an isocitrate dehydrogenase (IDH1/2) mutation in gliomas is associated with favorable outcomes compared to gliomas without the mutation (IDH1/2 wild-type, WT). The underlying biological mechanisms accounting for improved clinical outcomes in IDH1/2 mutant gliomas remain poorly understood, but may, in part, be due to the glioma CpG island methylator phenotype (G-CIMP) and epigenetic silencing of genes. We performed profiling of IDH1/2 WT versus IDH1/2 mutant Grade II and III gliomas and identified transgelin-2 (TAGLN2), an oncogene and actin-polymerizing protein, to be expressed at significantly higher levels in IDH1/2 WT gliomas compared to IDH1/2 mutant gliomas. This differential expression of TAGLN2 was primarily due to promoter hypermethylation in IDH1/2 mutant gliomas, suggesting involvement of TAGLN2 in the G-CIMP. Our results also suggest that TAGLN2 may be involved in progression due to higher expression in glioblastomas compared to IDH1/2 WT gliomas of lower grades. Furthermore, our results suggest that TAGLN2 functions as an oncogene by contributing to proliferation and invasion when overexpressed in IDH1/2 WT glioma cells. Taken together, this study demonstrates a possible link between increased TAGLN2 expression, invasion and poor patient outcomes in IDH1/2 WT gliomas and identifies TAGLN2 as a potential novel therapeutic target for IDH1/2 WT gliomas.

Based on the latest medical research, it is supposed that lichen planus is an inflammatory disorder, associated with autoimmune diseases, hepatitis C infection, oxidative stress or antioxidant deficiency. The purpose of the present work is to determine a panel of serum antioxidants, possibly involved in the development/persistence of the disease. The determination of extracellular antioxidants (bilirubin, uric acid, albumin, iron, transferrin, ferritin, copper, ceruloplasmin, total antioxidant capacity) in patients with lichen planus during exacerbations have revealed a significant reduction in non-enzymatic antioxidant systems. Hepatitis C virus enhances the deficit of antioxidants in patients with lichen planus. Based on these findings, the authors consider that lichen planus is a complex disease of unidentified cause and its pathogenic mechanisms are still incompletely elucidated. It may be speculated that several interconnected mechanisms are involved in the onset and evolution of lichen planus.

Die Strahlentherapie (RT) ist eine der wichtigen Saulen der Behandlung von Gliomen. Standig werden neue Studien zum optimalen Bestrahlungszeitpunkt, der Dosierung und Fraktionierung und zur optimalen Kombination mit anderen Therapieformen publiziert. Die aktuellen Leitlinien und Studienergebnisse werden dargestellt und fur die klinische Praxis zusammengefasst. Eine Literaturrecherche wurde durchgefuhrt, und die wichtigsten Publikationen und Leitlinien wurden als Grundlage der Empfehlungen fur die klinische Praxis genommen. Fur die RT von Low-grade-Gliomen (WHO II) beim Erwachsenen ist das individuelle Risikoprofil entscheidend. Fur die Patienten mit erhohtem Rezidivrisiko ist eine fruhe adjuvante RT mit 45–54 Gy empfohlen. Patienten mit High-grade-Gliomen sollten dagegen alle eine adjuvante RT mit einer Dosis von 59,4–60 Gy erhalten. Die Zielvolumendefinition und ob eine konkomittante oder adjuvante Chemotherapie notwendig ist, richtet sich nach dem WHO-Grad und der molekularen Diagnostik. Fur Patienten in hohem Alter, mit reduziertem Allgemeinzustand und im Fall von Rezidiven gibt es immer mehr gute strahlentherapeutische Optionen. Die RT von Gliomen ist hinsichtlich der Zielvolumendefinition, Dosis und der Kombination mit Chemotherapie masgeblich auf die WHO-Klassifikation, die molekulare Diagnostik und den klinischen Allgemeinzustand des Patienten ausgerichtet.

Extensive analyses of known monogenic causes of stroke by whole-exome/genome sequencing are technically possible today. We here aimed to compile a comprehensive panel of genes associated with monogenic causes of stroke for use in clinical and research situations. We systematically searched the publically available database Online Mendelian Inheritance in Man, and validated the entries against original peer-reviewed publications in PubMed. First, we selected known pathogenic or putatively pathogenic stroke genes reported in at least one person with stroke, and classified the stroke phenotype for each gene into eight subgroups: (1) large artery atherosclerotic, (2) large artery non-atherosclerotic (tortuosity, dolichoectasia, aneurysm, non-atherosclerotic dissection, occlusion), (3) cerebral small-vessel diseases, (4) cardioembolic (arrhythmia, heart defect, cardiomyopathy), (5) coagulation dysfunctions (venous thrombosis, arterial thrombosis, bleeding tendency), (6) intracerebral hemorrhage, (7) vascular malformations (cavernoma, arteriovenous malformations), and (8) metabolism disorders. Second, we selected other genes that may plausibly cause stroke through diseases related to stroke, but without any documented stroke patient description. A third section comprised SNPs associated with stroke in genome-wide association studies (GWAS). We identified in total 214 genes: 120 associated with stroke, 62 associated with diseases that may cause stroke, and 32 stroke-related genes from recent GWAS. We describe these 214 genes and the clinical stroke subtype(s) associated with each of them. The resulting gene panel can be used to interpret exome sequencing results regarding monogenic stroke. Based on the panel’s clinical phenotype description, the pathogenicity of novel variants in these genes may be evaluated in specific situations.

The extent of pregnancy in adolescents and young adults, especially in low and middle-income countries, is a source of increasing concern given its social and economic impact.We hypothesized that there would be correlations between female patients becoming pregnant at a young age and practices such as harmful alcohol misuse, cigarette smoking, and drug use, the use of toxic substances, low educational attainment, and an essential absence of health care seeking about the outcome of adolescent pregnancies.We performed a prospective cross-sectional study of patients who gave birth between August and November 2017 at St. Pantelimon Emergency Hospital in Bucharest, Romania. Seventy-four patients aged 14 to 20 years, with a mean maternal age of 18.07 years, were enrolled in the study and answered a 15-item questionnaire about their social, educational, and medical background.Fifty-three patients (71.6%) gave birth by caesarean section and 21 (28.3%) by vaginal delivery. Notably, patients aged 14 to 16 years had a lower rate of caesarean delivery compared with those aged 17 to 20 years. Moreover, 83.0% of the caesarean sections and 76.1% of the vaginal deliveries were at term. With reference to age and type of delivery, women are more likely to give birth by caesarean section at any age group (the association is not statistically significant at P .05), except for the age of 15 years (five out of six patients in our sample had a spontaneous birth). Smoking was the most common risk behavior in the sample (45.9%, n = 34), followed by alcohol consumption (17.5%, n = 13) and drug use (5.40%, n = 4).A high percentage of caesarean delivery was reported, particularly in patients aged17 years. The percentage of female participants who underwent a caesarean delivery for their second pregnancy was significantly higher than compared with primipara participants. Patients receiving consistent antenatal care visits compared with those who did not monitor their pregnancy did not differ in the likelihood of undergoing a caesarean section.

Numerous plants are currently used for both their curative and preventive effects in a wide range of pathologies. They possess multiple beneficial effects, including the well-known antioxidant capacity. Agrimonia eupatoria L. and Filipendula spp., from the Rosaceae family have emerged as a potential source of phenolic constituents, showing antioxidant activities. The aim of this study was to obtain ethanolic extracts from Agrimonia eupatoria L., Filipendula ulmaria (L.) Maxim. and Filipendula vulgaris Moench. collected from the West part of Romania and to determine their antioxidant capacity. Two DPPH assays were used to determine the antioxidant activity of the extracts, ethanolic solution of 1 and 0.1 mM DPPH. Our data indicated that all the extracts, regardless of the place of harvest possess significant antioxidant activity. The most potent activity was recorded for the extracts prepared from Agrimonia eupatoria L. collected from Bazia� � Locva Mountains in mixture with ethanolic solution of 0.1 mM DPPH, followed by Filipendula ulmaria (L.) Maxim, using the same concentration of ethanolic solution of standard antioxidant.

Human papillomavirus (HPV) is a small double-stranded DNA virus with tropism for epithelial cells. To this date, over 150 genotypes are known and are classified into two major groups, low-risk and high-risk strains, depending on the ability of the virus to induce malignant transformation. The host’s immunity plays a central role in the course of the infection; therefore, it may not be clinically manifest or may produce various benign or malignant lesions. The pathogenic mechanisms are complex and incompletely elucidated. Recent research suggests the role of chronic inflammation and oxidative stress (OS) in the pathogenesis of HPV infection and the associated carcinogenic processes. Chronic inflammation induces OS, which in turn promotes the perpetuation of the inflammatory process resulting in the release of numerous molecules which cause cell damage. Reactive oxygen species exert a harmful effect on proteins, lipids, and nucleic acids. Viral oncogenes E5, E6, and E7 are involved in the development of chronic inflammation through various mechanisms. In addition, HPV may interfere with redox homeostasis of host cells, inducing OS which may be involved in the persistence of the infection and play a certain role in viral integration and promotion of carcinogenesis. Knowledge regarding the interplay between chronic inflammation and OS in the pathogenesis of HPV infection and HPV-induced carcinogenesis has important consequences on the development of new therapeutic strategies.

Chemicals used in the manufacture of synthetic fibers have been associated with undesirable side effects such as itching or skin lesions and it seems that they are involved in the induction of pathological processes such as oxidative stress and inflammation. Lichen planus (LP) can be regarded as an inflammatory disorder, chemical and physical factors playing an important role in the perpetuation of the inflammatory process. Gamma-glutamyl transpeptidase (GGT) plays an important role in the preservation of skin architecture and modulation of skin inflammation. In this study, we found that GGT activity is increased in LP patients with mild inflammation, whilst GGT is inactivated under conditions of severe inflammation. Therefore, GGT is involved in the inflammatory process, but there is no a positive correlation between its activity and the intensity of the inflammatory response. This functional adaptation of the enzyme may be due to down-regulation of its synthesis under free radical overload conditions. Understanding the molecular mechanisms involved in the modulation of intracellular redox homeostasis is an important step in the pharmacological management of patients with LP.

Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke sub-types. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.

Objective: Patient refusal of and nonadherence to treatment with disease-modifying antirheumatic drugs (DMARDs) can adversely affect disease outcomes in rheumatoid arthritis (RA). This qualitative study describes how RA patients' feelings in response to experiences and information affected their decisions to accept (agree to adopt, initiate and implement) or resist (refuse, avoid and discontinue) DMARD treatment regimens. Methods: 48 RA patients were interviewed about their experiences making decisions about DMARDs. The interviews were transcribed, coded, and analyzed for themes related to their internal motivations for accepting or resisting treatment regimens, using a narrative analysis approach. Results: In addition to feelings about the necessity and dangers of medications, patients' feelings towards their identity as an ill person, the act of taking medication, and the decision process itself were important drivers of patient's decisions. For patients' motivations to accept treatment regimens, two themes emerged: 1) desire to return to a "normal" life and 2) fear of future disability due to RA. For motivations to resist treatment regimens, five themes emerged: 1) fear of medications, 2) maintaining control over health, 3) denial of sick identity, 4) disappointment with treatment, and 5) feeling overwhelmed by the cognitive burden of deciding. Conclusion: Feelings in response to experiences and information played a major role in how patients weighed the benefits and costs of treatment options, suggesting that addressing patients' feelings may be important when rheumatologists counsel about therapeutic options. Further research is needed to learn how best to address patients' feelings throughout the treatment decision making process. This article is protected by copyright. All rights reserved.