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Genetic susceptibility to schizophrenia through neuroinflammatory pathways is associated with retinal thinning: Findings from the UK-Biobank.
Get PDFThe human retina is part of the central nervous system and can be easily and noninvasively imaged through optical coherence tomography. Imaging the retina may provide insights on central nervous system related disorders such as schizophrenia. Here, our objective was to investigate if variations in retinal phenotypes could be attributed to common genetic variations conveying a risk of schizophrenia as measured by polygenic risk scores. We used population data from the UK Biobank, including White British and Irish individuals without diagnosed schizoprenia, and estimated a polygenic risk score for schizophrenia based on the newest genome-wide association study (PGC release 2022). We hypothesized that greater genetic susceptibility to schizophrenia is associated with retinal thinning, especially within the macula. To gain additional mechanistic insights, we conducted pathway-specific polygenic risk score associations analyses, focusing on gene pathways that are related to schizophrenia. Of 65484 individuals recruited, 48208 participants with available matching imaging-genetic data were included in the analysis of whom 22427 (53.48%) were female and 25781 (46.52%) were male. 5148 individuals were excluded on the basis of incomplete optical coherence tomography data (for all phenotypes), 198 individuals based on the use of antipsychotics and 197 individuals with schizophrenia, schizotypal- and delusional disorders. Our robust principal component regression results showed that polygenic risk scores for schizophrenia were associated with retinal thinning while controlling for confounding factors (b = -0.03, p = 0.007). Similarly, we found that polygenic risk for schizophrenia specific to neuroinflammation gene sets revealed significant associations with retinal thinning (b = -0.03, self-contained p = 0.041 (reflecting the level of association), competitive p = 0.05 (reflecting the level of enrichment)). These results go beyond previous studies suggesting a relationship between manifested schizophrenia and retinal phenotypes. They indicate that the retina is a mirror reflecting the genetic complexities of schizophrenia. These associations also suggest the potential involvement of the neuroinflammatory pathway, with indications of genetic overlap in certain retinal phenotypes. The findings further indicate that this gene pathway in individuals with a high polygenic risk for schizophrenia could contribute through acute-phase proteins to structural changes in the retina
Hypnosis in psychotherapy, psychosomatics and medicine. A brief overview.
Get PDFAspects of hypnosis and its application in psychotherapy, psychosomatics and medicine are examined and contextualized in the 250-year history of hypnosis. Imagination as an essential element of hypnotic treatments appeared as early as 1784 as an argument rejecting the theory of animal magnetism of Franz Anton Mesmer. In somnambulism of German romanticism, another proto-form of hypnosis after 1800, concepts of the mind-body problem were dealt with, which still characterize the understanding of unconscious mental processes today. Hypnosis was at the beginning of psychoanalysis, but was not pursued further by Sigmund Freud from 1900 onwards. Nevertheless, there were some hypnoanalytical approaches in the 20th century, as well as attempts to integrate hypnosis into behavior therapy. Techniques of imagination and relaxation combine both; in particular findings from cognitive psychology explain processes of both hypnosis and cognitive behavioral therapy. The influence of social psychology brought a new perspective to the debate about the nature of hypnosis, which continues to this day: is hypnosis to be understood as a special state of consciousness or is it a completely normal, mundane interaction? The experiments that were carried out to support one side or the other were also dependent on the hypnotizability of the subjects involved, as the more difficult hypnotic phenomena such as paralysis, hallucinations or identity delusions can only be demonstrated by highly hypnotizable subjects. The fact that these are not mere compliance reactions has now been proven by many studies using imaging techniques. But even those who are moderately hypnotizable benefit from hypnosis rituals. Variables postulated by socio-cognitive hypnosis researchers, such as motivation and expectation, are relevant, as is a good "hypnotic rapport." Practical application of hypnotherapy today is characterized by the innovative techniques and strategies developed by Milton H. Erickson. Research into the effectiveness of hypnosis in the field of psychotherapy and psychosomatics still leaves much to be done. The situation is different in the field of medical hypnosis, where there are considerably more studies with a satisfactory design and verifiable effects. However, the impact in practical application in everyday medical practice is still low. Newer developments such as virtual reality and artificial intelligence are being looked at with critical interest
Effective detection of BRAFV595E mutation in canine urothelial and prostate carcinomas using immunohistochemistry.
Get PDFCanine urothelial carcinoma (UC) and prostate carcinoma (PC) frequently exhibit the BRAFV595E mutation, akin to the BRAFV600E mutation common in various human cancers. Since the initial discovery of the BRAF mutation in canine cancers in 2015, PCR has been the standard method for its detection in both liquid and tissue biopsies. Considering the similarity between the canine BRAFV595E and human BRAFV600E mutations, we hypothesized that immunohistochemistry (IHC) using a BRAFV600E-specific antibody could effectively identify the canine mutant BRAFV595E protein. We tested 122 canine UC (bladder n = 108, urethra n = 14), 21 PC, and benign tissue using IHC and performed digital droplet PCR (ddPCR) on all 122 UC and on 14 IHC positive PC cases. The results from ddPCR and IHC were concordant in 99% (135/136) of the tumours. Using IHC, BRAFV595E was detected in 72/122 (59%) UC and 14/21 (65%) PC. Staining of all benign bladder and prostate tissues was negative. If present, mutant BRAF staining was homogenous, with rare intratumour heterogeneity in three (4%) cases of UC. Additionally, the BRAFV595E mutation was more prevalent in tumours with urothelial morphology, and less common in glandular PC or UC with divergent differentiation. This study establishes that BRAFV600-specific IHC is a reliable and accurate method for detecting the mutant BRAFV595E protein in canine UC and PC. Moreover, the use of IHC, especially with tissue microarrays, provides a cost-efficient test for large-scale screening of canine cancers for the presence of BRAF mutations. This advancement paves the way for further research to define the prognostic and predictive role of this tumour marker in dogs and use IHC to stratify dogs for the treatment with BRAF inhibitors
True Donor Cell Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation: Diagnostic and Therapeutic Considerations-Brief Report.
Get PDFDonor cell leukemia (DCL) is a rare complication after allogeneic hematopoietic stem cell transplantation (HSCT) accounting for 0.1% of relapses and presenting as secondary leukemia of donor origin. Distinct in phenotype and cytogenetics from the original leukemia, DCL's clinical challenge lies in its late onset. Its origin is affected by donor cell anomalies, transplant environment, and additional mutations. A 43-year-old woman, treated for early stage triple-negative breast cancer, developed mixed-phenotype acute leukemia (MPAL), 12 years later. Following induction chemotherapy, myeloablative conditioning, and allo-HSCT from her fully HLA-matched brother, she exhibited multiple cutaneous relapses of the original leukemia, subsequently evolving into DCL of the bone marrow. Cytogenetic analysis revealed a complex male karyotype in 20 out of 21 metaphases, however, still showing the MPAL phenotype. DCL diagnosis was confirmed by 90.5% XY in FISH analysis and the male karyotype. Declining further intensive chemotherapy including a second allo-HSCT, she was subsequently treated with repeated radiotherapy, palliative systemic therapies, and finally venetoclax and navitoclax but died seven months post-DCL diagnosis. This case underlines DCL's complexity, characterized by unique genetics, further complicating diagnosis. It highlights the need for advanced diagnostic techniques for DCL identification and underscores the urgency for early detection and better prevention and treatment strategies
One-Piece Mini Dental Implant-Retained Mandibular Overdentures: 10-Year Clinical and Radiological Outcomes of a Non-Comparative Longitudinal Observational Study.
Get PDFThis study presents the first 10-year follow-up investigation of the implant survival and peri-implant outcomes of one-piece mini dental implants (MDIs) retaining mandibular implant overdentures (IODs), including marginal bone level alterations (ΔMBLs), clinical peri-implant parameters, and complications. Twenty participants with horizontally atrophied mandibles received complete dentures and four MDIs (diameter 1.8 mm) at baseline. The dentures were converted into IODs with O-ring attachments. The 10-year follow-up comprised a radiological assessment of ΔMBLs, peri-implant parameters, as well as biological and technical complications. Results from a 10-year follow-up of 14 participants showed a 100% implant survival rate for all 56 implants. The mean ΔMBL after 10 years was -1.12 ± 0.80 mm, with 49 implants classified as successful (ΔMBL < 2 mm) and 7 implants with satisfactory survival (ΔMBL 2-4 mm). Time after implant placement significantly influenced ΔMBL, with stable MBLs after 5 years. The prosthetic survival rate after 10 years was 93%. ΔMBLs were not influenced by implant position or gender but were significantly smaller in subjects older than 65 years. Conclusively, one-piece MDIs with O-ring attachments offer a reliable treatment option for horizontally atrophied mandibles after 10 years, with high implant and prosthetic survival rates, potentially benefiting from advanced age regarding peri-implant bone stability
Intranodal Injection of Immune Activator Demonstrates Antitumor Efficacy in an Adjuvant Approach.
Get PDFThe tumor-draining lymph nodes (tdLN) are the initial site of metastases and are the prime site for generating robust antitumor responses. In this study, we explored the efficacy of a universal immune activator (ImmAct) targeted to the tdLN. This approach can be viewed as an attempt to turn a cold, unresponsive tdLN into a hot, responsive site. The adjuvant antitumor efficacy of our novel intranodal injection was evaluated in an aggressive metastatic mammary carcinoma murine model. The cancer cells were inoculated subcutaneously in the lower quadrant of the mouse to provoke the tdLN (inguinal lymph node). The study encompasses a range of methodologies, including in vivo and in vitro assays and high-dimensional flow cytometry analysis. Our findings demonstrated that intranodal administration of ImmAct following the dissection of the primary tumor led to improved tumor-free survival and minimized weight loss. ImmAct led to both local and systemic alterations in the cellular and humoral immunity. Additionally, after ImmAct treatment, non-responders showed a higher rate of exhausted CD8+ T cells compared to responders. Indeed, our innovative approach surpassed the gold standard surgery of sentinel lymph node excision. Overall, intranodal administration of ImmAct yielded a robust antitumor immune response, offering protection against micrometastases and relapse
Does Diglossia Impact Brain Structure? Data from Swiss German Early Diglossic Speakers.
Get PDF(1) Background: Bilingualism has been reported to shape the brain by inducing cortical changes in cortical and subcortical language and executive networks. Similar yet different to bilingualism, diglossia is common in Switzerland, where the German-speaking population switches between an everyday spoken Swiss German (CH-GER) dialect and the standard German (stGER) used for reading and writing. However, no data are available for diglossia, defined as the use of different varieties or dialects of the same language, regarding brain structure. The aim of our study is to investigate if the presence of this type of diglossia has an impact on the brain structure, similar to the effects seen in bilingualism. (2) Methods: T1-weighted anatomical MRI scans of participants were used to compare the grey matter density and grey matter volume of 22 early diglossic CH-GER-speaking and 20 non-diglossic French-speaking right-handed university students, matched for age, linguistics and academic background. The images were processed with Statistical Parametric Mapping SPM12 and analyzed via voxel- and surface-based morphometry. (3) Results: A Bayesian ANCOVA on the whole brain revealed no differences between the groups. Also, for the five regions of interest (i.e., planum temporale, caudate nucleus, ACC, DLPFC and left interior parietal lobule), no differences in the cortical volume or thickness were found using the same statistical approach. (4) Conclusion: The results of this study may suggest that early diglossia does not shape the brain structure in the same manner as bilingualism
Recipient donor sex combinations in solid organ transplantation and impact on clinical outcome: A scoping review.
Get PDFINTRODUCTION
Solid organ transplantation (SOT) is a lifesaving treatment for end-stage organ failure. Although many factors affect the success of organ transplantation, recipient and donor sex are important biological factors influencing transplant outcome. However, the impact of the four possible recipient and donor sex combinations (RDSC) on transplant outcome remains largely unclear.
METHODS
A scoping review was carried out focusing on studies examining the association between RDSC and outcomes (mortality, graft rejection, and infection) after heart, lung, liver, and kidney transplantation. All studies up to February 2023 were included.
RESULTS
Multiple studies published between 1998 and 2022 show that RDSC is an important factor affecting the outcome after organ transplantation. Male recipients of SOT have a higher risk of mortality and graft failure than female recipients. Differences regarding the causes of death are observed. Female recipients on the other hand are more susceptible to infections after SOT.
CONCLUSION
Differences in underlying illnesses as well as age, immunosuppressive therapy and underlying biological mechanisms among male and female SOT recipients affect the post-transplant outcome. However, the precise mechanisms influencing the interaction between RDSC and post-transplant outcome remain largely unclear. A better understanding of how to identify and modulate these factors may improve outcome, which is particularly important in light of the worldwide organ shortage. An analysis for differences of etiology and causes of graft loss or mortality, respectively, is warranted across the RDSC groups.
PRACTITIONER POINTS
Recipient and donor sex combinations affect outcome after solid organ transplantation. While female recipients are more susceptible to infections after solid organ transplantation, they have higher overall survival following SOT, with causes of death differing from male recipients. Sex-differences should be taken into account in the post-transplant management
Gegenderte Lebensläufe in der Schweiz: Befunde aus der TREE-Studie
Get PDFWie viele postindustrielle, wissensbasierte Gesellschaften bzw. Volkswirtschaften hat haben sich auch in der Schweiz die geschlechtsspezifischen Unterschiede hinsichtlich des Bildungsstands umgekehrt: Innerhalb von weniger als zwei Jahrzehnten hat der Anteil der jungen Frauen, die einen Bildungsabschluss auf Tertiärstufe erreichen, denjenigen der jungen Männer überstiegen - im Falle der Schweiz um 10 Prozentpunkte. Diese Entwicklung schlägt sich jedoch mitnichten in der Situation der Frauen auf dem Arbeitsmarkt nieder. Sie sind in Führungspositionen deutlich unterrepräsentiert, in schlecht bezahlten Berufen überrepräsentiert und mit persistenten "unerklärten" Lohnunterschieden zu ihren Ungunsten konfrontiert. Die Geschlechtersegregation ist sowohl im Bildungssystem als auch auf dem Arbeitsmarkt nach wie vor ausgeprägt. Die Dominanz der Berufsbildung in der Schweiz ist ausserdem mit einer starken Koppelung von Bildung und Beruf gekennzeichnet, die die Geschlechtertrennung tendenziell verstärkt. Die geschlechtsspezifischen Erwerbsverläufe akzentuieren sich überdies durch die sozialen, rechtlichen, fiskalischen und wirtschaftlichen Rahmenbedingungen, die die Vereinbarkeit von Familie und Erwerbstätigkeit erschweren, wodurch Frauen mit Kindern auf dem Arbeitsmarkt tendenziell marginalisiert oder zeitweise ganz aus diesem verdrängt werden.
Die detaillierten, reich kontextualisierten Verlaufsdaten der TREE-Panelbefragung erlauben es, die Vergeschlechtlichung von Lebensverläufen in ihrem Entstehungsprozess zu beobachten. Der vorliegende Beitrag gibt einen Überblick über die wichtigsten Befunde, die sich aus Analysen TREE-Daten über die verschiedenen Lebensphasen ab Ende der obligatorischen Schule ergeben. Die Ergebnisse tragen insbesondere dazu bei, den komplexen, aber wirkmächtigen Mechanismen auf die Spur zu kommen, die den Übergang in die nachobligatorische Bildung und in den Arbeitsmarkt prägen.Like many post-industrial, knowledge-based societies and economies, Switzerland has experienced a reversal of the gender gap with respect to educational attainment: Within less than two decades, the share of young women attaining a tertiary level degree has exceeded that of young men – by 10% points in the Swiss case. However, this development is far from translating into women’s situation in the labour market. They are markedly underrepresented in managerial positions, overrepresented in low-paying jobs, and experience persistent “unexplained” wage gaps. Both the Swiss education system and the labour market remain deeply affected by gender segregation. As a country with a VET-dominated education system, Switzerland is characterized by a strong education-occupation linkage, which tends to reinforce gender segregation. Gendered labour market trajectories are further accentuated by a social, legislative, fiscal, and economic context hampering reconciliation of family and work, which tends to marginalize or exclude women with children from the labour market.
The detailed, richly contextualized trajectory data of the TREE panel survey allow us to observe and analyse the progressive gendering of life courses, as it were, “in its making.” The present contribution provides a synopsis of salient findings drawing on TREE data across the various stages of educational, labour market, and family formation pathways after young people in Switzerland leave compulsory schooling at the age of 15–16. The findings particularly contribute to disentangling the complex, yet powerful mechanisms at work during the transition to post-compulsory education and to the labour market
Germline cis variant determines epigenetic regulation of the anti-cancer drug metabolism gene dihydropyrimidine dehydrogenase (DPYD).
Get PDFEnhancers are critical for regulating tissue-specific gene expression, and genetic variants within enhancer regions have been suggested to contribute to various cancer-related processes, including therapeutic resistance. However, the precise mechanisms remain elusive. Using a well-defined drug-gene pair, we identified an enhancer region for dihydropyrimidine dehydrogenase (DPD, DPYD gene) expression that is relevant to the metabolism of the anti-cancer drug 5-fluorouracil (5-FU). Using reporter systems, CRISPR genome-edited cell models, and human liver specimens, we demonstrated in vitro and vivo that genotype status for the common germline variant (rs4294451; 27% global minor allele frequency) located within this novel enhancer controls DPYD transcription and alters resistance to 5-FU. The variant genotype increases recruitment of the transcription factor CEBPB to the enhancer and alters the level of direct interactions between the enhancer and DPYD promoter. Our data provide insight into the regulatory mechanisms controlling sensitivity and resistance to 5-FU
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