Golexanolone reduces glial activation in the striatum and improves non-motor and some motor alterations in a rat model of Parkinson's disease.

Background: Parkinson's disease (PD) affects more than 6 million people worldwide. Along with motor impairments, patients and animal models exhibiting PD symptoms also experience cognitive impairment, fatigue, anxiety, and depression. Currently, there are no drugs available for PD that alter the progression of the disease. A body of evidence suggests that increased GABA levels contribute to the reduced expression of tyrosine hydroxylase (TH) and accompanying behavioral deficits. TH expression may be restored by blocking GABAA receptors. We hypothesized that golexanolone (GR3027), a well-tolerated GABAA receptor-modulating steroid antagonist (GAMSA), may improve Parkinson's symptoms in a rat model of PD. Objectives: The aims of this study were to assess whether golexanolone can ameliorate motor and non-motor symptoms in a rat model of PD and to identify some underlying mechanisms. Methods: We used the unilateral 6-OHDA rat model of PD. The golexanolone treatment started 4 weeks after surgery. Motor symptoms were assessed using Motorater and CatWalk tests. We also analyzed fatigue (using a treadmill test), anhedonia (via the sucrose preference test), anxiety (with an open field test), and short-term memory (using a Y maze). Glial activation and key proteins involved in PD pathogenesis were analyzed using immunohistochemistry and Western blot. Results: Rats with PD showed motor incoordination and impaired locomotor gait, increased fatigue, anxiety, depression, and impaired short-term memory. Golexanolone treatment led to improvements in motor incoordination, certain aspects of locomotor gait, fatigue, anxiety, depression, and short-term memory. Notably, golexanolone reduced the activation of microglia and astrocytes, mitigated TH loss at 5 weeks after surgery, and prevented the increase of α-synuclein levels at 10 weeks. Conclusions: Golexanolone may be useful in improving both motor and non-motor symptoms that adversely affect the quality of life in PD patients, such as anxiety, depression, fatigue, motor coordination, locomotor gait, and certain cognitive alterations.

Localized pemphigus vulgaris on scalp: an atypical presentation.

We present two middle-aged patients with pruritic, crusted scalp erosions. Skin biopsy showed epidermal acantholysis with IgG and C3 intercellular deposits on direct immunofluorescence, leading to the diagnosis of localized pemphigus vulgaris. Resolution of the lesions without relapse occurred after low doses of oral prednisone and intralesional triamcinolone acetonide.

Pre-exposure prophylaxis program in the Community of Madrid: Two years of experience.

INTRODUCTION: Pre-exposure prophylaxis (PrEP) against the human immunodeficiency virus (HIV) is an effective and safe preventive measure. However, it has not reached all target users who could benefit from it. The study aimed to understand the sociodemographic, clinical and behavioral baseline characteristics of PrEP users. As a secondary objective, the use of concomitant medication and drug consumption were described. METHODOLOGY: Observational, retrospective and descriptive study of the sociodemographic, clinical and behavioral characteristics of the users who were included in the PrEP program of the Community of Madrid during the first two years of experience. RESULTS: Two thousand two hundred fifty-six PrEP users were included, 99.0% men, with a mean age of 36.9 years (SD 8.68). 33.1% presented a sexually transmitted infection (STI) on the first visit, highlighting chlamydiasis and rectal gonococci. 70.4% reported using drugs associated with sex, and 42.4% participated in chemsex sessions in the last 3 months. A high percentage of users with concomitant medication was observed (37.6%), highlighting drugs related to mental health and alopecia. CONCLUSIONS: A multidisciplinary approach is required to cover all the needs of PrEP users, including mental health evaluation measures and addiction treatment with the clinical approach.

Granulomatous dermatitis in the context of chronic myelomonocytic leukemia: More than just reactive infiltrates. An illustrative case report with literature review.

Traditionally, skin involvement in chronic myelomonocytic leukemia (CMML) has been considered to be either specific (leukemia cutis) or non-specific, with granulomatous dermatitis included in the latter group. More recently, the true nature of the myeloid cells present in the cutaneous infiltrates of this theoretically reactive dermatitis is being clarified with the use of new molecular techniques such as next-generation sequencing. The same mutations in bone marrow (BM) myeloid neoplastic cells and in the cells of cutaneous infiltrates have been found. We present the case of a 77-year-old man who presented with spread and treatment-resistant skin granulomatous lesions previous to the diagnosis of CMML. The same clonal mutations in SRSF2, IDH1, and RUNX1 were found in both skin and BM with resolution of the lesions after the initiation of azacytidine. In conclusion, we report an exceptional case in which specific granulomatous cutaneous lesions have preceded and allowed the earlier diagnosis of an underlying CMML and a review of all previous similar cases in the literature, including molecular alterations.

Environmentally dependent and independent control of 3D cell shape.

How cancer cells determine their shape in response to three-dimensional (3D) geometric and mechanical cues is unclear. We develop an approach to quantify the 3D cell shape of over 60,000 melanoma cells in collagen hydrogels using high-throughput stage-scanning oblique plane microscopy (ssOPM). We identify stereotypic and environmentally dependent changes in shape and protrusivity depending on whether a cell is proximal to a flat and rigid surface or is embedded in a soft environment. Environmental sensitivity metrics calculated for small molecules and gene knockdowns identify interactions between the environment and cellular factors that are important for morphogenesis. We show that the Rho guanine nucleotide exchange factor (RhoGEF) TIAM2 contributes to shape determination in environmentally independent ways but that non-muscle myosin II, microtubules, and the RhoGEF FARP1 regulate shape in ways dependent on the microenvironment. Thus, changes in cancer cell shape in response to 3D geometric and mechanical cues are modulated in both an environmentally dependent and independent fashion.

[ChatGPT is an above-average student at the Faculty of Medicine of the University of Zaragoza and an excellent collaborator in the development of teaching materials]. / ChatGPT es un estudiante por encima de la media en la Facultad de Medicina de la Universidad de Zaragoza y un colaborador excelente en la elaboración de material docente.

INTRODUCTION AND OBJECTIVE: Artificial intelligence is fully present in our lives. In education, the possibilities of its use are endless, both for students and teachers. MATERIAL AND METHODS: The capacity of ChatGPT has been explored when solving multiple choice questions based on the exam of the subject «Anatomopathological Diagnostic and Therapeutic Procedures¼ of the first call of the 2022-23 academic year. In addition, to comparing their results with those of the rest of the students presented the probable causes of incorrect answers have been evaluated. Finally, its ability to formulate new test questions based on specific instructions has been evaluated. RESULTS: ChatGPT correctly answered 47 out of 68 questions, achieving a grade higher than the course average and median. Most failed questions present negative statements, using the words «no¼, «false¼ or «incorrect¼ in their statement. After interacting with it, the program can realize its mistake and change its initial response to the correct answer. Finally, ChatGPT can develop new questions based on a theoretical assumption or a specific clinical simulation. CONCLUSIONS: As teachers we are obliged to explore the uses of artificial intelligence and try to use it to our benefit. Carrying out tasks that involve significant consumption, such as preparing multiple-choice questions for content evaluation, is a good example.

Incidence of sexually transmitted infections and screening models among pre-exposure prophylaxis users.

INTRODUCTION: There is discussion about the frequency of STI screening among pre-exposure prophylaxis (PrEP) users. The aim of this study was to analyse the incidence of STIs and to evaluate different screening models in order to optimise the follow-up. METHODOLOGY: A prospective study was conducted between 2017 and 2023, including 138 PrEP users in a STI clinic. Participants were tested for STIs every three months. Unscheduled visits were performed for those with STI-related symptoms or for people who were notified for an STI by a sexual partner. We performed a survival analysis of repeated events, estimating the cumulative incidence (CI) and incidence rate (IR). RESULTS: The overall CI by quarterly screening was 8.3 (95% CI: 7.6-9.1) infections per person over six years, with a decreasing trend. The most frequently diagnosed pathogen was Neisseria gonorrhoeae, with a IR of 0.76 (95% CI: 0.68-0.84). If the frequency of screening is reduced to every six months, the IR of STIs is reduced by (95% CI: 0.5-0.66) infections per user per year, and at 12 months by 0.82 (95% CI: 0.73-0.89). In the case of no pharyngeal or urethral screening, IR is reduced by 0.37 (95% CI: 0.32-0.42) infections per person per year and in those over 35 years of age by 0.33 (95% CI: 0.25-0.4). Eliminating unscheduled visits, the reduction in IR is 0.33 (95% CI: 0.24-0.42). CONCLUSIONS: The incidence of STIs among PrEP users is high, especially in the rectum, but it does not increase over time. STI screening could be optimised reducing the frequency of pharyngeal and urethral testing, particularly in those over 35 years of age. It is essential to redistribute health resources for unscheduled visits, which have been shown to be the most cost-effective screening.

Gorlin-Like Phenotype in a Young Girl With a De Novo PTCH2 Variant Mutation of Uncertain Significance.

ABSTRACT: Gorlin syndrome, also known as basal cell nevus syndrome, is an autosomal dominant genetic disorder that predisposes humans to tumors. In most cases, this syndrome results from inactivating mutations in the patched homologue 1 gene. Basal cell carcinomas are one of the main characteristics of this syndrome and serve as a major diagnostic criterion. Gorlin syndrome shows a variable phenotype, and recently, other less common mutations in the suppressor of fused homologue or patched homologue 2 genes have been documented in individuals with this syndrome. We present the case of a patient with early-onset basal cell carcinomas and a mild Gorlin syndrome phenotype, attributed to a de novo patched homologue 2 variant of uncertain significance, which has not been previously reported in the literature.

Cutaneous Alternariosis in Immunosuppressed Patients Treated with Photodynamic Therapy and Oral Antifungals, a Synergistic Strategy.

Cutaneous alternariosis is a rare condition, more frequently presented in immunocompromised patients, which usually requires long courses of systemic antifungals that may interact with other medications. The presented series shows three cases of cutaneous alternariosis in immunocompromised patients and organ transplant recipients that were successfully treated with photodynamic therapy and oral antifungals, allowing a reduction in the systemic treatment duration and therefore decreasing the risk of side effects and drug interactions.

[Collision tumours in skin: usually an incidental finding. A retrospective study with literature revision]. / Tumores de colisión en la piel: un hallazgo incidental en la mayoría de los casos. Estudio retrospectivo y revisión de la literatura.

A collision tumour (CT) is a neoplastic lesion comprised of two or more distinct cell populations that maintain distinct borders. Mostly, these are incidental findings in skin biopsies, whose pathologic mechanism and prevalence remain unknown, with few references among literature. Here, we present a retrospective study of CT, diagnosed by a dermatopathologist in our hospital between 2019-2022. Lesions have been defined individually and organized into three categories: benign-benign (BB), benign-malignant (BM) and malignant-malignant (MM). A total of 108 CT were diagnosed (1,4% of the biopsies from the dermatopathologist during this period), from which BM was the most frequent collision (48,5%). Globally, basal cell carcinoma (BCC) was the main malignant lesion and melanocytic nevus (MN) the main benign lesion. We have used the software Stata 14.2 in order to analyse results, and we have detected a statistically significant difference between age and collision type.

Golexanolone improves fatigue, motor incoordination and gait and memory in rats with bile duct ligation.

BACKGROUND AND AIMS: Many patients with the chronic cholestatic liver disease primary biliary cholangitis (PBC) show fatigue and cognitive impairment that reduces their quality of life. Likewise, rats with bile duct ligation (BDL) are a model of cholestatic liver disease. Current PBC treatments do not improve symptomatic alterations such as fatigue or cognitive impairment and new, more effective treatments are therefore required. Golexanolone reduces the potentiation of GABAA receptors activation by neurosteroids. Golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in rats with chronic hyperammonemia. The aims of the present study were to assess if golexanolone treatment improves fatigue and cognitive and motor function in cholestatic BDL rats and if this is associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. METHODS: Rats were subjected to bile duct ligation. One week after surgery, oral golexanolone was administered daily to BDL and sham-operated controls. Fatigue was analysed in the treadmill, motor coordination in the motorater, locomotor gait in the Catwalk, and short-term memory in the Y-maze. We also analysed peripheral inflammation, neuroinflammation, and GABAergic neurotransmission markers by immunohistochemistry and Western blot. RESULTS: BDL induces fatigue, impairs memory and motor coordination, and alters locomotor gait in cholestatic rats. Golexanolone improves these alterations, and this was associated with improvement of peripheral inflammation, neuroinflammation, and GABAergic neurotransmission in the cerebellum. CONCLUSION: Golexanolone may have beneficial effects to treat fatigue, and motor and cognitive impairment in patients with the chronic cholestatic liver disease PBC.

Hydroa Vacciniforme Lymphoproliferative Disorder in a Young Spanish Woman: An Infrequent Case With Fatal Outcome.

ABSTRACT: Hydroa vacciniforme (HV) lymphoproliferative disorder is a rare NK/T-cell lymphoma mainly affecting children and with a clinical resemblance to HV, which is mostly reported in Latin American and some Asian countries. Overall, the mature T cell and NK-cell neoplasms are now grouped into 9 families based on diverse concepts: cell of origin/differentiation state, clinical scenario, disease localization, and cytomorphology. HV lymphoproliferative disorder is listed within the group of Ebstein Barr Virus-positive T-cell and NK-cell lymphoid proliferations and lymphomas of childhood according to the fifth edition of the World Health Organization Classification of mature lymphoid neoplasms. We report the extraordinary case of a 22-year-old white woman, native of Spain, first presented in 2016 when she started suffering from recurrent facial edema. Four years later, the disease progressed with lymph node spreading and a fatal outcome. Here, we describe the clinical and histological presentation of the lymphoma throughout its evolution. Cases like this can be difficult to classify posing a real challenge to clinicians and pathologists. So, it is vital to be aware of the rare presentation of this disease to be able to identify the clinical and histological picture to make a correct diagnosis and establish an early treatment.

Enhanced Activation of the S1PR2-IL-1ß-Src-BDNF-TrkB Pathway Mediates Neuroinflammation in the Hippocampus and Cognitive Impairment in Hyperammonemic Rats.

Hyperammonemia contributes to hepatic encephalopathy. In hyperammonemic rats, cognitive function is impaired by altered glutamatergic neurotransmission induced by neuroinflammation. The underlying mechanisms remain unclear. Enhanced sphingosine-1-phosphate receptor 2 (S1PR2) activation in the cerebellum of hyperammonemic rats contributes to neuroinflammation. in In hyperammonemic rats, we assessed if blocking S1PR2 reduced hippocampal neuroinflammation and reversed cognitive impairment and if the signaling pathways were involved. S1PR2 was blocked with intracerebral JTE-013, and cognitive function was evaluated. The signaling pathways inducing neuroinflammation and altered glutamate receptors were analyzed in hippocampal slices. JTE-013 improved cognitive function in the hyperammonemic rats, and hyperammonemia increased S1P. This increased IL-1ß, which enhanced Src activity, increased CCL2, activated microglia and increased the membrane expression of the NMDA receptor subunit GLUN2B. This increased p38-MAPK activity, which altered the membrane expression of AMPA receptor subunits and increased BDNF, which activated the TrkB → PI3K → Akt → CREB pathway, inducing sustained neuroinflammation. This report unveils key pathways involved in the induction and maintenance of neuroinflammation in the hippocampus of hyperammonemic rats and supports S1PR2 as a therapeutic target for cognitive impairment.

Association between biomarkers of iron status and cardiometabolic risk in Spanish children aged 9-10 years. The ELOIN study.

The relationship between iron metabolism and cardiometabolic risk factors has been scarcely studied in children, and the results are controversial. The objective of this study was to evaluate the association between iron parameters and lipid, glycemic and blood pressure alterations in the pediatric population. This was a cross-sectional study of 1954 children between 9 and 10 years of age in Madrid (Spain), participants in a longitudinal study of childhood obesity. Iron metabolism parameters, i.e., serum iron (Is), ferritin (Fs), transferrin (Tf) and transferrin saturation (STf) and lipid, glycemic and blood pressure profiles were evaluated. Odds ratios (ORs) were estimated using logistic regression models adjusted for sociodemographic characteristics, diet, physical activity, C-reactive protein and body mass index. Compared with the participants in the low Is and STf tertiles, those in the upper tertiles had a lower risk of low HDL-Chol (OR: 0.34; 95%CI: 0.17; 0.67) and OR: 0.44 (95%CI: 0.23; 0.84), respectively, and children in the upper Fs tertile had an OR of 2.07 (95%CI: 1.16; 3.68) for low HDL-Chol. Children in the highest Is and STf tertiles had a lower risk of prediabetes [OR: 0.63 (95%CI: 0.41; 0.97) and OR: 0.53 (95%CI: 0.34; 0.82)] and insulin resistance (IR) (OR: 0.37; 95%CI: 0.22; 0.64), and those in the upper Tf tertile had a higher risk of IR (OR: 1.90; 95%CI: 1.16; 3.12). An increased risk of hypertension was found only in children in the upper Fs tertile (OR: 1.46; 95%CI: 1.01; 2.13). CONCLUSIONS: Biomarkers of iron metabolism are associated with cardiometabolic alterations in the pediatric population, with a variable direction and magnitude depending on the indicators used. WHAT IS KNOWN: • Iron metabolism is related to important cardiometabolic alterations such as metabolic syndrome and its components. • Association between biomarkers of iron status and cardiometabolic risk have been less explored in children. WHAT IS NEW: • Biomarkers of iron metabolism are associated with cardiometabolic alterations in the pediatric population. • Iron parameters in the pediatric population could be of great help to detect and prevent cardiometabolic abnormalities early.

Hepatitis C antibody prevalence and active hepatitis C infection in HIV-negative gay, bisexual, and other men who have sex with men in Barcelona and Madrid, Spain (March 2018-March 2021).

Objectives: Hepatitis C virus (HCV) has been recognized as a sexually transmitted infection (STI) in HIV-positive men who have sex with men (MSM), with an increased notification in HIV-negative MSM. The aim of this study was to determine the prevalence of HCV antibody and active HCV infection in HIV-negative gay, bisexual, and other MSM (GBMSM), and their characteristics, in Barcelona and Madrid, from March 2018 to March 2021. Methods: Cross-sectional study conducted on 3548 HIV-undiagnosed GBMSM, across four HIV/STI testing centers. Respondents submitted an online, self-administered questionnaire after consultation, which collected information on sociodemographics, sexual health history, HCV knowledge, and substance consumption. Prevalence of HCV antibodies was determined by a reactive result in a rapid anti-HCV test or enzyme-linked immunosorbent assay (ELISA), while active HCV infection was determined by participants who were also positive on an HCV-RNA test. Crude and adjusted Poisson analyses with robust variance are presented for both prevalence and active infection. Results: In total, 97.6% of participants (n = 3463) were HIV-negative. Of those, 18 were found to have HCV antibodies (0.52%), of which nine (0.26%) were also HCV-RNA positive. Those with HCV antibodies were associated to have lived with an HCV (+) person (adjusted prevalence ratio [APR]: 7.84, [95% confidence interval: 2.50-24.53]), using injectable drugs for sex (APR: 6.92, [1.20-39.79]) and testing positive for an STI in the previous year (APR: 4.06, [1.09-15.12]). Presenting an active infection was strongly associated with a previous HCV diagnosis (APR: 100.82 [22.16-458.76]), sexualized injectable drug use (APR: 17.53 [2.70-113.76]), and sharing douching material (APR: 7.45, [2.12-25.95]). Conclusion: Sexual practices with a higher risk of bleeding and sexualized drug use, particularly sexualized injectable drug use, were associated with higher rates of HCV diagnosis in GBMSM. Identifying these practices during consultation, contact tracing new cases and regularly testing those with a previous history of HCV, will facilitate HCV eradication.

Patients who died with steatohepatitis or liver cirrhosis show neuroinflammation and neuronal loss in hippocampus.

BACKGROUND: Neuroinflammation in the cerebral cortex of patients who died with liver cirrhosis and neuroinflammation, and neuronal death in the cerebellum of patients who died with steatohepatitis or cirrhosis, were reported. Hippocampal neuroinflammation could contribute to cognitive decline in patients with liver disease, but this has yet to be studied. The study aims were to assess if hippocampus from patients who died with steatohepatitis or cirrhosis showed: (i) glial activation, (ii) altered cytokine content, (iii) immune cell infiltration, (iv) neuronal apoptosis and (v) neuronal loss. METHODS: Post-mortem hippocampus was obtained from 6 controls, 19 patients with steatohepatitis (SH) and 4 patients with liver cirrhosis. SH patients were divided into SH1 (n = 9), SH2 (n = 6) and SH3 (n = 4) groups depending on disease severity. Glial activation, IL-1ß and TNFα content, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss were analyzed by immunohistochemistry. RESULTS: Patients who died in SH1 showed astrocyte activation, whereas those who died in SH2 also showed microglial activation, CD4 lymphocyte and monocyte infiltration, neuronal apoptosis and neuronal loss. These changes remained in patients in SH3, who also showed increased IL-1ß and TNFα. Patients who died of liver cirrhosis did not show CD4 lymphocyte infiltration, neuronal apoptosis or increase in TNFα, but still showed glial activation, increased IL-1ß and neuronal loss. CONCLUSIONS: Patients with steatohepatitis showed glial activation, immune cell infiltration, apoptosis and neuronal loss. Glial activation and neuronal loss remained in cirrhotic patients. This may explain the irreversibility of some cognitive alterations in hepatic encephalopathy. Cognitive reserve may contribute to different grades of cognitive impairment despite similar neuronal loss.

Differences in weight loss and safety between the glucagon-like peptide-1 receptor agonists: A non-randomized multicenter study from the titration phase.

INTRODUCTION: Obesity increases the risk of type 2 diabetes mellitus and cardiovascular disease (CVD). Weight loss (≥5 %) reduces the risk of CVD. Glucagon-like peptide-1 receptor agonists (GLP1 RA) have shown clinically weight loss. OBJECTIVES: 1) To assess differences in the efficacy of weight loss and HbA1c; 2) to evaluate the safety and adherence during the titration phase. METHODS: It is a multicenter, prospective, and observational study on GLP1 RA naïve patients. The primary end point was the weight loss (≥5 %). Changes in weight, BMI and HbA1c were also calculated as co-primary endpoints. Secondary endpoints were safety, adherence, and tolerance. RESULTS: Among 94 subjects, 42.4 % received dulaglutide, 29,3 % subcutaneous semaglutide, 22,8 % oral semaglutide. 45 % female and the mean age was 62. Baseline characteristics were body weight 99.3 kg, BMI 36.7 kg/m2 and Hba1c 8.2 %. Oral semaglutide achieved the highest reduction: 61.1 % of patients achieving ≥ 5 %, subcutaneous semaglutide 45.8 % and dulaglutide 40.6 %. GLP1 RA significantly reduced body weight (-4.95 kg, p < 0.001) and BMI (-1.86 kg/m2, p < 0.001), without significant differences between groups. Gastrointestinal disorders were the most frequently reported events (74.5 %). 62 % of patients on dulaglutide, 25 % on oral semaglutide and 22 % on subcutaneous semaglutide. CONCLUSIONS: Oral semaglutide achieved the highest proportion of patients that lost ≥ 5 %. GLP1 RA significantly reduced BMI and HbA1c. Most of the reported adverse events were gastrointestinal disorders and they were reported in a major frequency in the dulaglutide group. Oral semaglutide would be a reasonable switch in case of future shortages.