The cycling and aging mouse female reproductive tract at single-cell resolution.

The female reproductive tract (FRT) undergoes extensive remodeling during reproductive cycling. This recurrent remodeling and how it shapes organ-specific aging remains poorly explored. Using single-cell and spatial transcriptomics, we systematically characterized morphological and gene expression changes occurring in ovary, oviduct, uterus, cervix, and vagina at each phase of the mouse estrous cycle, during decidualization, and into aging. These analyses reveal that fibroblasts play central-and highly organ-specific-roles in FRT remodeling by orchestrating extracellular matrix (ECM) reorganization and inflammation. Our results suggest a model wherein recurrent FRT remodeling over reproductive lifespan drives the gradual, age-related development of fibrosis and chronic inflammation. This hypothesis was directly tested using chemical ablation of cycling, which reduced fibrotic accumulation during aging. Our atlas provides extensive detail into how estrus, pregnancy, and aging shape the organs of the female reproductive tract and reveals the unexpected cost of the recurrent remodeling required for reproduction.

Diacylglycerol acyltransferase (DGAT) in Crangon crangon and Pandalus montagui (Decapoda, Caridea) - Implications for lipid storage capacities and life history traits.

Lipids play essential roles in cell-structuring, cell-signaling, and as efficient metabolic energy stores. Lipid storage capacities determine life history traits of organisms and, thus, their ecological function. Among storage lipids, triacylglycerols (TAGs) are widespread in marine invertebrates. However, abilities to accumulate TAGs can vary even between closely related species, such as the caridean shrimps Crangon crangon and Pandalus montagui. The first species shows low TAG levels throughout the year in the main storage organ, the midgut gland, while the latter accumulates high TAG-levels, peaking in summer. TAGs synthesis is facilitated by the terminal step of the Kennedy-pathway, where the enzyme diacylglycerol-acyltransferase (DGAT) catalyzes the esterification of diacylglycerols with activated fatty acids. We investigated DGAT activity in the midgut gland using a fluorescent enzyme assay. Sequence information was extracted from whole transcriptome shotgun assembly data, that is publicly available on NCBI, and catalytic properties were deduced from molecular structure analysis. C. crangon showed significantly lower TAG synthesis rates than P. montagui, which explains the native TAG levels. Transcriptome data yielded several isoforms of DGAT enzymes in both species. C. crangon DGAT showed point mutations, which are capable of obstructing the catalytic capacity. The consequences are limited starvation resistance and, thus, presumably restricting C. crangon to a habitat with year-round sufficient food. In contrast, higher TAG synthesis rates presumably enable P. montagui to extend into northern subarctic habitats with limited food availability in winter. Moreover, the limited TAG synthesis and accumulation in the midgut gland may force C. crangon to direct energy into the ovaries, which results in multiple spawnings.

Antipsychotic-Related Prolactin Levels and Sexual Dysfunction in Mentally Ill Youth: A 3-Month Cohort Study.

OBJECTIVE: Although these agents are used frequently, prospective data comparing serotonin/dopamine antagonists/partial agonists (SDAs) in youth regarding prolactin levels and sexual adverse effects (SeAEs) are scarce. METHOD: Youth aged 4 to 17 years, SDA-naive (≤1 week exposure) or SDA-free for ≥4 weeks were followed for ≤12 weeks on clinician's-choice aripiprazole, olanzapine, quetiapine, or risperidone. Serum prolactin levels, SDA plasma levels, and rating scale-based SeAEs were assessed monthly. RESULTS: Altogether, 396 youth (aged 14.0 ± 3.1 years, male participants = 55.1%, mood spectrum disorders = 56.3%, schizophrenia spectrum disorders = 24.0%, aggressive-behavior disorders = 19.7%; SDA-naive = 77.8%) were followed for 10.6 ± 3.5 weeks. Peak prolactin levels/any hyperprolactinemia/triple-upper-limit-of-normal-prolactin level were highest with risperidone (median = 56.1 ng/mL/incidence = 93.5%/44.5%), followed by olanzapine (median = 31.4 ng/mL/incidence = 42.7/76.4%/7.3%), quetiapine (median = 19.5 ng/mL/incidence = 39.7%/2.5%) and aripiprazole (median = 7.1 ng/mL/incidence = 5.8%/0.0%) (all p < .0001), with peak levels at 4 to 5 weeks for risperidone and olanzapine. Altogether, 26.8% had ≥1 newly incident SeAEs (risperidone = 29.4%, quetiapine = 29.0%, olanzapine = 25.5%, aripiprazole = 22.1%, p = .59). The most common SeAEs were menstrual disturbance = 28.0% (risperidone = 35.4%, olanzapine = 26.7%, quetiapine = 24.4% aripiprazole = 23.9%, p = .58), decreased erections = 14.8% (olanzapine = 18.5%, risperidone = 16.1%, quetiapine = 13.6%, aripiprazole = 10.8%, p = .91) and decreased libido = 8.6% (risperidone = 12.5%, olanzapine = 11.9%, quetiapine = 7.9%, aripiprazole = 2.4%, p = .082), with the least frequent being gynecomastia = 7.8% (quetiapine = 9.7%, risperidone = 9.2%, aripiprazole = 7.8%, olanzapine = 2.6%, p = 0.61), galactorrhea = 6.7% (risperidone = 18.8%, quetiapine = 2.4%, olanzapine = 0.0%, aripiprazole = 0.0%, p = .0008), and mastalgia = 5.8% (olanzapine = 7.3%, risperidone = 6.4%, aripiprazole = 5.7%, quetiapine = 3.9%, p = .84). Postpubertal status and female sex were significantly associated with prolactin levels and SeAEs. Serum prolactin levels were rarely associated with SeAEs (16.7% of all analyzed associations), except for the relationship between severe hyperprolactinemia and decreased libido (p = .013) and erectile dysfunction (p = .037) at week 4, and with galactorrhea at week 4 (p = .0040), week 12 (p = .013), and last visit (p < .001). CONCLUSION: Risperidone, followed by olanzapine, was associated with the largest prolactin elevations, with little prolactin-elevating effects of quetiapine and, especially, aripiprazole. Except for risperidone-related galactorrhea, SeAEs did not differ significantly across SDAs, and only galactorrhea, decreased libido, and erectile dysfunction were associated with prolactin levels. In youth, SeAEs are not sensitive markers for significantly elevated prolactin levels.

Immunological Risk Factors in Paediatric Kidney Transplantation.

PURPOSE: The aim of this study was to identify factors impacting recipient sensitization rates and paediatric renal transplant patient outcomes. PATIENTS AND METHODS: For this purpose, a retrospective analysis of 143 paediatric renal transplants was carried out. This included the evaluation of patient's and donor's demographic data, HLA mismatches, immunosuppressive therapy, rejection episodes, panel reactive antibody (PRA) and post-transplant lymphoproliferative disease (PTLD). RESULTS: The mean patient age at the point of transplant receival was 11.5 years with a mean follow up time of 9.33±5.05 years. It was noted that graft survival rates for donors over 59 years had the worst outcome. HLA match did not show statistically significant influence on graft outcome. Graft survival for more than one biopsy-proven rejection was also significantly shorter (p=0.008). PRA were found in 28% of the recipient's post-transplantation and showed association with lower graft survival rates (p<0.001). In the present study, 22.7% (5/22) of the patients with EBV infections presented a PTLD. CONCLUSION: In conclusion, good graft survival with reduced sensitization for future transplantations and minimize the risk of PTLD, can be ensured through a balance between donor age, HLA match and condition of the recipient should be sought. Furthermore, paediatric patients should preferably receive organs from donors between the age of 10 and 59. EBV infection could be a relevant factor for developing PTLD.

Efficacy, Safety And Feasibility Of Antiemetic Prophylaxis With Fosaprepitant, Granisetron And Dexamethasone In Pediatric Patients With Hemato-Oncological Malignancies.

BACKGROUND: Chemotherapy-induced nausea and vomiting (CINV) are a major burden for patients undergoing emetogenic chemotherapy. International guidelines recommend an antiemetic prophylaxis with corticosteroids, 5-HT3R-antagonists and NK1R-antagonists. The NK1R-antagonist fosaprepitant has shown favorable results in pediatric and adult patients. There is little pediatric experience with fosaprepitant. METHODS: This non-interventional observation study analyzed 303 chemotherapy courses administered to 83 pediatric patients with a median age of 9 years (2-17 years), who received antiemetic prophylaxis either with fosaprepitant and granisetron with or without dexamethasone (fosaprepitant group/FG; n=41), or granisetron with or without dexamethasone (control group/CG; n=42), during moderately (CINV risk 30-90%) or highly (CINV risk>90%) emetogenic chemotherapy. The two groups' results were compared with respect to the safety and efficacy of the antiemetic prophylaxis during the acute (0-24hrs after chemotherapy), delayed (>24-120hrs after chemotherapy) and both CINV phases. Laboratory and clinical adverse events were compared between the two cohorts. RESULTS: Adverse events were not significantly different in the two groups (p>0.05). Significantly fewer vomiting events occurred during antiemetic prophylaxis with fosaprepitant in the acute (23 vs 142 events; p<0.0001) and the delayed (71 vs 255 events; p<0.0001) CINV phase. In the control group, the percentage of chemotherapy courses with vomiting was significantly higher during the acute (24%/FG vs 45%/CG; p<0.0001) and delayed CINV phase (28%/FG vs 47%/CG; p=0.0004). Dimenhydrinate (rescue medication) was administered significantly more often in the CG, compared to the FG (114/FG vs 320/CG doses; p<0.0001). Likewise, in the control group, dimenhydrinate was administered in significantly more (p<0.0001) chemotherapy courses during the acute and delayed CINV phases (79 of 150; 52.7%), compared to the fosaprepitant group (45 of 153; 29.4%). CONCLUSION: Antiemetic prophylaxis with fosaprepitant and granisetron with or without dexamethasone was well tolerated, safe and effective in pediatric patients. However, larger prospective trials are needed to evaluate these findings.

Cannabis Use and Dependence among French Schizophrenic Inpatients.

BACKGROUND: To assess the prevalence of cannabis use and dependence in a population of schizophrenic inpatients and to compare schizophrenics with and without cannabis consumption. METHODS: One hundred one schizophrenic patients were examined during their first week of hospitalization. They answered the PANNS scale of schizophrenia, the CAGE and the Fagerström questionnaire, and the DSM-IV-TR criteria for cannabis, alcohol, opiates, and nicotine use dependence were checked. We also assessed socio-demographic characteristics, the motive of cannabis consumption, and the number of cannabis joints and alcoholic drinks taken. RESULTS: The prevalence of cannabis consumption was 33.6% among schizophrenic inpatients. Schizophrenics consuming cannabis were younger than non-schizophrenics (33.3 vs. 44.7 years p < 0.0001), more often male (77 vs. 54%, p = 0.02) and had been hospitalized for the first time in psychiatry earlier (24.3 vs. 31.3 p = 0.003). Eighty-eight percent of cannabis consumers were dependent on cannabis. They were more often dependent on opiates (17 vs. 0%) and alcohol (32 vs. 7.4%, p = 0.001) and presented compulsive buying more often (48 vs. 27%, p = 0.04). Logistic regression revealed that factors associated to cannabis consumption among schizophrenics were cannabis dependence, male gender, pathological gambling, opiate dependence, number of joints smoked each day, and compulsive buying. CONCLUSION: 33.6% of the schizophrenic patients hospitalized in psychiatry consume cannabis and most of them are dependent on cannabis and alcohol. Hospitalization in psychiatry may provide an opportunity to systematically identify a dependence disorder and to offer appropriate information and treatment.