Donor Sex Research Articles

Increased Expression of Y-Encoded Demethylases During Differentiation of Human Male Neural Stem Cells.

Human neural stem cells (hNSCs) have long been used as an in vitro model to study neurogenesis and as candidates for nervous system therapy. Many parameters have been considered when evaluating the success of transplantation, but sex of donor and recipients is often not discussed. We investigated two commercial NSC lines, the female hNSC-H9 and male hNSC-H14, and we observed faster growth rates in the male cells. At 4 days of differentiation, male cells presented a significant increase in expression of DCX, an immature neuronal marker, while female cells showed a significant increase in RMST, a long noncoding RNA, which is indispensable during neurogenesis. In addition, expression of neural markers MAP2, PSD95, SYP, DCX, and TUJ1 at day 14 of differentiation suggested a similar differentiation potential in both lines. The most significant differences at day 14 of differentiation were the expression levels of RELN, with almost 100-fold difference between the sexes, and MASH1, with more than 1,000-fold increase in male cells. To evaluate whether some of the observed differences may be sex related, we measured the expression of gametologous genes located on the X- and Y-chromosome. Most noticeable was the increase of Y-encoded demethylases KDM6C (UTY) and KDM5D during differentiation of male cells. Our results indicate that attention should be paid to sex when planning neurogenesis and transplantation experiments.

DNMT3A clonal Hematopoiesis in Older Donors Is Associated with Improved Survival in Recipients after Allogeneic Hematopoietic Cell Transplant

DNMT3A clonal Hematopoiesis in Older Donors Is Associated with Improved Survival in Recipients after Allogeneic Hematopoietic Cell Transplant

Analysis of Risk Factors for Hepatic Sinusoidal Obstruction Syndrome after Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients

Background: Hepatic sinusoidal obstruction syndrome (SOS), which is also called veno-occlusive disease of the liver, remains a serious complication after hematopoietic stem cell transplantation (HSCT). Over the last years, some risk factors have already been identified to be associated with SOS. However, the cause of SOS is still not fully understood and the mortality remains high, especially for SOS leading to multi-organ failure with a mortality rate up to 84%. The aim of our study was to analyze several risk factors of SOS in pediatric patients undergoing allogeneic HSCT. In addition, we investigated new potential risk factors. Methods: We retrospectively analyzed 105 children who underwent allogeneic HSCT for the first time and did not receive a defibrotide prophylaxis. All transplantations were performed between January 2007 and December 2018 in a single center. The median age was 8.6 years and stem cell source was either bone marrow (n = 74) or peripheral blood (n = 31). Underlying diseases were acute lymphoblastic leukemia (n = 27), acute myeloid leukemia (n = 25), myelodysplastic syndrome (n = 14), lymphoma (n = 2), solid tumor (n = 12) and genetic disease (n = 25). All patients received a myeloablative conditioning regimen. We analyzed the transplantation-related factors graft source, donor-recipient human leukocyte antigen match, donor age, donor sex and conditioning regimen based on busulfan or total body irradiation. Furthermore, we investigated the patient-related factors patient age, patient sex, prior treatment with gemtuzumab ozogamicin as well as the following laboratory parameters: aspartate transaminase, alanine transaminase, cholinesterase, glutamyl transpeptidase, lactate dehydrogenase, alkaline phosphatase, ferritin, albumin, total bilirubin, C-reactive protein and international normalized ratio (INR). All laboratory parameters were measured before HSCT and cutoffs were determined by reference values and receiver operating characteristic (ROC) curves. SOS was defined by modified pediatric Seattle criteria up to day +30 after HSCT because nearly all transplantations were performed before the new pediatric criteria of the European Society for Blood and Marrow Transplantation have been published. In univariate analysis, chi-square test and Fisher's exact test were used. Additionally, the Mann-Whitney U-test was performed to compare the median values of continuous variables. Significant variables (P < .05) were entered in multivariate analysis, which was carried out by using backward stepwise logistic regression. Results: SOS occurred in 15 out of 105 transplantations (14.3%). The median time of SOS onset was 12 days after HSCT (range, 1 day - 26 days). Three patients died of multi-organ failure following SOS (20%). This mortality rate was very low compared to other studies because our patients were treated with defibrotide immediately after being diagnosed with SOS. In univariate analysis, we found a significant association between patient age <1 year and SOS (Odds Ratio (OR) = 7.25, P = .037). Furthermore, a prior treatment with gemtuzumab ozogamicin (OR = 11.00, P = .020) showed a significant correlation. Patients who developed SOS had a significantly higher median ferritin level (2816.9 ng/mL vs. 1554.0 ng/mL, P = .026). Based on this observation, different ferritin cutoffs were selected by ROC analysis. Ferritin >1500 ng/mL (OR = 4.00, P = .033), ferritin >2000 ng/mL (OR = 4.69, P = .016) as well as ferritin >2400 ng/mL (OR = 5.29, P = .005) revealed significant P values. Besides these results, INR ≥1.3 (OR = 5.91, P = .009) was significantly associated with SOS. In multivariate analysis, the following variables showed P values less than .05: treatment with gemtuzumab ozogamicin (OR = 9.24, P = .048), ferritin >2400 ng/mL (OR = 5.74, P = .023) and INR ≥1.3 (OR = 8.02, P = .007). Conclusions: Our data confirm the risk factors of young patient age (<1 year), prior treatment with gemtuzumab ozogamicin and high serum ferritin (>2400 ng/mL) in the pediatric population. Moreover, we report for the first time that there is a significant association between high INR (≥1.3) before HSCT and the occurrence of SOS. Especially this new finding could improve the risk stratification of SOS and should be evaluated in further trails. Disclosures No relevant conflicts of interest to declare.

Factors associated with registrant availability for unrelated adult donor hematopoietic stem cell donation: Analysis of the stem cell registry at Canadian Blood Services.

Greater use of unrelated donors to support hematopoietic cell transplantation can be hampered by unavailability of registrants when identified as potential candidates for donation. Multivariate analysis was performed to identify donor factors associated with availability for verification of human leukocyte antigen typing (VT) needed before donor activation. All VT requests for registrants on the Canadian Blood Services Stem Cell Registry between 1 January and 31 December 2018 were reviewed (n = 1358). Potential donors identified by transplant centers were categorized as available at the time of VT but ineligible for medical or other reasons (n = 130 and excluded from further analysis), available (n = 622) or unavailable (n = 566) due to scheduling, loss of interest, and/or inability to contact. With multivariate analysis, registrants who previously donated blood, those recruited online or from blood donation clinics, and a shorter interval between registration and VT request were significantly correlated with increased donor availability. Donor sex and geographic location, however, displayed no correlation. Online registration and recruitment at whole blood donation centers should be enhanced to increase the availability of registrants at VT. More insight is needed to maintain registrant availability following community in-person recruitment events, especially if the interval between registration and activation is prolonged. Recruitment of male registrants who are well informed should not negatively impact availability.

Sex-related aspects of the red blood cell storage lesion.

Several factors contribute to the manifestation of red blood cell (RBC) storage lesions, with one of the most interesting being the "donor variation effect". Since many haematological characteristics of blood donors are sex-dependent, sex hormones and their age-dependent variation may affect the storage profile of RBCs. Fresh blood from 200 healthy male and female donors underwent haematological, biochemical and physiological analysis. Three selected groups of donors (men, n=8; pre-menopausal women, n=8; and post-menopausal women, n=4) exhibiting as similar as possible baseline values were recruited for blood donation in leukoreduced CPD/SAGM units. RBC indices, haemolysis and propensity for haemolysis, reactive oxygen species (ROS) and plasma antioxidant capacity were measured bi-weekly. Female blood was characterised by lower plasma antioxidant capacity and free haemoglobin (Hb) levels in vivo, in spite of the higher RBC osmotic fragility, compared to male blood. Comparatively low Hb concentration was also measured in stored RBCs from female donors, as in vivo. Mean corpuscular Hb (MCH), mean corpuscular Hb concentration (MCHC), and plasma antioxidant capacity were also lower in female donors throughout storage, even though baseline levels were equal to those of the male group. There was no difference in propensity of stored RBCs for haemolysis between male and female units but intracellular ROS levels were significantly lower in female RBCs. Increased end-of-storage extracellular potassium and recruitment of protein stress markers (clusterin, Hb) to the RBC membrane were observed in the units of post- vs pre-menopausal female donors at mid-storage onwards. Donor's sex has an impact on Hb concentration and redox parameters of stored RBCs. In addition, menopause seems to promote RBC membrane remodelling, at least during prolonged storage. Our pilot study provides new insights on the different effects on RBC storage lesion according to sex.

Robotic Versus Open Right Lobe Donor Hepatectomy for Adult Living Donor Liver Transplantation: A Propensity Score-Matched Analysis.

Robotic right lobe donor hepatectomy (RRLDH) is rarely performed, and data concerning its safety and efficacy are lacking. Here we compare our series of RRLDHs with a similar cohort undergoing open right lobe donor hepatectomy (ORLDH) with a propensity score-matched (PSM) analysis. Among 263 consecutive adult patients undergoing right lobe living donor hepatectomy from January 2015 until July 2019, 35 RRLDHs were matched to 70 ORLDHs. A 1:2 PSM analysis was performed to make the groups comparable for donor sex, age, and body mass index (BMI) and for recipient sex, age, BMI, Model for End-Stage Liver Disease score, and indication for transplant. Operative time was longer in RRLDHs compared with ORLDHs (504±73.5 versus 331±65.1minutes; P<0.001) but significantly decreased with the number of patients (P<0.001). No conversions occurred. First warm ischemia time was longer and blood loss significantly less in RRLDHs (P=0.001 and 0.003, respectively). Overall donor complications were similar: 2 (6%) in RRLDHs versus 12 (17%) in ORLDHs (P=0.13). Biliary leak occurred in 1 (3%) patient receiving a robotic procedure and 2 (3%) patients receiving the conventional approach. Donors undergoing robotic surgery required less patient-controlled analgesia and had a shorter hospital stay compared with the open surgery group (P<0.001 and P=0.001, respectively). No significant differences in graft anatomical data and recipient outcomes were recorded. RRLDH is feasible, safe, and reproducible, with significantly decreased blood loss and a shorter hospital stay compared with the open procedure. The first 35 patients receiving the robotic procedure showed a substantial reduction in operative time, reflecting a rapid shortening of the learning curve.

Lower soluble Klotho levels in the pretransplant period are associated with an increased risk of renal function decline in renal transplant patients.

Serum soluble Klotho levels are associated with renal function in predialysis patients with chronic kidney disease. However, few reports exist regarding the association between soluble Klotho levels and renal function in kidney transplant (KTx) recipients. This was a retrospective observational study of 41 living KTx recipients. The serum soluble Klotho levels were classed as "high" (>456 pg/mL [i.e., high-Klotho group]) or "low" (≤456 pg/mL [i.e., low-Klotho group]). Renal function decline was defined as a decrease in the estimated glomerular filtration rate (eGFR) of 30% or more from the baseline value within 3 months after KTx. A multivariable time-to-event analysis between the groups was conducted. Among the KTx recipients, the incidence of a 30% decrease in the eGFR was significantly higher in the low-Klotho group than in the high-Klotho group (P = .036). After adjusting for donor age, donor sex, the presence of rejection, and the number of cytomegalovirus infections, multivariable Cox models revealed that low soluble Klotho levels remained associated with a higher risk of a 30% decrease in the eGFR (hazard ratio, 2.38; 95% confidence interval, 1.02-6.41). These findings suggested that lower soluble Klotho levels in the pre-KTx period are associated with an increased risk of renal function decline in KTx recipients.

Gender medicine in corneal transplantation: influence of sex mismatch on rejection episodes and graft survival in a prospective cohort of patients.

To evaluate the effect of donor-to-recipient sex mismatched (male donor corneas to female recipients) on the incidence of rejection episodes and failures up to 1year after corneal transplantation. Prospective observational cohort study, with donor corneas randomly assigned and surgeons blind to the sex of donor. A unique eye bank retrieved and selected the donor corneas transplanted in 4 ophthalmic units in patients with clinical indication for primary or repeated keratoplasty for optical reasons, perforating or lamellar, either anterior or posterior. Rejection episode defined as any reversible or irreversible endothelial, epithelial or stromal sign, with or without development of corneal edema, and graft failure as a permanently cloudy graft or a regraft for any reason detected or acknowledged during a postoperative ophthalmic visit at any time up to 1year after surgery were recorded.156 (28.6%) patients resulted donor-to-recipient gender mismatched for H-Y antigen (male donor to female recipient). During the 12months follow-up, 83 (14.7%, 95% CI 12.0-17.9) grafts showed at least 1 rejection episode and 17 (3.2%, 95% CI 2.0-5.0) failed after immune rejection, among 54 (9.6%, 95% CI 7.4-12.3) grafts failed for all causes. No significant differences between matched and mismatched patients were found for cumulative incidence of both rejection episodes (15.2% and 13.5%) and graft failures following rejection (3.2% and 2.6%), respectively. Multivariable analyses showed that H-Y matching either is not a predictive factor for rejection or graft failure nor seems to influence incidence of failures on respect to patient's risk category. The lack of influence of donor-to-recipient mismatched on the rate of rejections and graft failures resulting from this study do not support the adoption of donor-recipient matching in the allocation of corneas for transplantation.

Effect of donor non-muscle myosin heavy chain (MYH9) gene polymorphisms on clinically relevant kidney allograft dysfunction

BackgroundDespite its established association with chronic kidney disease (CKD) the role of myosin-9 (MYH9) gene variation on transplanted kidney function remains unknown. This study aimed at evaluating the effect of donor MYH9 nephrogenic variants on renal allograft function within the first post transplantation year.MethodsIn the longitudinal kidney transplant study 207 deceased donors were genotyped for previously known risk MYH9 single nucleotide polymorphisms (SNPs). The predictor was MYH9 high–risk variants status. The primary outcome was mean eGFR found in low vs. high risk MYH9 genotypes between third and twelfth post-transplant month, the secondary outcome was the risk of proteinuria.ResultsDistribution of genotypes remained in Hardy-Weinberg equilibrium. The T allele of rs3752462 (dominant model, TT or TC vs. CC) was associated with higher filtration rate (P = 0.05) in a multivariate analysis after adjusting for delayed graft function and donor sex. Two G alleles of rs136211 (recessive model, GG vs. GA or AA) resulted in doubling the risk of proteinuria (OR = 2.22; 95% CI = 1.18–4.37, P = 0.017) after adjusting for donor and recipient sex.ConclusionDeceased donor kidneys of European descent harboring MYH9 SNPs rs3752462 T allele show significantly superior estimated filtration rate while those of rs136211 GG genotype excessive risk of proteinuria. These findings, if replicated, may further inform and improve individualization of allocation and treatment policies.

IMPACT OF AGE OF THE ADULT DECEASED DONOR AND AGE AND SEX OF THE ADULT RECIPIENT ON KIDNEY GRAFT SURVIVAL

Introduction: The purpose of this study was to investigate the impact, on kidney graft survival, of age and sex of the adult deceased donor, donor-recipient sex mismatch, and age and sex of the adult recipient. Materials and Methods: The study was conducted in a single-center cohort with 6,006 kidney transplants from adult (age ≥ 18 years) deceased donors performed in adult recipients, from January 1, 2002 to December 31, 2017. There were 3,189 transplants from 18-49-year old (younger donors) and 2,817 transplants from ≥ 50-year old (older donors) donors. The recipients were divided into three age categories: 18-49, 50-59 and ≥ 60 years of age. Graft failure was defined as patient death or return to dialysis. Five-year graft survival curves were constructed with the Kaplan-Meier method and compared with log-rank test or Cox regression analysis. Statistical significance was set at p <0.05. Results: (1) Donor and recipient age ≥ 50 years and recipient male sex, but not donor sex or donor-recipient sex mismatch, had a negative impact on 5-year graft survival, in the univariate analysis; (2) Cox regression analysis showed that donor age ≥ 50 years, recipient age between 50-59 years, ≥ 60 years, and recipient male sex were independently associated with lower graft survival, with hazard ratios (HR) of 1.41, 1.23, 1.69 and 1.13, respectively; (3) older age of the donor was associated with poorer graft survival in transplants in 18-49-year old (HR=1.63) and in 50-59-year old (HR=1.56) recipients, but did not impact on graft survival in recipients with 60 or more years of age; (4) male sex of the recipient was a risk factor only in recipients with 50 or more years of age that received a transplant from a younger donor: HR of 1.61, in 50-59-year old recipients, and of 1.44, in ≥ 60-year old recipients. Conclusion: The main findings of this study are that (a) the inferior graft survival in male than in female recipients is restricted to transplants from younger donors into ≥ 50-year old recipients and (b) there is no difference in graft survival from younger and older donors when the recipients are ≥ 60-year old. The results of this study underline the importance of analyzing combinations of age and sex of donor and recipient in order to better estimate the risks conferred by these variables. Future studies, with larger number of transplants, are warranted to confirm the finding of our study and to explore the mechanisms behind the negative effect of the older age of the donor and the male sex of the recipient on graft survival.

DONOR AND RECIPIENT SEX AFFECT TRANSPLANT OUTCOMES IN AN AGE-SPECIFIC FASHION

In diseases outside of transplantation, sex has been shown to impact immune responses. Effects of donor/recipient sex and hormonal changes over a life-time on alloimmune responses and transplant outcomes have not been delineated. We analyzed SRTR data from 408,000 kidney transplant and determined the influence of recipient and donor sex in an age-specifically. Death-censored 5-year graft survival in in age-matched young female recipients (15-34 y) had been inferior to that of male recipients. This outcome was independent of donor-sex (P < 0.0001 and P = 0.0002 for male and female donors, respectively). In contrast, graft survival was superior in older female recipients (55-74 years) (P = 0.0294 and P = 0.0032 vs. male recipients of comparable age receiving either female or male kidneys). To delineate potential mechanisms, we made use of an experimental model that dissected the effects of recipient age and hormonal deprivation (ovariectomies). Skin transplants in ovariectomized young female recipients (2-3 mos) was prolonged vs. naive female and sham controls of comparable age (P = 0.0094). In contrast, graft survival was comparable in old (18 months) naïve, ovariectomized or sham control female recipients (P = 0.6798). Assessing alloimmune responses, we observed a compromised proliferation and reduced CD4+ and CD8+ T cell counts in young ovariectomized mice (CD4 + 25.2 vs 23.3 %, P = 0.0008; CD8+, 17.2 vs 12.4 %, P < 0.0001). Moreover, ovariectomies in young females reduced the production of IFN-g+ and IL-17+ by CD4+ T cells while increasing amounts of CD4+CD25+FOXP3+ regulatory T cells (P = 0.0015). When adding increased estradiol concentrations (17-b estradiol; 10-12 M and 10-10 M) in-vitro under Th1 polarizing conditions, naïve CD4+ T cells responded in a dose dependent manner (33.1 vs 35.2 %, P = 0.025). In contrast, high estradiol concentrations (10-8M reflective of levels during pregnancy) reduced amounts of CD4+ T-cells (P = 0.028, under Th1 polarizing conditions). In line, with those in-vitro findings, we observed a prolongation of graft survival when treating female recipients with pregnancy equivalent estrogen levels (sham vs treated, 9 vs 14 days, P = 0.0031). Those data demonstrate significant effects of sex, aging, and hormonal levels on alloimmune responses and transplant outcomes.

Donor-dependent aging of young and old red blood cell subpopulations: Metabolic and functional heterogeneity.

Characteristics of red blood cells (RBCs) are influenced by donor variability. This study assessed quality and metabolomic variables of RBC subpopulations of varied biologic age in red blood cell concentrates (RCCs) from male and female donors to evaluate their contribution to the storage lesion. Red blood cell concentrates from healthy male (n = 6) and female (n = 4) donors were Percoll separated into less dense ("young", Y-RCCs) and dense ("old", O-RCCs) subpopulations, which were assessed weekly for 28 days for changes in hemolysis, mean cell volume (MCV), hemoglobin concentration (MCHC), hemoglobin autofluorescence (HGB), morphology index (MI), oxygen affinity (p50), rigidity, intracellular reactive oxygen species (ROS), calcium ([Ca2+ ]), and mass spectrometry-based metabolomics. Young RCCs having disc-to-discoid morphology showed higher MCV and MI, but lower MCHC, HGB, and rigidity than O-RCCs, having discoid-to-spheroid shape. By Day 14, Y-RCCs retained lower hemolysis and rigidity and higher p50 compared to O-RCCs. Donor sex analyses indicated that females had higher MCV, HGB, ROS, and [Ca2+ ] and lower hemolysis than male RBCs, in addition to having a decreased rate of change in hemolysis by Day 28. Metabolic profiling indicated a significant sex-related signature across all groups with increased markers of high membrane lipid remodeling and antioxidant capacity in Y-RCCs, whereas O-RCCs had increased markers of oxidative stress and decreased coping capability. The structural, functional, and metabolic dissimilarities of Y-RCCs and O-RCCs from female and male donors demonstrate RCC heterogeneity, where RBCs from females contribute less to the storage lesion and age slower than males.

Sex-Specific Transcriptome Differences in Human Adipose Mesenchymal Stem Cells.

In humans, sexual dimorphism can manifest in many ways and it is widely studied in several knowledge fields. It is increasing the evidence that also cells differ according to sex, a correlation still little studied and poorly considered when cells are used in scientific research. Specifically, our interest is on the sex-related dimorphism on the human mesenchymal stem cells (hMSCs) transcriptome. A systematic meta-analysis of hMSC microarrays was performed by using the Transcriptome Mapper (TRAM) software. This bioinformatic tool was used to integrate and normalize datasets from multiple sources and allowed us to highlight chromosomal segments and genes differently expressed in hMSCs derived from adipose tissue (hADSCs) of male and female donors. Chromosomal segments and differentially expressed genes in male and female hADSCs resulted to be related to several processes as inflammation, adipogenic and neurogenic differentiation and cell communication. Obtained results lead us to hypothesize that the donor sex of hADSCs is a variable influencing a wide range of stem cell biologic processes. We believe that it should be considered in biologic research and stem cell therapy.

Allograft Donor Characteristics Significantly Influence Graft Rupture After Anterior Cruciate Ligament Reconstruction in a Young Active Population

Background: Graft selection in anterior cruciate ligament (ACL) surgery can be difficult in a young active population given their high rates of reinjury. Allografts allow for control over graft size and reduce morbidity of autograft harvest. There are mixed results about the use of allograft in the literature; however, the influence of the properties of the allograft on outcomes has not been considered. Hypothesis: ACL reconstruction with allografts from older donors will have a higher rate of graft rupture when compared with allograft from young donors. Study Design: Cohort study; Level of evidence, 3. Methods: Patients (N = 211) aged 13 to 25 years underwent primary ACL reconstruction with fresh-frozen nonirradiated allograft. Four graft types were used: patellar tendon, Achilles tendon, tibialis anterior, and tibialis posterior. Details were collected on allograft donor age and sex. At a minimum of 24 months, patients were evaluated for any further injuries and subjective analysis by International Knee Documentation Committee (IKDC) questionnaire. Results: ACL graft rupture occurred in 23.5%. When grafts were separated into single strand (patellar and Achilles tendon) and multistrand (tibialis anterior and posterior), there was a significantly higher rate of reinjury in the single-strand grafts (29.9% vs 11%; P = .014). Grafts from female donors aged ≥50 years had significantly higher rates of ACL graft rupture (52.6%; P = .003) with increased odds by 6.7 times when compared with grafts from male donors aged <50 years. There was no significant difference in mean IKDC scores among the groups based on the age and sex of the allograft donor. Conclusion: The age and sex of the allograft donor and the morphology of the graft significantly influenced the rate of ACL graft rupture in young active patients. Tendons from female donors aged ≥50 years should be avoided given the higher rerupture rates as compared with male donors of any age and younger females.

Sex differences in olfactory social recognition memory in meadow voles, Microtus pennsylvanicus

AbstractTerrestrial mammals, like rodents, use odors, and scent marks to indicate their presence in an area to conspecifics. These odors convey information about the scent donor's genotype, sex, condition, and age. The ability to discriminate among the scent marks of conspecifics and later recollect the identity of the donor is essential for choosing between familiar and unfamiliar mates. We tested the hypothesis that the promiscuous meadow vole (Microtus pennsylvanicus) can recollect the odor of a familiar, opposite‐sex conspecific and distinguish it from that of an unfamiliar, opposite‐sex conspecific. We also hypothesized that because reproductive success is highly skewed among male meadow voles and competition for mates is intense, males will be more likely than females to recollect the odor of a familiar, opposite‐sex conspecific and distinguish it from that of an unfamiliar, opposite‐sex conspecific, for a longer period of time. Using a habituation task, we first exposed the voles, 4 times successively, to the anogenital area scent of an opposite‐sex conspecific. Then, 1 hr, 24 hrs, 72 hrs, or 96 hrs after the fourth exposure, voles were presented with the odor of the donor from the exposure phase (familiar donor) and that of an unfamiliar, opposite‐sex conspecific. Female meadow voles spent similar amounts of time investigating the scent of the familiar male donor and that of an unfamiliar male donor after the 1‐hr and 24‐hr intervals. Male meadow voles, however, spent more time with the scent of an unfamiliar female donor than that of the familiar female donor after the 1‐hr, 24‐hr, and 72‐hr intervals, suggesting that male voles could recollect the scent mark of a familiar female for at least three days. The implications of these sex differences in social memory may reflect the different strategies male and female meadow voles use in the recognition of previous and potential mates. Recognition of an individual's scents may enhance fitness by allowing animals to direct appropriate behaviors toward those individuals.

Long-term compensation of renal function after donor nephrectomy.

BackgroundLiving donors are the major source of kidneys in countries with a shortage of deceased donors. Kidney donation after careful donor selection is generally accepted as a safe procedure, but the physiologic consequences after donor nephrectomy are not fully verified. In this study we retrospectively reviewed the renal function of the residual kidney in living donors.MethodsPost-nephrectomy laboratory data of 1,175 living donors (60.7%) from 1,933 living donors who received uninephrectomy from January 1999 to December 2017 at Yonsei University, Severance Hospital, Korea were retrospectively collected. Post-nephrectomy renal function was monitored by the relative ratio of estimated glomerular filtration rate (e-GFR; pre-nephrectomy e-GFR ratio vs. post-nephrectomy e-GFR) that was calculated by the Modification of Diet in Renal Disease formula.ResultsDuring 36.3±37.6 months of mean follow-up, two cases (0.17%, 2/1,175) of renal failure developed. The mean e-GFR decreased to 64.3±14.2 mL/min/1.73 m2 immediately after nephrectomy from 99.2±19.9 mL/min/1.73 m2 of the pre-nephrectomy e-GFR. Early decrement of e-GFR was prominent in male and obese donors (body mass index >25 kg/m2, P<0.05). The e-GFR ratio increased according to post-nephrectomy duration, and the mean increment degree of e-GFR ratio after nephrectomy calculated by linear regression analysis was 1.94% per year. Unlike the early decrement of e-GFR ratio after nephrectomy, donor factors such as degree of obesity and donor sex did not affect the late increment of e-GFR ratio after nephrectomy (P>0.05).ConclusionsOur data showed that long-term compensation of the renal function after nephrectomy occurs independently of preoperative donor characteristics.

Differential Expression of Ormdl Genes in the Islets of Mice and Humans with Obesity

SummaryThe orosomucoid-like (Ormdl) proteins play a critical role in sphingolipid homeostasis, inflammation, and ER stress, all of which are associated with obesity and βcell dysfunction. However, their roles in β cells and obesity remain unknown. Here, we show that islets from overweight/obese human donors displayed marginally reduced ORMDL1-2 expression, whereas ORMDL3 expression was significantly downregulated compared with islets from lean donors. In contrast, Ormdl3 was substantially upregulated in the islets of leptin-deficient obese (ob/ob) mice compared with lean mice. Treatment of ob/ob mice and their islets with leptin markedly reduced islet Ormld3 expression. Ormdl3 knockdown in a β cell line induced expression of pro-apoptotic markers, which was rescued by ceramide synthase inhibitor fumonisin B1. Our results reveal differential expression of Ormdl3 in the islets of a mouse model and humans with obesity, highlight the potential effect of leptin in this differential regulation, and suggest a role for Ormdl3 in β cell apoptosis.

Blood Serum Stimulates p38-Mediated Proliferation and Changes in Global Gene Expression of Adult Human Cardiac Stem Cells.

During aging, senescent cells accumulate in various tissues accompanied by decreased regenerative capacities of quiescent stem cells, resulting in deteriorated organ function and overall degeneration. In this regard, the adult human heart with a generally low regenerative potential is of extreme interest as a target for rejuvenating strategies with blood borne factors that might be able to activate endogenous stem cell populations. Here, we investigated for the first time the effects of human blood plasma and serum on adult human cardiac stem cells (hCSCs) and showed significantly increased proliferation capacities and metabolism accompanied by a significant decrease of senescent cells, demonstrating a beneficial serum-mediated effect that seemed to be independent of age and sex. However, RNA-seq analysis of serum-treated hCSCs revealed profound effects on gene expression depending on the age and sex of the plasma donor. We further successfully identified key pathways that are affected by serum treatment with p38-MAPK playing a regulatory role in protection from senescence and in the promotion of proliferation in a serum-dependent manner. Inhibition of p38-MAPK resulted in a decline of these serum-mediated beneficial effects on hCSCs in terms of decreased proliferation and accelerated senescence. In summary, we provide new insights in the regulatory networks behind serum-mediated protective effects on adult human cardiac stem cells.

Donor body size and sex steroid hormones impact germ cell production for creation of xenogenic catfish

Xenogenesis is emerging as an innovative technology for hybrid catfish (channel catfish, Ictalurus punctatus ♀ × blue catfish, I.furcatus ♂) production, where primordial germ cells (PGC), spermatogonial stem cells (SSCs) or oogonial stem cells (OSCs) are transplanted into infertile host species such as triploid fish to produce xenogens. Currently, donor cells are collected from randomly selected immature fish without having prior knowledge regarding the best donor stage, which is critical to increase the efficiency and success of germ cell transplantation in catfish breeding. Therefore, the current study was carried out with the objective of determining the relationships between quantity of stem cells, total length (TL), total weight (TW), and the level of androgens [testosterone (T) and 11-ketotestosterone (11-KT)] in blue catfish (donor fish). Positive quadratic relationships were observed between TL and the number of extracted live SSCs (r2 = 0.51; P < .0001) as well as TW and the number of live SSCs (r2 = 0.37; P < .0001), revealing that a TL of 25 to 39.9 cm and TW of 100 to 499.9 g, yield the highest number of extracted live SSCs. Similar to the findings from males, TL (r2 = 0.76; P < .0001) and TW (r2 = 0.67; P < .0001), also revealed positive quadratic relationships to the number of extracted live OSCs, where 25 to 39.9 cm and 200 to 600 g females yielded the greatest number of extracted live cells. Positive quadratic relationships were also detected between levels of T (r2 = 0.60; P < .0001), 11-KT (r2 = 0.60; P < .0001) and number of extracted live SSCs in male catfish, where 49 to 51.9 pg/mL of serum T and 37 to 48.9 pg/mL of 11-KT yielded the maximum number of live SSCs. Overall, these relationships between the quantity of stem cells and body size as well as the profile of sex steroid hormones reveal promising results as reliable biomarkers to enhance the efficiency of germ cell transplantation. These results can also be used to make precise predictions on the number of stem cells at a certain body size without sacrificing precious fish housed in living genetic repositories.

Sex differences in postsurgical skeletal muscle depletion after donation of living-donor liver transplantation, although minimal, should not be ignored

BackgroundDonor safety is the top priority in living-donor liver transplantation. Splenic hypertrophy and platelet count decrease after donor surgery are reported to correlate with the extent of hepatectomy, but other aftereffects of donor surgeries are unclear. In this study, we evaluated the surgical effects of donor hepatectomy on skeletal muscle depletion and their potential sex differences.MethodsAmong a total of 450 consecutive donor hepatectomies performed from April 2001 through March 2017, 277 donors who completed both preoperative and postoperative (60–119 days postsurgery) evaluation by computed tomography were the subjects of this study. Donors aged 45 years or older were considered elderly donors. Postoperative skeletal muscle depletion was assessed on the basis of the cross-sectional area of the psoas major muscle. Postoperative changes in the spleen volume and platelet count ratios were also analysed to evaluate the effects of major hepatectomy.ResultsThe decrease in the postoperative skeletal muscle mass in the overall donor population was slight (99.4 ± 6.3%). Of the 277 donors, 59 (21.3%) exhibited skeletal muscle depletion (i.e., < 95% of the preoperative value). Multivariate analysis revealed that elderly donor (OR:2.30, 95% C.I.: 1.27–4.24) and female donor (OR: 1.94, 95% C.I. 1.04–3.59) were independent risk factors for postoperative skeletal muscle depletion. Stratification of the subjects into four groups by age and sex revealed that the elderly female donor group had significantly less skeletal muscle mass postoperatively compared with the preoperative values (95.6 ± 6.8%), while the other three groups showed no significant decrease. Due to their smaller physical characteristics, right liver donation was significantly more prevalent in the female groups than in the male groups (112/144, 77.8% vs 65/133, 48.9%; p < 0.001). The estimated liver resection rate correlated significantly with the splenic hypertrophy ratio (r = 0.528, p < 0.001) and the extent of the platelet count decrease (r = − 0.314, p < 0.001), but donor age and sex did not affect these parameters.ConclusionElderly female donors have a higher risk of postoperative skeletal muscle depletion. Additionally, female donors are more likely to donate a right liver graft, whose potential subclinical risks include postoperative splenic enlargement and a platelet count decrease.