Gender-dependent Changes Research Articles

Evaluation of cortical thickness and volume differences of the cerebellum in Parkinson's cases

Parkinson's disease (PD) is the most common neurodegenerative disease after Alzheimer's disease. PD causes degenerative changes in the cerebellum. It is known that the cerebellum does not have a symmetrical anatomy and some pathological disorders may cause asymmetric changes in the cerebellum. In this study, our aim is evaluate whether or not cases with PD show age and gender dependent cerebellar changes and cerebellar asymmetry comparing with healthy subjects. We also aimed to depict the probable cortical thickness differences in cases with PD by using a stereological technique. The study evaluated the volumetric assesment of each cortical cerebellar hemisphere and total cerebellum by applying a stereological technique on magnetic resonance images. The age and gender-matched study was composed of 47 adult cases with PD and 47 healthy subjets as control. In the PD group, right and left cerebellar hemisphere volume, total cerebellum volume, and cortical thickness of the right and left cerebellar hemispheres were significantly lower than the control group (p<0.01). Although there was significant cerebellar atrophy and asymmetry in PD cases with age between 40-71, the study showed no statistically significant cerebellar asymmetry in cases over 70 years of age. However, no significant difference was detected depending on gender. Our findings suggest that in PD, cerebellum’s cortical thickness and volume decreases. The decrease in the volume and cortical thickness of the cerebellum increases with age, regardless of gender, compared to healthy individuals. However, this difference begins to close with age.

Role of Gender in the Protection Against Doxorubicin-Induced Oxidative Stress

Background: There are gender differences in the oxidation-reduction reactions. Doxorubicin (Dox) is a chemotherapeutic drug that can produce oxidative stress which may require prevention by antioxidants. Aim: The study aimed to investigate the gender-dependent changes in Dox-induced oxidative stress, and the protective effects of coenzyme Q10 (CoQ10). Materials and Methods: Rats were administered CoQ10 orally for 17 days. On day 13, some rats receiving CoQ10 received a single intraperitoneal dosage of Dox, whereas other rats received normal saline. Glutathione (GSH), malondialdehyde (MDA), and total anti-oxidant capacity (T-AOC) were measured in both genders of albino rats. Results: Dox significantly reduced both GSH and T-AOC levels and caused a significant increase in MDA. The administration of CoQ10 significantly prevented these changes. Dox caused a larger reduction in GSH in males than in females, while CoQ10 caused more protection in females. Dox caused a higher increase in MDA levels in males. Conclusion: Pre-treatments with CoQ10 may protect against Dox-induced oxidative stress, with gender-dependent variations in the extent of these Dox/CoQ10 effects.

Влияние пола пациентов на изменения глазной поверхности после синустрабекулэктомии

Background: the effect of gender on the rate and course of ocular surface diseases (in particular, conjunctival and corneal xerosis) is fairly well known. Meanwhile, gender-dependent changes in the ocular surface after trabeculectomy have not yet been studied. Aim: to analyze the effect of gender on changes in the ocular surface after trabeculectomy. Patients and Methods: this study enrolled 443 patients (168 men and 275 women) who underwent surgical interventions for uncontrolled primary open-angle glaucoma (POAG) in 2016–2020 and were followed up for 6–24 months. Trabeculectomy was performed as the first IOP- lowering procedure in 418 patients (150 men and 268 women) and reoperation in 25 patients (18 men and 7 women). Changes in subjective symptoms (OSDI) and clinical and functional signs of dry eye syndrome (tear film break-up time/TBUT and total tear production by Schirmer's I test) characterizing the ocular surface in various surgical outcomes (complete and partial success, failure) in men and women were analyzed. Results: women have more severe subjective symptoms but not functional signs of dry eye preoperatively. They are characterized by strict adherence to treatment (manifested in lower initial IOP compared with men) but more frequent eye drop instillations and greater cumulative preservative load on the ocular surface. Gender is not an independent risk factor for surgical failure. Successful trabeculectomy results in a significant reduction in the severity of conjunctival and corneal xerosis symptoms (OSDI) for at least 2 years in both genders. Despite clear postoperative improvement, women are significantly inferior to men in this parameter at all study control points. TBUT in both men and women increases significantly during the first 6 months postoperatively, and over the next 1.5 years TBUT stabilizes at the achieved level. An increase in Schirmer's I test results in men becomes significant only at the end of the second year of follow-up. In women, a significant increase in total tear production is reported as early as 6 months after trabeculectomy and changes slightly over the next 1.5 years. Restarting IOP-lowering medications in partial success and failure of trabeculectomy eliminates the improvement of ocular surface condition achieved during the drug-free period as early as after 6 months. Conclusions: regardless of gender, successful trabeculectomy results in a significant and long-term (at least 2 years) improvement of subjective symptoms (OSDI) and functional signs (in particular, TBUT) of conjunctival and corneal xerosis. Women are characterized by a clearer improvement in the parameters studied than men. Significant gender differences are found only when comparing subjective symptoms in the first year after surgery. Restarting IOP-lowering medications postoperatively brings the parameters back to baseline levels. KEYWORDS: gender, glaucoma, trabeculectomy, ocular surface, dry eye disease, OSDI, tear film break-up time, TBUT, Norn's test, Schirmer's I test. FOR CITATION: Antonova A.V., Nikolaenko V.P., Brzheskiy V.V., Vuks A.Ja. Effect of gender on the ocular surface after trabeculectomy. Russian Journal of Clinical Ophthalmology. 2023;23(3):136–145 (in Russ.). DOI: 10.32364/2311-7729-2023-23-3-5.

High Expression Level of PPARγ in CD24 Knockout Mice and Gender-Specific Metabolic Changes: A Model of Insulin-Sensitive Obesity.

Background: The heat-stable HSA/CD24 gene encodes a protein that shows high expression levels in adipocyte precursor cells but low levels in terminally differentiated adipocytes. Its high expression in many types of human cancer suggests an association between cancer, diabetes, and obesity, which is currently unclear. In addition, peroxisome proliferator-activated receptor gamma (PPARγ) is a regulator of adipogenesis that plays a role in insulin sensitivity, lipid metabolism, and adipokine expression in adipocytes. Aim: To assess gender-dependent changes in CD24 KO and its association with PPARγ expression. Experimental approach: WT and CD24 KO mice were monitored from birth up to 12 months, and various physiological and molecular characteristics were analysed. Mean body weight and adipose mass were higher in KO mice than in WT mice. Male, but not female, KO mice showed increased insulin sensitivity, glucose uptake, adipocyte size, and PPARγ expression than WT mice. In addition, enteric bacterial populations, assessed through high-throughput sequencing of stool 16S rRNA genes, were significantly different between male KO and WT mice. Conclusions: CD24 may negatively regulate PPARγ expression in male mice. Furthermore, the association between the CD24 and insulin sensitivity suggests a possible mechanism for diabetes as a cancer risk factor. Finally, CD24 KO male mice may serve as a model of obesity and insulin hyper-sensitivity.

Changes of the mice intestinal microbes by the oligosaccharides-enriched fermented milk in a gender-dependent pattern

Oligosaccharides are prebiotics that can be used to regulate microbes in the host intestine. In this study, we investigated the effects of different oligosaccharides on the changes of the intestinal microbial communities and co-related functional genes in the intestinal microbes. Fructo-oligosaccharide (FOS), galacto-oligosaccharide (GOS) and oligomannose (MOS) were enriched in milk and fermented by Lactobacillus plantarum and tested in ICR mice model in vivo. Then the changes of the fecal microbial communities were examined by 16S rDNA gene sequencing approach. We found that the relative abundance of several taxa was markedly different between genders at the level of phylum and genera, additionally to the changes in the microbial community. Meanwhile, compared with male mice, the intestinal microbes of the female mice group had significant changes. Furthermore, the intestinal microbial diversity was enhanced in the female mice when treated with the FOS enriched fermented milk. Therefore, this data suggests that oligosaccharides have the potential to improve the host microbial diversity in the intestinal tract, and FOS has potential applications in the fermented dairy industry. It revealed a gender-dependent changes of different oligosaccharides-enriched fermented milk on the intestinal microbes of mice, providing a reference for regulating the intestinal microbes by oligosaccharides.

The effect of single and multiple intravenous administration of magnetic iron oxide nanoparticles to rats on the blood coagulation

Background . Magnetic nanoparticles (MNPs) are considered as a means of targeted delivery, diagnosis and treatment, the main route of administration for them is intravascular, so it is important to evaluate their interaction with blood. We previously studied the effect of two samples of MNPs (MNP1 and MNP2) on the viability of human umbilical vein endothelial cells and hemocompatibility on human heparinized whole blood. Objective . The aim of the present study is to evaluate the effect of MNP1 and MNP2 on hemostasis. Design and methods . MNP1 and MNP2 suspensions were administered intravenously in outbred Wistar rats once and repeatedly (7 days); prothrombin time (PT), thrombin time (TT), activated partial thromboplastin time (APTT), and fibrinogen concentration were evaluated before administration, on the 15th and 31st days after the last administration. Results . It was shown that MNP1 and MNP2 decreased in TT and an increased in APTT (in the MNCH1 and MNCH2 groups) as well as its increased in the fibrinogen concentration (in the MNCH2 groups) after a single dose (400 mg/kg) on day 31. Repeated administration of 60 mg/kg MNCH1 led to decrease the fibrinogen concentration (day 15) and to increase in APTT (day 31) in females. Repeated administration of 10 mg/kg MNCH2 caused an increase in APTT (males and females) and a decrease in fibrinogen concentration (females) on the 15th and 31st days. Conclusion . Thus, a single administration of 400 mg/kg MNPs caused an imbalance in the blood coagulation system, changes were independed on the sex of animals, but depended on the time after administration. Repeated administration of MNPs caused gender-dependent hypocoagulation changes (more pronounced in females).

Comparing alpha-cypermethrin induced dose/gender-dependent responses of lizards in hepatotoxicity and nephrotoxicity in a food chain

Pesticides are proposed as one reason for the worldwide decline in the reptile. Effects of pesticides on food intake and organ toxicity could affect wildlife populations dynamics. To explore the hepatotoxicity of alpha-cypermethrin (ACP) in reptiles, we designed a tri-trophic food chain with three concentrations (0, 2, and 20 mg/kgwet weight). Although the enzymes changes were similar between male and female lizards, the significant variations in anti-oxidative enzymes’ activities, lactic dehydrogenase activities and acetylcholine esterase activities in liver and kidney suggesting that oxidative stress, decreased metabolic ability and neurotoxicity on lizards. The results of hepatic metabolomics showed that ACP could affect amino acid, energy and lipid metabolism on lizards. Comparing with female lizards, there were more significant changes of metabolites in male lizards. The histopathology analysis in the liver (such as hepatic lobule congestion and hepatocyte vacuolation) and kidney (such as renal tubule necrosis and glomerulus necrosis), dose- and gender dependent changes of lesions suggested the functions of organ were damaged. In summary, the reduction of detoxification and elimination capacities of the liver and kidney showed dose/gender-dependent in lizards.

Altered transient brain dynamics in multiple sclerosis: Treatment or pathology?

Multiple sclerosis (MS) is a demyelinating, neuroinflammatory, and -degenerative disease that affects the brain's neurophysiological functioning through brain atrophy, a reduced conduction velocity and decreased connectivity. Currently, little is known on how MS affects the fast temporal dynamics of activation and deactivation of the different large-scale, ongoing brain networks. In this study, we investigated whether these temporal dynamics are affected in MS patients and whether these changes are induced by the pathology or by the use of benzodiazepines (BZDs), an important symptomatic treatment that aims at reducing insomnia, spasticity and anxiety and reinforces the inhibitory effect of GABA. To this aim, we employed a novel method capable of detecting these fast dynamics in 90 MS patients and 46 healthy controls. We demonstrated a less dynamic frontal default mode network in male MS patients and a reduced activation of the same network in female MS patients, regardless of BZD usage. Additionally, BZDs strongly altered the brain's dynamics by increasing the time spent in the deactivating sensorimotor network and the activating occipital network. Furthermore, BZDs induced a decreased power in the theta band and an increased power in the beta band. The latter was strongly expressed in those states without activation of the sensorimotor network. In summary, we demonstrate gender-dependent changes to the brain dynamics in the frontal DMN and strong effects from BZDs. This study is the first to characterise the effect of multiple sclerosis and BZDs in vivo in a spatially, temporally and spectrally defined way.

Highly Sensitive O-Glycan Profiling for Human Serum Proteins Reveals Gender-Dependent Changes in Colorectal Cancer Patients.

A newly developed microscale protocol for profiling serum O-glycans has been validated here with multiple serum samples obtained from different cohorts of colorectal cancer patients. The simultaneous cleavage and permethylation steps in this procedure preserve the integrity of released minor O-glycans, so that 39 O-linked oligosaccharides could be reliably recorded in a profile. This is far more detected components than shown in any previous studies. The analytical results were further subjected to a battery of statistical tests. Our O-glycan compositions compare favorably with the previous results obtained with solid tumors and cancer cell lines, suggesting that smaller circulatory mucins protruding into the blood circulation may be one source of O-glycans that we observe in the serum samples. While the control vs cancer statistical comparisons generally agree with the expected glycosylation trends, the comparisons of male vs female subjects have led to some surprising results for which we do not have a ready explanation due to lack of any literature describing hormonal control of O-glycosylation. Our results thus underscore the necessity of applying new analytical technologies to clinically interesting sample sets.

Therapeutic effects of melatonergic networks on propionic acid‐mediated autism‐like rat model: Sex difference based study

Autism spectrum disorder (ASD) is characterized not only by altered neurobehavioral symptoms including repetitive and restricted behaviors, defects in social interactions, intestinal malfunctions such as constipation, and sleep disorders but also pathological brain damages. As the cause of this disorder is not clear, early diagnosis is limited and it may remain permanently disabled. Therefore, this study aims to explain the therapeutic potential of melatonergic network‐related materials in propionic acid‐mediated ASD animal models. Especially, to identify genderdependent changes, male and female 3‐week‐old Sprague‐Dawley rats were randomly divided and used. They were divided into control, propionic acid‐mediated ASD group, ASD with melatonin treatment group, and ASD with fermented milk treatment group. To verify the therapeutic effects of melatonergic‐related materials, intestine length, sleep quality and neurobehavioral tests were performed. ASD animals showed decreased intestine length compared to control. Interestingly, exogenous melatonin and fermented milk treatment to ASD animals restored intestine length in both sexes. However, no difference was found in the intestine length of both genders. Also, melatonin and fermented milk administration to ASD group showed restored sleep quality regardless of sexes. Additionally, ASD animals showed abnormal neurobehaviors compared to control animals, and this abnormality is thought to be recovered by exogenous melatonin and fermented milk in both male and female animals. Accordingly, melatonergic network may exert its potential as a therapeutic agent in ASD.Support or Funding InformationNRF‐2017R1A2A2A01067169, KGM4611821, 2016 Creative Research Program of Inje University, Republic of KoreaThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Влияние степени гипоксии, пола животного и 17β-эстрадиола на проявления гипоксической формы легочной гипертензии

We studied the effect of chronic administration of female sex hormone –17β estradiol (E2) at a dose of 15 µg/kg/day on the development of pulmonary hypertension (PH) caused by intermittent hypoxia with O2 content of 13%, 10%, and 8% for 2 weeks. The study was carried out on gonadoectomized Wistar rats of both sexes. The degree of PH development was assessed by the magnitude of right ventricular systolic pressure (RVSP) and right ventricular hypertrophy. It was shown that all animals exposed to hypoxia developed PH, the degree of which depended on the O2 concentration in the inhaled air. In males, the hypoxia (10% O2) increased the RVSP 19% less than in females (p <0.05). Chronic administration of E2 caused gender-dependent changes in PH only at 10% O2. Thus, in males, the administration of E2 increased RVSP by 31% (p <0.05), and in females it reduced hypertrophy by 10%. Also, E2 increased the survival rate of females at 8% O2 by 2.5 times, but not males. An increase in hematocrit during hypoxia (10% O2) in females occurred due to an increase in the number of erythrocytes, and in males - due to an increase in their volume. Thus, the degree of development of the hypoxic pulmonary hypertension depends on the O2 concentration in the inhaled air and has gender differences. E2 affects the development of this disease.

Maternal fructose induces gender-dependent changes in both LXRα promoter methylation and cholesterol metabolism in progeny

Fructose consumption from added sugars correlates with the epidemic rise in obesity, metabolic syndrome and cardiovascular diseases. However, consumption of beverages containing fructose is allowed during gestation. We have investigated whether maternal fructose intake produces subsequent changes in cholesterol metabolism of progeny. Carbohydrates were supplied to pregnant rats in drinking water (10% w/v solution) throughout gestation. Adult male and female descendants from fructose-fed, control or glucose-fed mothers were studied. Male offspring from fructose-fed mothers had elevated plasma HDL-cholesterol levels, whereas female progeny from fructose-fed mothers presented lower levels of non-HDL cholesterol vs. the other two groups. Liver X-receptor (LXR), an important regulator of cholesterol metabolism, and its target genes such as scavenger receptor B1, ATP-binding cassette (ABC)G5 and cholesterol 7-alpha hydroxylase showed decreased gene expression in males from fructose-fed mothers and the opposite in the female progeny. Moreover, the expression of a number of LXRα target genes related to lipogenesis paralleled to that for LXRα expression. In accordance with this, LXRα gene promoter methylation was increased in males from fructose-fed mothers and decreased in the corresponding group of females. Surprisingly, plasma folic acid levels, an important methyl-group donor, were augmented in males from fructose-fed mothers and diminished in female offspring. Maternal fructose intake produces a fetal programming that influences, in a gender-dependent manner, the transcription factor LXRα epigenetically, and both hepatic mRNA gene expression and plasma parameters of cholesterol metabolism in adult progeny. Changes in the LXRα promoter methylation might be related to the availability of the methyl donor folate.

Gender-Dependent Changes in Time Production Following Quadrato Motor Training in Dyslexic and Normal Readers.

Time estimation is an important component of the ability to organize and plan sequences of actions as well as cognitive functions, both of which are known to be altered in dyslexia. While attention deficits are accompanied by short Time Productions (TPs), expert meditators have been reported to produce longer durations, and this seems to be related to their increased attentional resources. In the current study, we examined the effects of a month of Quadrato Motor Training (QMT), which is a structured sensorimotor training program that involves sequencing of motor responses based on verbal commands, on TP using a pre-post design. QMT has previously been found to enhance attention and EEG oscillatory activity, especially within the alpha range. For the current study, 29 adult Hebrew readers were recruited, of whom 10 dyslexic participants performed the QMT. The normal readers were randomly assigned to QMT (n = 9) or Verbal Training (VT, identical cognitive training with no overt motor component, and only verbal response, n = 10). Our results demonstrate that in contrast to the controls, longer TP in females was found following 1 month of intensive QMT in the dyslexic group, while the opposite trend occurred in control females. We suggest that this longer TP in the female dyslexics is related to their enhanced attention resulting from QMT. The current findings suggest that the combination of motor and mindful training, embedded in QMT, has a differential effect depending on gender and whether one is dyslexic or not. These results have implications for educational and contemplative neuroscience, emphasizing the connection between specifically-structured motor training, time estimation and attention.

A novel real-space navigation paradigm reveals age- and gender-dependent changes of navigational strategies and hippocampal activation.

To establish a novel multimodal real-space navigation paradigm and define age- and gender-related normative values for navigation performance and visual exploration strategies in space. A group of 30 healthy subjects (mean age 45.9 ± 16.5years, 16 men) performed a real-space navigation paradigm, requiring allo- and egocentric spatial orientation abilities. Visual exploration behaviour and navigation strategy were documented by a gaze-controlled, head-fixed camera. Allo- and egocentric spatial orientation performance were compared in younger and older subjects (age threshold 50years) as well as men and women. Navigation-induced changes of regional cerebral glucose metabolism (rCGM) were measured by [18F]-fluorodeoxyglucose-positron emission tomography in a subgroup of 15 subjects (8 men) and compared across age and gender. The majority of healthy subjects (73.3%) completed the navigation task without errors. There was no gender difference in navigation performance. Normalized total error rates increased slightly, but significantly with age (r = 0.36, p = 0.05). Analysis of navigation path indicated a significantly reduced use of short cuts in older age (r = 0.44, p = 0.015). Visual exploration analysis revealed that older subjects made significantly more total saccades (r = 0.49, p = 0.006) and search saccades (r = 0.54, p = 0.002) during navigation. All visual exploration parameters were similar in men and women. Navigation-induced rCGM decreased with age in the hippocampus and precuneus and increased in the frontal cortex, basal ganglia and cerebellum. Women showed an increase of rCGM in the left hippocampus and right middle temporal gyrus, men in the superior vermis. Real-space navigation testing was a feasible and sensitive method to depict age-related changes in navigation performance and strategy. Normalized error rates, total mean durations per item and total number of saccades were the most sensitive and practical parameters to indicate deterioration of allocentric navigation strategies and right hippocampal function in age irrespective of gender.

Gender-dependent changes in physical development, BDNF content and GSH redox system in a model of acute neonatal hypoxia in rats

Perinatal hypoxia–ischaemia is one of the leading factors that negatively influence the development of the central nervous system. Our aim was to investigate the effects of sex on the outcomes of acute neonatal hypoxia (ANH) in rat pups. Male and female Wistar rats were exposed to a hypoxic condition (8% oxygen for 120 min) at postnatal day 2 (P2). Immediately after ANH an increase in HIF1-α gene expression was observed in the rat brains, independently of sex. Brain-derived neurotrophic factor (BDNF) and glutathione peroxidase-4 gene expression was increased in female animals only. Hypoxic pups of both sexes showed a decreased reduced/oxidised glutathione (GSH/GSSG) ratio in the blood and only males had an increased GSH content in the whole brain immediately after hypoxia. Furthermore, an increased BDNF content in the brain was found in both male and female rat pups at 0 h and in serum 4 h after hypoxia, but at 4 h after hypoxia only males had an increased BDNF level in the brain. Only hypoxic males displayed retarded performance in the righting reflex, but in a negative geotaxis test hypoxic pups of both sexes had an increased turnaround time. Moreover, hypoxic female but not male pups demonstrated less weight gain than control littermates for the entire observation period (until P18). These results demonstrate that ANH at P2 leads to both molecular and physiological impairments in a sex-specific manner and the described model could be used to represent mild hypoxic brain damage in very preterm infants.

Chronic iron overload induces gender-dependent changes in iron homeostasis, lipid peroxidation and clinical course of experimental autoimmune encephalomyelitis

To analyze iron- and gender-dependent mechanisms possibly involved in pathogenesis of multiple sclerosis (MS) in this study we evaluated the effects of iron overload (IO) on iron status and lipid peroxidation processes (LPO) in tissues of female and male DA rats during chronic relapsing experimental autoimmune encephalomyelitis, a well-established MS animal model.Rats were treated by iron sucrose (75mg/kg bw/day) or with saline solution during two weeks before the sensitization with bovine brain homogenate in complete Freund's adjuvant. Clinical signs of EAE were monitored during 29 days. Serum and tissues of CNS and liver were sampled before immunization and at day 13th post immunization (during acute phase of EAE). The determination of ferritin, iron, malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) and evaluation of histopathology were performed by ELISA, ICP spectrometry and immunohistochemistry.Results showed that IO in female EAE rats accelerated the onset of disease. In contrast, in male rats it accelerated the progression of disease and increased the mortality rate. During acute phase of EAE female IO rats sequestered more Fe in the liver, spinal cord and in the brain and produced more ferritin than male EAE rats. Male rats, however, reacted on IO by higher production of MDA or 4-HNE in the neural tissues and showed greater signs of plaque formation and gliosis in spinal cord.The data point to sexual dimorphism in mechanisms that regulate peripheral and brain iron homeostasis and imply that men and women during MS might be differentially vulnerable to exogenous iron overload.

Toxicogenomic Analysis for Livers from Sprague-Daley Rats Following 12-Week Inhalation Exposure to Silver Nanoparticles

Silver nanoparticles (AgNPs) have been extensively applied to many industrial and biomedical fields due to their antibacterial effect. However, a large number of applications is also lead to health and environmental safety concerns. Up to date, it was well-known that AgNPs induced reactive oxygen species (ROS) production, cytotoxicity, pro-inflammatory effect, DNA damage, cell cycle disturb, necrosis and apoptosis by many researches. Also, several studies have been performed to investigate the microarray test for AgNPs in many cell types. However, no work reports the AgNPs toxicogenomic study in liver cell line and tissue until now. For this reason, we performed to in vivo toxicogenomic study for AgNPs inhalation exposed liver tissue. After 12 weeks inhalation exposure to AgNPs for the Sprague-Daley rats, we carried out silver concentration measurement for liver tissues and toxicogenomic analysis. As a result, we found that silver concentrations in livers were dose-dependently increased in male and female rats. However, a gender-different accumulation of silver in the livers did not observe. In toxicogenomic study, we observed that 109 and 150 genes significantly up- and down regulated by AgNPs inhalation exposure in male and female rats, respectively. The significantly altered male rat genes were involved in 54 biological pathways which were typically related with diabetes and metabolism. In female rat, the significantly expression changed genes were involved in 89 biological pathways which were mainly connected with metabolism and cell signaling. Plus, the gender-dependent gene expression changes of more than 2 fold were linked to 240 genes, with 114 genes in the male livers and 126 genes in the female livers. These were related to steroids and xenobiotics metabolism pathway.

Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.

Decitabine (5-aza-2'-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and β-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (∼ 10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts.

Gender-dependent changes in haematological parameters in patients with Cushing's disease before and after remission

Glucocorticoids stimulate several steps in red blood cell (RBC) development; however, little is known on changes in erythroid parameters in patients with Cushing's disease. The aim of this study was to assess both RBC and white blood cell (WBC) parameters in a large cohort of patients with Cushing's disease and report on alterations in the active phase and after surgical remission. A total of 80 patients with Cushing's disease (63 women and 17 men) were studied before and for up to 254 months' follow-up (mean follow-up 65.8 ± 6.71 months) after pituitary/adrenal surgery. Details of blood counts were reviewed and compared with data obtained from a database of healthy subjects. The RBC counts and haemoglobin levels were low in men with active Cushing's disease (over 80% of values in the lowest quartile) and four patients were overtly anaemic, whereas erythrocyte counts and haemoglobin levels were evenly distributed across the normal range in women with active Cushing's disease. Low erythroid parameters were linked to hypogonadism in men with Cushing's disease. Recovery in erythroid parameters occurred slowly after remission of hypercortisolism in men, in parallel with improvements in testosterone levels. Over 50% of patients with active disease presented increased WBC counts, irrespective of gender, and prompt normalisation within 1 month after surgery. Male patients with Cushing's disease present reduced RBC counts and haemoglobin levels, associated with low testosterone concentrations, which resolve over time after remission of hypercortisolism. Anaemia should therefore be regarded as another unfavourable feature in men with Cushing's disease.

Maternal Separation during Breastfeeding Induces Gender-Dependent Changes in Anxiety and the GABA-A Receptor Alpha-Subunit in Adult Wistar Rats

Different models of rodent maternal separation (MS) have been used to investigate long-term neurobiological and behavioral changes, associated with early stress. However, few studies have involved the analysis of sex-related differences in central anxiety modulation. This study investigated whether MS during breastfeeding affected adult males and females in terms of anxiety and brain GABA-A receptor-alpha-subunit immunoreactivity. The brain areas analyzed were the amygdale (AM), hippocampus (HP), medial prefrontal cortex (mPFC), medial preoptic area (POA) and paraventricular nucleus (PVN). Rats were housed under a reversed light/dark cycle (lights off at 7∶00 h) with access to water and food ad libitum. Animals underwent MS twice daily during the dark cycle from postnatal day 1 to postnatal day 21. Behavior was tested when rats were 65–70 days old using the elevated plus maze and after brains were treated for immunohistochemistry. We found that separated females spent more time in the open arms and showed more head dipping behavior compared with controls. The separated males spent more time in the center of the maze and engaged in more stretching behavior than the controls. Immunohistochemistry showed that separated females had less immunostained cells in the HP, mPFC, PVN and POA, while separated males had fewer immunolabeled cells in the PFC, PVN and AM. These results could indicate that MS has gender-specific effects on anxiety behaviors and that these effects are likely related to developmental alterations involving GABA-A neurotransmission.