Protective Effect Of Female Gender Research Articles

Influence of Gender and Reproductive Factors on Liver Fibrosis in Patients With Chronic Hepatitis B Infection.

INTRODUCTION:The role of reproductive factors in the development of chronic hepatitis B (CHB) remains unknown. We assessed the potential contributions of gender, menopausal status, and menarche age to liver fibrosis in CHB.METHODS:A cross-sectional prospective study included 716 women and 716 age-matched men with CHB who were not currently receiving antiviral therapy. Liver stiffness measurement using transient elastography was used to stage liver fibrosis as F0–F1 (<7.2 kPa), F ≥ 2 (7.2 kPa), F ≥ 3 (9.4 kPa), and F = 4 (12.2 kPa). Female patients were asked regarding their age at menarche and menopausal status using a questionnaire.RESULTS:Of the 716 women, 121 (16.9%) were postmenopausal, and 80 (11.2%) had advanced liver fibrosis. Multivariate logistic regression analysis showed that the postmenopausal status compared with the premenopausal status (odds ratio [OR] = 3.65–8.83; P < 0.05) and age at menarche of >14 years compared with <13 years (OR = 2.85–3.95; P < 0.05) were significantly associated with advanced fibrosis. Compared with premenopausal women, age-matched men had a higher OR for advanced fibrosis (P < 0.05). Compared with postmenopausal women, age-matched men did not show a significant difference in the degree of liver fibrosis (P > 0.05). Longitudinal data analysis showed that postmenopausal women (n = 31) were significantly less likely to undergo regression of liver fibrosis after antiviral treatment vs premenopausal women (n = 19) (26.3% vs 74.2%, respectively; P < 0.001).DISCUSSION:Menopause and late menarche aggravated liver fibrosis in untreated CHB, besides menopause delayed fibrosis regression under antiviral therapy. The protective effect of female gender against fibrosis was lost for postmenopausal women.TRANSLATIONAL IMPACT:It is important to consider menopausal status and age at menarche in establishing surveillance strategies among CHB females. Postmenopausal estrogen therapy may be considered for the prevention or treatment of liver fibrosis.

Female gender lost protective effect against disease progression in elderly patients with chronic hepatitis B.

Female gender and younger age are protective factors against disease progression in chronic hepatitis B (CHB). However, it is not clear whether the disease progression still remains slow in elderly females. This study investigated the interaction of female gender and older age on the development of cirrhosis in patients recorded in China Registry of Hepatitis B. A total of 17,809 CHB patients were enrolled in this multi-center cross-sectional study. The prevalence of cirrhosis in female CHB patients increased faster than that in male CHB patients over 50 years old. Multivariate analysis showed that the increase of adjusted ORs for developing cirrhosis in females started to accelerate after 50 years old: 11.19 (95% CI: 5.93–21.11) in women versus 14.75 (95% CI: 8.35–26.07) in men at ages of 50–59 years, 21.67 (95% CI: 11.05–42.47) versus 24.4 (95% CI: 13.00–45.80) at ages 60–69 years, and 18.78 (95% CI: 6.61–53.36) versus 12.09 (95% CI: 4.35–33.61) in those over 70 years. In conclusion, the protective effect of female gender against cirrhosis gradually lost with increasing age, therefore disease progression should be monitored more closely in elderly women with CHB.

Social isolation from extended family members and friends among African Americans: Findings from a national survey

ABSTRACTThis study investigated the correlates of objective social isolation from extended family members and friends among a national sample of African Americans. The analysis is based upon the African American subsample (n = 3,570) of the National Survey of American Life. The dependent variable examines four categories of respondents: 1) socially isolated from both family and friends, 2) socially isolated from friends only, 3) socially isolated from family only, and 4) not socially isolated. Overall, 23% of respondents indicated some degree of objective social isolation from family, friends or both groups, while the complementary 77% of the sample were not isolated from family or friends. Only 4% of respondents indicated being isolated from both family and friends. Multinomial logistic regression analysis revealed several gender, education, marital status and region differences. In particular, African American women were less likely to be socially isolated from family members than African American men. This finding was sustained even when controlling for differences in subjective isolation from family members, underscoring the protective effect of female gender. Study findings are discussed in relation to previous research on social isolation, as well as prior research on African American social support networks.

Aromatase is required for female abdominal aortic aneurysm protection

The protective effects of female gender on the development of abdominal aortic aneurysms (AAAs) have been attributed to anti-inflammatory effects of estrogen. Estrogen synthesis is dependent on the enzyme aromatase, which is located both centrally in the ovaries and peripherally in adipose tissue, bone, and vascular smooth muscle cells. It is hypothesized that deletion of aromatase in both ovarian and peripheral tissues would diminish the protective effect of female gender and would be associated with increased aortic diameter in female mice. Male and female 8- to 10-week-old mice with aromatase (wild type: WT) and without aromatase (ArKO) underwent elastase aortic perfusion with aortic harvest 14 days following. For the contribution of central and peripheral estrogen conversion to be evaluated, female WT mice were compared with female WT and ArKO mice that had undergone ovariectomy (ovx) at 6 weeks followed by elastase perfusion at 8 to 10 weeks. At aortic harvest, maximal aortic dilation was measured and samples were collected for immunohistochemistry and protein analysis. Serum was collected for serum estradiol concentrations. Groups were compared with analysis of variance. Human and mouse AAA cross sections were analyzed with confocal immunohistochemistry for aromatase, smooth muscle markers, and macrophage markers. Female WT mice had significant reduction in aortic dilation compared with male WT mice (F WT, 51.5% ± 15.1% vs M WT, 78.7% ± 14.9%; P < .005). The protective effects of female gender were completely eliminated with deletion of aromatase (F ArKO, 82.6% ± 13.8%; P < .05 vs F WT). Ovariectomy increased aortic dilation in WT mice (F WT ovx, 70.6% ± 11.7%; P < .05 vs F WT). Aromatase deletion with ovariectomy further increased aortic dilation compared with WT ovx mice (F ArKO ovx, 87.3% ± 14.7%, P < .001 vs F WT and P < .05 vs F WT ovx). Accordingly, female ArKO ovx mice had significantly higher levels of the proinflammatory cytokines monocyte chemoattractant protein 1 and interleukin-1β and were associated with increased macrophage staining and decreased elastin staining. Regarding serum hormone levels, decreasing estradiol levels correlated with increasing aortic diameter (R = -0.565; P < .01). By confocal immunohistochemistry, both human and mouse AAA smooth muscle cells (smooth muscle α-actin positive) and macrophages (CD68 positive or Mac-2 positive) expressed aromatase. The protective effect of female gender on AAAs is due to estrogen synthesis and requires the presence of both ovarian and extragonadal/peripheral aromatase. Peripheral estrogen synthesis accounts for roughly half of the protective effect of female gender. If peripheral aromatase could be targeted, high levels of local estrogen could be produced and may avoid the side effects of systemic estrogen.

Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women

BackgroundThe aim of this study is to evaluate the effect of gender and menopause in cardiometabolic risk in a type 2 diabetes mellitus (T2DM) population, based on classical and non-traditional markers.MethodsSeventy four volunteers and 110 T2DM patients were enrolled in the study. Anthropometric data, blood pressure, body mass index (BMI), waist circumference (WC) and the following serum markers were analyzed: glucose, Total-c, TGs, LDL-c, Oxidized-LDL, total HDL-c and large and small HDL-c subpopulations, paraoxonase 1 activity, hsCRP, uric acid, TNF-α, adiponectin and VEGF.ResultsNon-diabetic women, compared to men, presented lower glycemia, WC, small HDL-c, uric acid, TNF-α and increased large HDL-c. Diabetes abrogates the protective effect of female gender, since diabetic women showed increased BMI, WC, small HDL-c, VEGF, uric acid, TNF-α and hsCRP, as well as reduced adiponectin, when compared with non-diabetic. In diabetic females, but not in males, WC is directly and significantly associated with TNF-α, VEGF, hsCRP and uric acid; TNF-α is directly associated with VEGF and hsCRP, and inversely with adiponectin. Postmenopausal females presented a worsen cardiometabolic profile, viewed by the increased WC, small HDL-c, VEGF, uric acid, TNF-α and hsCRP. In this population, WC is directly and significantly associated with TNF-α, VEGF, hsCRP; TNF-α is directly associated with VEGF; and uric acid is inversely associated with large HDL-c and hsCRP with adiponectin, also inversely.ConclusionsDiabetes abrogates the protective effect of gender on non-diabetic women, and postmenopausal diabetic females presented worsen cardiometabolic risk, including a more atherogenic lipid sketch and a pro-inflammatory and pro-angiogenic profile. The classical cardiovascular risk factors (CVRFs) fail to completely explain these differences, which are better clarified using “non-traditional” factors, such as HDL-c subpopulations, rather than total HDL-c content, and markers of inflammation and angiogenesis, namely TNF-α, hsCRP, uric acid and VEGF. Multi-therapeutic intervention, directed to obesity, atherogenic lipid particles and inflammatory mediators is advisory in order to efficiently prevent the serious diabetic cardiovascular complications.

Gender and kidney diseases: the clinical importance and mechanisms of modifying effects

This review focuses on the underlying pathways of gender-dependent renal diseases and presents specific examples of diseases influenced by gender. In the literature it has been shown, in many clinical and experimental observations, that the incidence and the rate of progression of renal disease are influenced by many gender-dependent factors, such as kidney and glomerular size, differences in glomerular hemodynamics, and direct effects of sex hormones on renal tissue and signal pathways such as the renin-angiotensin-aldosterone system and signal molecules (e.g. nitric oxide, reactive oxygen species, cytokines and growth factors). It has been shown that the main female hormone, 17 β estradiol, is capable of inhibiting inflammatory and pro apoptotic processes and protects the renal tissue. In contrast, the male hormones, testosterone and dehydroepiandrosterone, have the opposite effect. Hormonal manipulation by male or female castration changes the course of renal disease progression and confirms the influence of the sex hormones. Female gender is therefore considered a protective factor in many kidney diseases, such as primary glomerulonephritis, autosomal dominant polycystic kidney disease (ADPKD) and hypertensive nephropathy. Similarly, women are more predisposed to autoimmune diseases with secondary glomerulonephritis, e.g. systemic lupus erythematosus, as the female sex hormones have the ability of autoimmune process activation. After menopause the protective effect of female gender is not observed, which confirms the role of the female sex hormones.

Is vasoplegic syndrome more prevalent with open-heart procedures compared with isolated on-pump CABG surgery?

Postoperative vasoplegic syndrome (PVS) is a frequent complication and can affect the early postoperative course. Our study investigated the incidence and risk factors of PVS after on-pump isolated coronary artery grafting bypass (CABG) and on-pump open-heart surgery. A total of 629 patients underwent on-pump cardiac surgery from November 21, 2005, to June 9, 2006, at our institution. Of those, 334 patients underwent on-pump isolated CABG and 295 patients had open-heart surgery. PVS was defined based on the recognized criteria. Multivariate logistic regression analysis was used to identify the risk factors for PVS. The overall incidence of PVS was 11.7%. The incidence in isolated on-pump CABG surgery was 6.9% and 17.0% in open-heart surgery (P<.01). In multivariate analysis, isolated CABG reduced by half the incidence of PVS [odds ratio (OR)=0.45, P=.02]; preoperative left ventricular ejection fraction (EF) <35% was identified as an independent predictor of PVS (OR=2.1, P=.01), and a protective effect of female gender for PVS was observed (OR=0.4, P=.01). The association between angiotensin-converting enzyme inhibitors and other preoperative medical treatments was not confirmed by our study. In conclusion, PVS occurred less often after isolated CABG surgery than after open-heart surgery. Advanced age and low preoperative EF strongly predicted PVS.

Interleukin-6 Polymorphisms and Gender: Relationship with the Occurrence of Hepatocellular Carcinoma in Patients with End-Stage Liver Disease

Objective: To investigate whether interleukin-6 (IL-6) polymorphisms could be associated with the occurrence of hepatocellular carcinoma (HCC) in patients with liver cirrhosis and whether this influence could act synergistically with the gender of the patient. Methods: We studied 219 consecutive patients who underwent liver transplantation for liver cirrhosis. All total hepatectomy specimens were sectioned at intervals of 1 cm in search for suspicious focal hepatic lesions. Genotyping for the IL-6 –1363 G>T, –597 G>A, –572 G>C, –174 G>C and +2954 G>C polymorphisms was performed by restriction fragment length polymorphism. Results: A significant association was found between the presence of the A-C/A-C low producer diplotype (–597 G>A/–174 G>C loci) and absence of HCC (18/153 vs. 1/66, p < 0.02). With respect to the IL-6 A-C/A-C low producer phenotype (n = 19), females (n = 60) and males (n = 140) with the high producer phenotypes had an adjusted odds ratio for the presence of HCC of 3.74 and 14.8, respectively (p < 0.001). Conclusions: Polymorphisms of IL-6, by determining differences in its expression, are associated with HCC occurrence among patients with liver cirrhosis. The protective effect of female gender against the occurrence of HCC occurs mainly among carriers of IL-6 high producer phenotypes.

Characterization of the gender dimorphism after injury and hemorrhagic shock: Are hormonal differences responsible?*

To characterize the gender dimorphism after injury with specific reference to the reproductive age of the women (young, <48 yrs of age, vs. old, >52 yrs of age) in a cohort of severely injured trauma patients for which significant variation in postinjury care is minimized. Secondary data analysis of an ongoing prospective multicenter cohort study. Academic, level I trauma and intensive care unit centers. Blunt-injured adults with hemorrhagic shock. None. Separate Cox proportional hazard regression models were formulated based on all patients to evaluate the effects of gender on mortality, multiple organ failure, and nosocomial infection, after controlling for all important confounders. These models were then used to characterize the effect of gender in young and old age groups. Overall mortality, multiple organ failure, and nosocomial infection rates for the entire cohort (n = 1,036) were 20%, 40%, and 45%, respectively. Mean Injury Severity Score was 32 +/- 14 (mean +/- SD). Men (n = 680) and women (n = 356) were clinically similar except that men required higher crystalloid volumes, more often had a history of alcoholism and liver disease, and had greater ventilatory and intensive care unit requirements. Female gender was independently associated with a 43% and 23% lower risk of multiple organ failure and nosocomial infection, respectively. Gender remained an independent risk factor in young and old subgroup analysis, with the protection afforded by female gender remaining unchanged. The independent protective effect of female gender on multiple organ failure and nosocomial infection rates remains significant in both premenopausal and postmenopausal women when compared with similarly aged men. This is contrary to previous experimental studies and the known physiologic sex hormone changes that occur after menopause in women. These results suggest that factors other than sex hormones may be responsible for gender-based differences after injury.

Protective effect of female gender on the development of albuminuria in a polygenetic rat model is enhanced further by replacement of a major autosomal QTL

Clinical and experimental studies indicate that the progression of renal disease is faster in males than females. These observations are corroborated by a sexual dimorphism observed in the polygenetic MWF (Munich Wistar Frömter) rat model. The age-dependent spontaneous progression of increased UAE (urinary albumin excretion) in male MWF rats is influenced by multiple QTLs (quantitative trait loci). In contrast, female MWF rats only develop a slight increase in UAE, while the role of genetic factors for this phenotype is unknown. In the present study, we show that, compared with resistant SHRs (spontaneously hypertensive rats), both male and female MWF rats develop a significant increase in UAE at 24 weeks of age (P<0.0001), although blood pressures were lower compared with SHRs (P<0.0001). UAE was significantly higher in male (7-fold) compared with female MWF rats (162.6+/-15.9 compared with 24.0+/-5.5 mg/24 h respectively; P<0.0001), and only male MWF rats developed significant glomerulosclerosis and tubulointerstitial damage in the kidney (P<0.0001). To test the role of genetic factors in the development of low grade albuminuria in female MWF rats, we analysed the role of a major UAE QTL on rat chromosome 6. To this end, we analysed a consomic MWF-6(SHR) strain in which chromosome 6 from SHRs was introgressed into the MWF rat background. Time course analysis of UAE in females indicated that the small increase in UAE in MWF rats was fully suppressed by exchange of rat chromosome 6. Thus, taken together with previous studies in males, we show that RNO6 protects against the increase in albuminuria with age in both female and male MWF rats.

Abstract 1528: Gender Differences In The Effect Of Traditional Cardiac Risk Factors On Age At Presentation With Stemi

For coronary artery disease (CAD), female gender is ’protective’, so that women typically present with clinically apparent CAD a decade later than men. We examined the extent to which traditional cardiovascular risk factor influence the age at presentation with STEMI in men and women. The Cardiovascular Patient Outcomes Research Team (C-PORT) primary PCI registry includes 7197 patients (5070 males and 2109 females) who presented with STEMI at 33 participating hospitals. The table below depicts the average age at presentation with STEMI in males and females with and without diabetes, hypercholesterolemia, hypertension, a family history of coronary artery disease and smoking history (current or former). The effect of smoking, family history and hypertension on age at presentation remained significant in multivariate analysis in both men and women. In both males and females, a family history of CAD and a positive smoking history are associated with presentation with STEMI at a younger age. Both have a greater effect in females. This is particularly true of smoking with lowers the age of presentation by 9 years in women, compared with 3.8 years in men. Male and female patients with a history of hypertension are older at presentation with STEMI, perhaps because the anti-ischemic effects of anti-hypertensive medications. We conclude that while the effect of most traditional risk factors for CAD on age at presentation with STEMI are similar in men and women, smoking lowers the age at presentation to a much greater degree in women. In women who do not smoke, STEMI is delayed for a decade or more compared to men; for women who do, the protective effect of female gender is nearly obliterated.

Protective effect of female gender against bone loss in the forearm following clean-cut tendon injuries, repair, and passive mobilization

The aim of this study was to investigate whether there is any significant difference in bone loss between female and male patients as a result of early passive mobilization after surgery for acute tendon-artery-nerve clean-cut injuries at the wrist level. A total of 51 patients who underwent such operations were enrolled in this study. Group I consisted of 40 male patients (mean age 30.2 +/- 9.1 years, age range 15-44 years) and group II consisted of 11 female patients (mean age 24.1 +/- 9.9 years, age range 14-43 years); postmenopausal women were not included in this group. Twenty-one patients in group I and six patients in group II were operated on for clean-cut tendon injury combined with nerve injury, artery injuries, or both. Bone mineral density (BMD) measurements of injuired forearms were obtained at 1 week, 6 weeks, 3 months, and 12 months after operation. The BMD of the radius and ulna did not change significantly throughout the follow-up period in group II (P > 0.05). In group I, BMD values were reduced significantly in the distal regions of the ulna and in the ultradistal region of the radius at the follow-up measurements when compared to the values at week 1 and the reduction was higher in month 3 than at other times. On the other hand, after 12 months, the BMD values of the ultra-distal region of the ulna and radius were higher than those after 3 months. In conclusion, our results showed that there is considerable bone loss of the radius and ulna in patients operated on for acute clean-cut tendon injuries on the volar side of the wrist at postoperative month 3 in male patients. These bone losses were recovered after 12 months. Additionally, female patients are less likely to experience immobilization-induced bone loss than male patients.

Unravelling the cardioprotective mechanism of action of estrogens

See article by Xu et al. [1] (pages 836–844) in this issue. Cardiovascular diseases are the major cause of morbidity and mortality in the developed world, and are increasing in significance in the developing world. Elucidation of the mechanisms involved in preventing the development of coronary artery disease and protecting the myocardium against the deleterious consequences of myocardial ischaemia therefore stays an important research goal. The sex hormone estrogen has received increased attention for its ability to exert cardioprotective effects against atherosclerosis, but it has become clear that estrogen also exerts a direct protective effect against ischaemia/reperfusion injury on the myocardium. In this edition of Cardiovascular Research Xu et al. [1] provide evidence for decreased TNFα production during ischaemia/reperfusion in the mechanism of estrogen-mediated cardiac protection. There is an abundance of scientific evidence for the protective effect of estrogen against atherosclerosis, such as short-term vasodilating effects as well as long-term vascular protective and anti-atherosclerotic effects [2]. Epidemiological evidence shows that pre-menopausal women have a reduced risk for mortality from cardiovascular diseases [3] and that women are at a lower risk for the development of heart failure [4] and have enhanced cognitive function and reduced neurodegeneration associated with Alzheimer's disease and stroke [5]. Further proof for the protective effect of female gender is the fact that post-menopausal women have a similar or even increased risk for cardiovascular disease compared to men [3] and have an increased risk for adverse outcome after myocardial infarction and acute coronary syndromes, despite similar treatment with thrombolysis and percutaneous interventions [6]. It was therefore postulated that estrogen replacement would be beneficial in preventing cardiovascular diseases in post-menopausal females. However, clinical trials designed to investigate the effects of estrogen replacement therapy in secondary prevention were surprising–in the Heart and Estrogen/Progestin Replacement Study (HERS) no … *Tel.: +27 21 9389392. Email address: jamool{at}sun.ac.za

Iron Chelation and Vascular Function

In 1981, Sullivan suggested that a state of iron depletion (ie, reduced iron stores without anemia) was potentially protective against coronary heart disease (CHD).1 This original “iron hypothesis” was an attempt to explain the known sex difference in cardiovascular (CV) risk and the subsequent loss of the protective effect of female gender with menopause. This initial hypothesis was based in part on the observation that men exhibited an age-dependent increase in the accumulation of iron that was not seen in women until after menopause. This, coupled with the observation that hysterectomy without oophorectomy was associated with an increased CHD risk, supported the concept that a diminution in iron stores was protective against CHD. Basic and clinical data have recently begun to provide plausible explanations for a link between iron and atherosclerosis.2,3 See page 2282 The toxic effect of free iron has been linked to oxidative stress through the Fenton reaction, where Fe2+ oxidizes H2O2 leading to its autooxidation and the generation of hydroxyl radicals4 which in turn initiate lipid peroxidation. In addition, biological forms of iron such as heme have the potential to catalyze other oxidative reactions. For example, heme can initiate the oxidation of isolated LDL in vitro4 and, in contrast to free transition metals, LDL in diluted serum.5 Iron is also essential for the synthesis of enzymes that can play a central role in vascular function and atherosclerosis (eg, eNOS, 5-lipoxygenase, and myeloperoxidase). The amount of free ferrous (Fe2+) iron is normally maintained at a very low level in …

Gender hormones and the progression of experimental polycystic kidney disease

Male gender is a risk factor for progression of autosomal-dominant polycystic kidney disease (ADPKD), clinically and in the Han:SPRD rat model. Orchiectomy limits progression, but mechanisms of the detrimental effect of androgen, and/or beneficial effects of estrogen, are not known. This protocol tested the hypothesis that male gender (intact androgen status) promotes progression, while female gender (intact estrogen status) is protective; and that these disease-modifying effects are due to changes in expression of known fibrotic mediators. Studies were performed in male and female noncystic control (+/+) and cystic (+/-) rats subjected to orchiectomy, ovariectomy, or sham operation. At 12 weeks of age, renal function was measured. Blood and kidneys were taken for measurement of plasma and renal renin, endothelin (ET-1), endothelial nitric oxide synthase (eNOS), and vascular endothelial growth factor (VEGF), using biochemical, protein expression, and immunohistochemical methods. Cystic male rats exhibited significantly reduced glomerular filtration (GFR) and effective renal plasma flow (ERPF) rates, with suppression of plasma and renal renin, up-regulation of renal ET-1 and eNOS, and down-regulation of renal VEGF expression. Orchiectomy attenuated the fall in GFR and ERPF, while numerically limiting changes in eNOS and VEGF. Female rats exhibited less cystic growth, with normal renin status, lesser elevation of renal ET-1, and proportionately lesser changes in VEGF and eNOS. Ovariectomy led to higher blood pressure and reduced GFR and ERPF, with a trend toward upregulation of ET-1, and significant down-regulation of VEGF and eNOS. Female gender is protective, but ovariectomy attenuates the protective effect of female gender, in association with changes in renal expression of ET-1, VEGF, and eNOS. The accelerated disease in male rats can be attenuated by orchiectomy and consequent changes in expression of disease mediators.

Modest maternal protein restriction fails to program adult hypertension in female rats

Modest maternal dietary protein restriction in the rat leads to hypertension in adult male offspring. The purpose of this study was to determine whether female rats are resistant to developing the increased blood pressure seen in male rats after maternal protein restriction. Pregnant rats were fed a normal protein (19%, NP) or low-protein (8.5%, LP) diet throughout gestation. Renal renin protein and ANG II levels were reduced by 50-65% in male LP compared with NP pups, but were not suppressed in female LP compared with female NP. Mean arterial pressure in conscious, chronically instrumented adult female offspring (22 wk) was not different in LP (LP: 120 +/- 3 mmHg vs. NP: 121 +/- 2 mmHg), and glomerular filtration rate was also not different in LP vs. NP. The number of glomeruli per kidney was similar in adult LP and NP female offspring (LP: 26,050 +/- 2,071 vs. NP: 26,248 +/- 1,292, NP), and individual glomerular volume was also not different (LP: 0.92 +/- 0.11 10(6) microm(3), LP vs. NP: 1.07 +/- 0.11 10(6) microm(3)); the total volume of all glomeruli per kidney was also not significantly different. Thus female rats are relatively resistant to the programming for adult hypertension by perinatal protein restriction that we have described in males. This resistance may be due to the fact that modest maternal protein restriction does not reduce the number of glomeruli with which females are endowed as it does in males. The intrarenal renin-angiotensin system during development may play a key role in this protective effect of female gender.

Does sexual dimorphism influence outcome of traumatic brain injury patients? The answer is no!

The protective effect of female gender on posttraumatic mortality or acute complications after traumatic brain injury (TBI) has been postulated. This effect might be seen if TBIs were analyzed by severity. To assess potential gender effects, we performed a retrospective case-controlled study matching female patients to male counterparts for overall injury severity; hemodynamic status at admission; and head, chest, and abdomen Abbreviated Injury Scale score. All female patients sustaining TBI admitted over 6.5 years were reviewed. An overall comparison between women (n = 914) and their male matched counterparts (n = 916) was performed. Patients were then stratified according to the severity of head injury on the basis of admission Glasgow Coma Scale (GCS) score into three groups: group 1, GCS score of 13 to 15 (788 female patients, 769 male patients); group 2, GCS score of 9 to 12 (40 female patients, 42 male patients); and group 3, GCS score < 9 (63 female patients, 87 male patients). Cohorts were compared for mortality or the development of acute respiratory distress syndrome, pneumonia, and systemic sepsis using standard definitions. A subset analysis was performed excluding patients with age above 50 years (789 women, 811 men) to exclude the effects of menopause on the results. There was no statistically significant difference in outcome overall or in subset analysis of mild (group 1), moderate (group 2), or severe (group 3) TBI. The exclusion of patients older than 50 years showed no protective effect of female gender on outcome. Gender does not play a role in posttraumatic mortality or in the incidence of acute complications after any degree of TBI.

17β-Estradiol Modulates Mechanical Strain-induced MAPK Activation in Mesangial Cells

Gender is an important determinant of clinical outcome across a broad spectrum of kidney diseases, but the mechanism(s) responsible for the protective effect of female gender have not been fully elucidated. Remnant kidney glomerular injury is limited in female rats compared with male rats despite similar elevations in glomerular capillary pressure. In vitro, mechanical strain leads to the activation of p44/42 mitogen-activated kinase (p44/42 MAPK) and Jun N-terminal kinase/stress-activated protein kinase (SAPK) in glomerular mesangial cells (MC). Accordingly, we studied the effect of 17beta-estradiol on mechanical strain-induced signal transduction in MC. Exposure of MC to mechanical strain increased p44/42 MAPK activation (3-fold) and SAPK activation (2.5-fold), and kinase activation was inhibited by pretreatment with 17beta-estradiol (10(minus sign8) to 10(minus sign11) m) for 24 h in a dose-dependent manner. Mechanical strain-induced nuclear translocation of p44/42 MAPK and SAPK and nuclear protein binding to AP-1 were also attenuated by 17beta-estradiol. The inhibitory effects of 17beta-estradiol were not reproduced by the cell-impermeable estrogen, BSA/17beta-estradiol, nor did preincubation with 17beta-estradiol lead to actin cytoskeleton disassembly or impaired stress fiber formation. However, 17beta-estradiol did increase base-line levels of the dual specificity phosphatase MKP-1. The inhibitory effects of 17beta-estradiol on p44/42 MAPK activation and SAPK activation, translocation, and AP-1 binding were all abrogated by the estrogen receptor antagonist, ICI-182,780. We conclude that attenuation of mechanical strain-induced MAPK activation by 17beta-estradiol is dependent on intracellular estrogen receptor. The attenuation of stretch-induced kinase activation may be due, at least in part, to an effect of 17beta-estradiol on MKP-1 expression. Together, these findings add insight into the protective effect of gender on renal disease progression.

Estradiol upregulates mesangial cell MMP-2 activity via the transcription factor AP-2.

The accumulation of extracellular matrix in the glomerular mesangium reflects the net balance between the synthesis and degradation of matrix components. We have shown that estradiol suppresses the synthesis of types I and IV collagen by cultured mesangial cells (Kwan G, Neugarten J, Sherman M, Ding Q, Fotadar U, Lei J, and Silbiger S. Kidney Int 50: 1173-1179, 1996; Neugarten J, Acharya A, Lei J, and Silbiger S. Am J Physiol Renal Physiol 279: F309-F318, 2000; Neugarten J, Medve I, Lei J, and Silbiger SR. Am J Physiol Renal Physiol 277: F1-F8, 1999; Neugarten J and Silbiger S. Am J Kidney Dis 26: 147-151, 1995; Silbiger S, Lei J, and Neugarten J. Kidney Int 55: 1268-1276, 1998; Silbiger S, Lei J, Ziyadeh FN, and Neugarten J. Am J Physiol Renal Physiol 274: F1113-F1118, 1998). In the present study, we evaluated the effects of sex hormones on the activity of matrix metalloproteinase-2 (MMP-2) in murine mesangial cells, the synthesis of which is regulated by the transcription factor activator protein-2 (AP-2). Estradiol stimulated MMP-2 activity by increasing MMP-2 protein levels in a dose-dependent manner. These effects occurred at physiological concentrations of estradiol and were receptor mediated. Estradiol also increased AP-2 protein levels and increased binding of mesangial cell nuclear extracts to an AP-2 consensus binding sequence oligonucleotide. The ability of estradiol to increase AP-2 protein expression, AP-2/DNA binding activity, MMP-2 protein expression, and metalloproteinase activity was reversed by PD-98059, a selective inhibitor of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling cascade. We conclude that estradiol upregulates the MAPK cascade, which in turn stimulates the synthesis of AP-2 protein. The resultant increased AP-2/DNA binding activity leads to increased synthesis of MMP-2 and increased metalloproteinase activity. Stimulation of metalloproteinase activity by estradiol may contribute to the protective effect of female gender on renal disease progression.

Neuronal and endothelial nitric oxide synthase gene knockout mice.

Targeted disruption of the neuronal nitric oxide synthase (nNOS) and endothelial nitric oxide synthase (eNOS) genes has led to knockout mice that lack these isoforms. These animal models have been useful to study the roles of nitric oxide (NO) in physiologic processes. nNOS knockout mice have enlarged stomachs and defects in the inhibitory junction potential involved in gastrointestinal motility. eNOS knockout mice are hypertensive and lack endothelium-derived relaxing factor activity. When these animals are subjected to models of focal ischemia, the nNOS mutant mice develop smaller infarcts, consistent with a role for nNOS in neurotoxicity following cerebral ischemia. In contrast, eNOS mutant mice develop larger infarcts, and show a more pronounced hemodynamic effect of vascular occlusion. The knockout mice also show that nNOS and eNOS isoforms differentially modulate the release of neurotransmitters in various regions of the brain. eNOS knockout mice respond to vessel injury with greater neointimal proliferation, confirming that reduced NO levels seen in endothelial dysfunction change the vessel response to injury. Furthermore, eNOS mutant mice still show a protective effect of female gender, indicating that the mechanism of this protection cannot be limited to upregulation of eNOS expression. The eNOS mutant mice also prove that eNOS modulates the cardiac contractile response to ss-adrenergic agonists and baseline diastolic relaxation. Atrial natriuretic peptide, upregulated in the hearts of eNOS mutant mice, normalizes cGMP levels and restores normal diastolic relaxation.