Representation of Women in Contemporary Kidney Transplant Trials.

Women are often underrepresented in clinical trials. It is unclear if this applies to trials in kidney transplant (KT) and whether the intervention or trial focus influences this. In this study, the weighted participation-to-prevalence ratio (PPR) for women enrollees in KT trials was determined for leading medical transplant or kidney journals between 2018 and 2023 using meta-regression overall and in three sensitivity analyses by: 1) Whether the intervention involved immunosuppression; 2) Area of trial focus; rejection, cardiometabolic, infection, lifestyle, surgical; 3) Whether the intervention was medical/surgical or social/behavioral. Overall, 33.7% of participants in 24 trials were women. The overall pooled PPR for the included trials was 0.80, 95% CI 0.76-0.85, with significant heterogeneity between trials (I 2 56.6%, p-value < 0.001). Women had a lower PPR when the trial involved immunosuppression (PPR 0.77, 95% CI 0.72-0.82) than when it did not (PPR 0.86, 95% CI 0.80-0.94) and were less likely to participate in trials with a medical/surgical versus behavioral intervention; the lowest PPR for women was in studies examining rejection risk (PPR 0.75, 95% CI 0.70-0.81). There is better representation of women in KT trials compared to other medical disciplines, however women remain underrepresented in transplant trials examining immunosuppression and rejection.

IgA nephropathy with early kidney disease is associated with increased arterial stiffness and renin-angiotensin system activity.

BACKGROUND: IgA nephropathy is associated with increased cardiovascular risk, though whether this is due to loss of kidney function or proteinuria is unclear. METHODS: For this study 10 normotensive IgA nephropathy subjects with early kidney disease (41±5 yrs, glomerular filtration rate (GFR) 87±9 ml/min, proteinuria 720±300 mg/d) and 10 gender- and blood pressure-matched healthy controls (36±1 yrs, estimated GFR 102±5 ml/min, proteinuria 70±6 mg/d) were studied in high-salt balance. Blood pressure and arterial stiffness, expressed as pulse wave velocity and aortic augmentation index, were measured at baseline and in response to 60 min of angiotensin II (AngII) infusion. RESULTS: At baseline, IgA nephropathy subjects demonstrated similar pulse wave velocity (8.6±0.7 vs. 8.0±0.4 m/s, p=0.5) but increased aortic augmentation index (12.6±3.1 vs. 1.8±4%, p=0.04) and a trend towards increased circulating renin-angiotensin system (RAS) components (plasma renin activity, 0.55±0.18 vs. 0.21±0.05 ng/l/s, p=0.08; angiotensin II, 25±5 vs. 16±1 ng/l, p=0.08) compared with controls. However, despite similar baseline blood pressure values (p=0.8), IgA nephropathy was associated with reduced arterial sensitivity to AngII challenge (Δmean arterial pressure: 19±4 vs. 29±1 mm Hg, p=0.05; Δpulse wave velocity: -0.06±0.6 vs. 1.5±0.3 m/s, p=0.07) compared with controls, even after multivariate analysis. CONCLUSION: Even in the setting of early kidney disease, IgA nephropathy is associated with increased arterial stiffness and decreased angiotensin II responsiveness, a marker of increased RAS activity.

Sex influences the effect of body mass index on the vascular response to angiotensin II in humans.

OBJECTIVE: Sex influences the cardiorenal risk associated with body mass index (BMI). The role of the renin-angiotensin-aldosterone system in adiposity-mediated cardiorenal risk profiles in healthy, non-obese men and women was investigated. METHODS: Systemic and renal hemodynamic responses to angiotensin-II (AngII) as a function of BMI, waist and hip circumference, waist-hip ratio, as well as fat and lean mass were measured in 18 men and 25 women in high-salt balance, stratified by BMI (<25 kg/m2 (ideal body weight (IBW)) vs. ≥25 kg/m2 overweight)). RESULTS: In men (n = 7, BMI 23 ± 1 kg/m2) and women (n = 14, BMI 22 ± 2 kg/m2) of IBW, BMI was not associated with the systolic blood pressure (SBP) response to AngII. In contrast, overweight men (n = 11, 29 ± 2 kg/m2) demonstrated a progressively more blunted vasoconstrictor SBP response to AngII challenge as BMI increased (P = 0.007), even after adjustment for covariates. Women maintained the same relationship between BMI and the SBP response to AngII irrespective of weight status (P = 0.2, IBW vs. overweight women). Compared to BMI, other adiposity measures showed similar associations to systemic AngII responsiveness in men but not in women. Increasing BMI was associated with a blunted renovasoconstrictor response to AngII in all subjects, but was more pronounced in men. CONCLUSION: Sex influences the effect of adiposity on vascular angiotensin-responsiveness.

Impact of gender on the cardiac autonomic response to angiotensin II in healthy humans.

Premenopausal women have a lower risk of cardiovascular disease (CVD) compared with men of a similar age. Furthermore, the regulation of factors that influence CVD appears to differ between the sexes, including control of the autonomic nervous system (ANS) and the renin-angiotensin system. We examined the cardiac ANS response to angiotensin II (Ang II) challenge in healthy subjects to determine whether differences in women and men exist. Thirty-six healthy subjects (21 women, 15 men, age 38 ± 2 years) were studied in a high-salt balance. Heart-rate variability (HRV) was calculated by spectral power analysis [low-frequency (LF) sympathetic modulation, high-frequency (HF) parasympathetic/vagal modulation, and LF:HF as a measure of overall ANS balance]. HRV was assessed at baseline and in response to graded Ang II infusions (3 ng·kg(-1)·min(-1) × 30 min; 6 ng·kg(-1)·min(-1) × 30 min). Cardiac ANS tone did not change significantly in women after each Ang II dose [3 ng·kg(-1)·min(-1) mean change (Δ)LF:HF (mean ± SE) 0.5 ± 0.3, P = 0.8, vs. baseline; 6 ng·kg(-1)·min(-1) ΔLF:HF (mean ± SE) 0.5 ± 0.4, P = 0.4, vs. baseline], whereas men exhibited an unfavorable shift in overall cardiac ANS activity in response to Ang II (ΔLF:HF 2.6 ± 0.2, P = 0.01, vs. baseline; P = 0.02 vs. female response). This imbalance in sympathovagal tone appeared to be largely driven by a withdrawal in cardioprotective vagal activity in response to Ang II challenge [ΔHF normalized units (nu), -5.8 ± 2.9, P = 0.01, vs. baseline; P = 0.006 vs. women] rather than an increase in sympathetic activity (ΔLF nu, -4.5 ± 5.7, P = 0.3, vs. baseline; P = 0.5 vs. women). Premenopausal women maintain cardiac ANS tone in response to Ang II challenge, whereas similarly aged men exhibit an unfavorable shift in cardiovagal activity. Understanding the role of gender in ANS modulation may help guide risk-reduction strategies in high-risk CVD populations.

[Primary digestive tract lymphoma in central region of Tunisia: anatomoclinical study and therapeutic results about 153 cases]. / Les lymphomes primitifs du tube digestif (LPTD) dans le centre tunisien: étude anatomoclinique et résultats thérapeutiques à propos de 153 cas.

Primary gastro-intestinal lymphoma (PGIL) is the most common type of extra-nodal non Hodgkin's lymphoma. Their clinical and histological presentations are heterogeneous depending on the site of the lesion. There is no consensus regarding the role of surgery and chemotherapy in the therapeutic approach. In our country epidemiology of the disease is unknown with IPSID being the most frequent type. We report anatomo-clinical features and prognostic factors of PGIL and compare intestinal to gastric forms in our region. This is a retrospective study of 153 cases of PGIL in adults diagnosed and treated in the department of medical oncology in Farhat Hached Hospital between 1994 and 2006. The median age was 52 years and the sex-ratio 2.1. Tumor sites were gastric (67%), intestinal (26%) and gastrointestinal (7%). Abdominal pain (87%) followed by vomiting and diarrhoea (37 and 15%) were the most common symptoms. Performance status (PS) < 2 was seen in 80% of patients, high grade lymphoma in 70.5% of cases and B phenotype was noted in 85%. MALT lymphoma accounts for 50% of cases, and IPSID for only 5% of PGIL. About 47.5% of cases were stage IE, 138 patients had chemotherapy with an objective response rate of 77%. Only 46% of patients had surgery (14 for surgical complication, 6 for residual tumor after chemotherapy and 22 to have histological diagnosis). The five-year overall survival (OS) was 62%. In high grade lymphoma patients favorable prognostic factors for OS included young age < or = 60 years, PS < 2, normal serum LDH, hemoglobin > 12 g/dL, B phenotype, localised stage (IE-IIE1), anthracycline-based chemotherapy regimen, achieving complete or partial response to induction chemotherapy and no relapse. In multivariate study only relapse and PS were significant prognostic factors for OS. In low-grade lymphoma patients, none of these factors had a significant correlation with OS: age < or = 60 years, PS < 2, stage (IE-IIE1), response to induction chemotherapy, relapse. Compared to gastric lymphomas, intestinal cases occurred at a younger age, frequently with diarrhoea, weight loss, and occlusion. They are more often high-grade, T phenotype and have locally advanced stage (IIE); surgery is more common in this group. We conclude that stomach is the main site of PGIL in our region, intestinal lymphoma is less frequent and IPSID has become rare. Recent progress in chemotherapy has allowed good therapeutic results with a conservative approach. Surgery may be performed in case of emergency or for residual lesions after medical treatment.

Oral contraceptive progestins and angiotensin-dependent control of the renal circulation in humans.

Oral contraceptive (OC) use is associated with increased intrarenal renin-angiotensin-aldosterone system (RAA System) activity and risk of nephropathy, though the contribution of progestins contained in the OC in the regulation of angiotensin-dependent control of the renal circulation has not been elucidated. A total of 18 OC users (8 non-diabetic, 10 Type 1 diabetic) were studied in high salt balance, a state of maximal RAA System suppression. Progestational and androgenic activity of the progestin in each OC was standardized to that of the reference progestin norethindrone. Renal plasma flow (RPF) was measured by para-aminohippurate clearance at baseline and in response to angiotensin-converting enzyme (ACE) inhibition. There was a positive correlation between OC progestational activity and the RPF response to ACE inhibition (r=0.52, P=0.03). Similar results were noted with OC androgenic activity (r=0.54, P=0.02). On subgroup analysis, only non-diabetic subjects showed an association between progestational activity and angiotensin-dependent control of the renal circulation (r=0.71, P=0.05 non-diabetic; r=0.14, P=0.7 diabetic; P=0.07 between groups). Similar results were noted with respect to androgenic activity (r=0.88, P=0.005 non-diabetic; r=-0.33, P=0.3 diabetic; P=0.002 between groups). Our results suggest that the OC progestin component is a significant influence on the degree of angiotensin-dependent control of the renal circulation, though these findings may not apply to women with diabetes.

Glutathione S-transferases (GSTT1 and GSTM1) gene deletions in Tunisians: susceptibility and prognostic implications in breast carcinoma.

Glutathione S-transferase Theta1 and Mu1 (GSTT1 and GSTM1) are involved in the metabolism and detoxification of a wide range of potential environmental carcinogens. Conversely, they contribute to tumour cell survival by detoxification of numerous products induced by cancer therapy. The authors designed a large study to investigate the susceptibility and prognostic implications of the GSTT1 and GSTM1 gene deletions in breast carcinoma. The authors used the polymerase chain reaction to characterise the variation of the GSTT1 and GSTM1 genes in 309 unrelated Tunisian patients with breast carcinoma and 242 healthy control subjects. Associations of the clinic-pathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival (OVS) and the disease-free survival (DFS) were assessed using univariate and multivariate analyses. A significant association was found between gene deletion of GSTT1 and the risk of early onset of breast carcinoma (OR=1.60, P=0.02). The lack of GSTT1 gene deletion was significantly associated with poor clinical response to chemotherapy (OR=2.29, P=0.03). This association was significantly higher in patients with axillary's lymph node-negative breast carcinoma (OR=12.60, P=0.005). The null-GSTT1 genotype showed a significant association with increased DFS in this selected population of patients. This association was even higher in patients carrying both null-GSTT1 and -GSTM1 genotypes. The gene deletion of GSTs may predict not only the early onset of breast carcinoma but also the clinical response to chemotherapy and the recurrence-free survival for patients with lymph node-negative breast carcinoma.

Comparative role of proteins in transport of HCH-isomers in desert locust, Schistocerca gregaria Forskal and bovines.

The studies on binding of hexachlorocyclohexane (HCH) with carrier proteins were carried out to establish the role of proteins in the transport of insecticides in insects. Sephadex G-200 column chromatography resolved haemolymph of adult male desert locust, Schistocerca gregaria into three major protein peaks. There was significant binding of gamma-HCH with first protein peak (F1). Two classes of binding sites were observed on first protein peak for gamma-HCH. However low level of binding was observed with the third protein peak (F3) of the haemolymph. Bindings of HCH-isomers (alpha, beta and gamma) with bovine serum albumin (BSA) were not related to their water solubilities. Moderate to low affinities (1.4 -1.84 x 10(6) M(-1)) of HCH-isomers for BSA were observed. The present studies showed that more HCH binds to haemolymph lipoprotein of locust as compared to BSA. This indicates a significant role of haemolymph proteins in the transport of insecticides in insects.

Genetic variation in the tumor necrosis factor-alpha promoter region and in the stress protein hsp70-2: susceptibility and prognostic implications in breast carcinoma.

BACKGROUND: Tumor necrosis factor-alpha (TNF-alpha) and stress proteins (heat shock proteins) are determining factors in the immune response to tumor cells. The authors designated a large study to investigate the susceptibility and prognostic implications of the genetic variation in TNF-alpha and hsp70-2 in breast carcinoma. METHODS: The authors used the polymerase chain reaction and restriction enzyme digestion to characterize the variation of the TNF-alpha promoter region and that of the hsp70-2 gene in 243 unrelated Tunisian patients with breast carcinoma and 174 healthy control subjects. Associations of the clinicopathologic parameters and the genetic markers with the rates of the breast carcinoma specific overall survival and the disease free survival (DFS) were assessed using univariate and multivariate analyses. RESULTS: A highly significant association was found between TNF2 homozygous genotype and breast carcinoma (relative risk [RR], 4.44; P = 0.006). A high relative risk of breast carcinoma was found to be associated with one hsp70-2 homozygous genotype (P2/P2; RR, 7.12; P = 0.0001). The TNF2 homozygous genotype showed a significant association with reduced DFS and/or overall survival by univariate test. Conversely, P2-hsp70-2 homozygous genotype associated with increased overall survival but not with DFS. Multivariate analysis retained significance for TNF2 homozygous genotype as an independent prognostic indicator for both DFS (RR, 2.75; P = 0.01) and overall survival (RR, 4.08; P = 0.01). CONCLUSIONS: Genetic variation in TNF-alpha and hsp70-2 may represent not only markers for the increased risk of breast carcinoma but also may predict the clinical outcome.

Polymorphism in the tumor necrosis factor-alpha promotor region and in the heat shock protein 70 genes associated with malignant tumors.

BACKGROUND: Tumor necrosis factors (TNFs) and heat shock protein 70 (hsp70) are determining factors in immunologic mechanisms to tumor cells. The authors designed a case-controlled study to investigate the potential association of the polymorphisms of TNF-alpha and of hsp70-2 and hsp70-hom genes with malignant tumors. METHODS: The authors used an allele specific polymerase chain reaction to characterize the variation of the TNF-alpha promotor region in 124 unrelated Tunisian patients with malignant tumors (non-Hodgkin's lymphoma, breast carcinoma, and other tumors) and 106 healthy control subjects. Using polymerase chain reaction and restriction enzyme digestion, polymorphic analysis of hsp70-2 and hsp70-hom genes was performed in patients with non-Hodgkin's lymphoma, in those with breast carcinoma, and in control subjects. RESULTS: Analysis of TNF-alpha polymorphism in patients with malignant tumors and in control subjects demonstrated a high relative frequency of the TNF2 allele in the cancer patients. The relative risk (RR) of lymphoma was especially high in association with TNF1/TNF2 heterozygotes (RR = 6.7; P < or = 0.0001). Polymorphism analysis of the hsp70-2 and hsp70-hom genes in patients with lymphoma and in those with breast carcinoma revealed that these patients had highly significant differences in the genotypic distribution of these biallelic loci compared with the control subjects. Homozygosity for one hsp70-2 allele was significantly associated with lymphoma (RR = 18.2; P < or = 0.0001) and with breast carcinoma (RR = 16.3; P < or = 0.001). CONCLUSIONS: Tunisian persons carrying the TNF2 allele may have an increased risk of cancer. In this study, non-Hodgkin's lymphoma and breast carcinoma were significantly associated with polymorphism in hsp70 genes.

The effect of ethanol feeding on zinc balance and tissue zinc levels in rats maintained on zinc-deficient diets.

We have studied tissue zinc levels and zinc balance in isocalorically pair-fed weanling rats on ZD liquid diets (0.9 microgram of zinc per milliliter of diet). Tissues were analyzed for zinc levels at weekly intervals while the animals were on the diets. The experimental animals were fed a ZDE diet, whereas sucrose was isocalorically substituted for alcohol in the pair-fed controls. After 1 week on ethanol feeding, the zinc content (microgram/gm wet weight) of the testes of the ethanol-fed rats was significantly lower than of the controls (p less than 0.001). After 2 weeks of ethanol, ethanol-fed animals also showed significantly lower zinc content in liver, hair, spleen, and kidneys (p less than 0.02) than their pair-fed controls. The zinc levels of the experimental animals in all tissues after 3 and 4 weeks of ethanol feeding were significantly lower (p less than 0.001) than that of the pair-fed controls with the exception of bone. Urinary and fecal zinc excretions of the ethanol-fed rats were significantly higher than that of the controls. Cumulative mean +/- S.D. fecal zinc excretions (microgram/28 days) were 1557 +/- 160 among the ethanol-fed animals vs. 730 +/- 150 among controls, p less than 0.01. Ethanol resulted in a mean negative zinc balance of 520 micrograms over 28 days, whereas controls showed a positive cumulative zinc balance of 300 micrograms. Thus ethanol ingestion resulted in negative zinc balance and decreased zinc concentrations of most tissues as compared to pair-fed controls.