Urinary cyclic AMP and vasopressin excretion in rat strains selected for their alcohol intake

Urinary excretion of adenosine 3′,5′-cyclic monophosphate (cAMP) and immunoreactive arginine vasopressin (AVP) were investigated after water loading and following ethanol loading in two rat strains selected for their voluntary ethanol intake. After ethanol loading ethanol preferring (AA) rats excreted more cAMP but less AVP than water preferring (ANA) rats. The results suggest that the strain difference in cAMP excretion is of renal origin and is not due to vasopressin or parathormone. Differences in the sympathetic nervous activity may be responsible for the difference in cAMP excretion.     

Retinyl acetate effects on the life span and the incidence of cryptogenic Neoplasms in C3H mice

The effect of feeding 0.02 % retinyl acetate on the development of cryptogenic neoplasms and the life span of C3H/HeJ (⁺) mice of both sexes was studied. The survival at 105 weeks was 58% in untreated males and 28% in untreated females vs. 39% in treated males and 14% in treated females. The average weight in treated groups was also 10–15% lower. The incidence (percent) of neoplasm‐bearing animals and total neoplasms was 87% and 57, respectively, in female controls vs. 93 % and 55 in treated females. In male controls, these values were 57% and 39 compared with 50% and38 in treated males. In treated animals, there was no reduction in the most common neoplasms, that is, neoplasms of the mammary gland and liver. The numbers of ovarian neoplasms and lung adenomas were slightly lower. Therefore, retinyl acetate exerted, at best, only a slight inhibitory effect on development of some types of cryptogenic neoplasms in mice.     

Synthesis and maturation of type I and type III collagens in endometrial adenocarcinoma

OBJECTIVE: The structure and distribution of type I and type III collagens in the extracellular matrix of malignant endometrium was evaluated for their roles in the development and progression of this neoplasm. STUDY DESIGN: Collagen synthesis and deposition in endometrial adenocarcinomas was determined by immunohistochemical analysis of type I and type III procollagen and verified by computer-assisted morphometry and in situ hybridization. RESULTS: In the stroma of well-differentiated adenocarcinomas increased intracellular collagen synthesis was observed in fibroblastic cells as well as increased extracellular formation of newly synthesized type I and type III procollagen. Collagen maturation was also rapid. In moderately differentiated tumors, destruction and dissolution occurred around invading islets, concomitantly with decreased deposits of both collagens, despite increases in corresponding mRNAs. In poorly differentiated neoplasms, solid epithelial islets coexisted with sparse and distinctly collagen-positive stroma. Poorly differentiated neoplasms also contained tumor cells exhibiting intracellular collagen staining as well as in situ hybridization signals. In highly malignant papillary adenocarcinomas, the tumor cells induced distinctly increased collagen synthesis and deposition of newly synthesized collagen but not the mature cross-linked protein. CONCLUSIONS: In malignancy, compression of surrounding stroma and a fibroproliferative response with increased collagen synthesis and deposition may prevent tumor growth. In more advanced lesions, stromal dissolution may permit tumor spread and in highly malignant lesions an abnormal stroma may promote neoplasm progression.     

Tumor promotion by foreign bodies (IUD)

Commercial intrauterine devices (IUDs) were cut into small fragments and implanted subcutaneously and intraperitoneally in mice initiated with 7,12-dimethylbenzanthracene (DMBA). The mice given intraperitoneal IUDs developed significantly more tumors in a shorter time than mice without the IUD. It is suggested that foreign bodies such as the IUD can promote tumors, even at a distance by a humoral mechanism such as autoantibody.     

Raised Endothelin Content in Bronchoalveolar Lavage Fluid During Lung Allograft Rejection in Pigs

Abstract

Objectives. Freedom Solo is a stentless biological aortic valve which is implanted supra-annularly with a single suture line. An increased risk of postoperative thrombocytopenia in the early postoperative period has been reported in recent studies. In our study we evaluated postoperative haemodynamic performance and thrombocyte-levels. Design. Thirty seven patients who underwent valve implantation of the Sorin Freedom Solo stentless valve were included. The haemodynamic performance of the valve was evaluated by transthoracic echocardiography postoperatively at the fourth day (mean) and after a median of 4.2 months. Results. The mean gradient (mmHg) of Freedom Solo was 7.5 at four days and 8.6 at 4.2 months. Postoperatively no patient had more than grade 1 leakage. Seven percent of the patients had a reduction of thrombocytes to less than 20% of the preoperative level. Seventy six percent had a minimum postoperative thrombocyte level less than 100*10⁹/L. The 30 days mortality in our patient material was zero. Conclusions. Implantation of the Freedom Solo valve was uncomplicated in our experience. Favourable transvalvular gradients and no significant leaks were found. In accordance with the literature, we found a high percentage of patients having a postoperative level of thrombocytes less than 100*10⁹/L after implantation of Freedom Solo.     

High‐density lipoprotein from end‐stage renal disease patients exhibits superior cardioprotection and increase in sphingosine‐1‐phosphate

Background

Chronic kidney disease (CKD) exacerbates the risk of death due to cardiovascular disease (CVD). Modifications to blood lipid metabolism which manifest as increases in circulating triglycerides and reductions in high‐density lipoprotein (HDL) cholesterol are thought to contribute to increased risk. In CKD patients, higher HDL cholesterol levels were not associated with reduced mortality risk. Recent research has revealed numerous mechanisms by which HDL could favourably influence CVD risk. In this study, we compared plasma levels of sphingosine‐1‐phosphate (S1P), HDL‐associated S1P (HDL‐S1P) and HDL‐mediated protection against oxidative stress between CKD and control patients.

Methods

High‐density lipoprotein was individually isolated from 20 CKD patients and 20 controls. Plasma S1P, apolipoprotein M (apoM) concentrations, HDL‐S1P content and the capacity of HDL to protect cardiomyocytes against doxorubicin‐induced oxidative stress in vitro were measured.

Results

Chronic kidney disease patients showed a typical profile with significant reductions in plasma HDL cholesterol and albumin and an increase in triglycerides and pro‐inflammatory cytokines (TNF‐alpha and IL‐6). Unexpectedly, HDL‐S1P content (P = .001) and HDL cardioprotective capacity (P = .034) were increased significantly in CKD patients. Linear regression analysis of which factors could influence HDL‐S1P content showed an independent, negative and positive association with plasma albumin and apoM levels, respectively.

Discussion

The novel and unexpected observation in this study is that uremic HDL is more effective than control HDL for protecting cardiomyocytes against oxidative stress. It is explained by its higher S1P content which we previously demonstrated to be the determinant of HDL‐mediated cardioprotective capacity. Interestingly, lower concentrations of albumin in CKD are associated with higher HDL‐S1P.     

Reduction in albuminuria translates to reduction in cardiovascular events in hypertensive patients: losartan intervention for endpoint reduction in hypertension study

Few data are available to clarify whether changes in albuminuria over time translate to changes in cardiovascular risk. The aim of the present study was to examine whether changes in albuminuria during 4.8 years of antihypertensive treatment were related to changes in risk in 8206 patients with hypertension and left ventricular hypertrophy in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study. Urinary albumin/creatinine ratio (UACR) was measured at baseline and annually. Time-varying albuminuria was closely related to risk for the primary composite end point (ie, when UACR decreased during treatment, risk was reduced accordingly). When the population was divided according to median baseline value (1.21 mg/mmol) and median year 1 UACR (0.67 mg/mmol), risk increased stepwise and significantly for the primary composite end point from those with low baseline/low year 1 (5.5%), to low baseline/high year 1 (8.6%), to high baseline/low year 1 (9.4%), and to high baseline/high year 1 (13.5%) values. Similar significant, stepwise increases in risk were seen for the components of the primary composite end point (cardiovascular mortality, stroke, and myocardial infarction). The observation that changes in UACR during antihypertensive treatment over time translated to changes in risk for cardiovascular morbidity and mortality was not explained by in-treatment level of blood pressure. We propose that monitoring of albuminuria should be an integrated part of the management of hypertension. If albuminuria is not decreased by the patient's current antihypertensive and other treatment, further intervention directed toward blood pressure control and other modifiable risks should be considered.     

Cardiovascular morbidity and mortality in hypertensive patients with lower versus higher risk: a LIFE substudy

We hypothesized that losartan was superior to atenolol in reducing cardiovascular events in a lower-risk group (LRG) versus a higher-risk group (HRG) of patients in a Losartan Intervention For Endpoint reduction (LIFE) substudy, independently of blood pressure (BP) reduction. In a post hoc analysis, we designated 4282 patients as LRG on the basis of: (1) no previous cardiovascular disease (coronary, cerebral, peripheral vascular disease); (2) no diabetes; (3) no isolated systolic hypertension; and (4) inclusion of the lowest 3 quartiles of electrocardiographically documented left ventricular hypertrophy. The HRG consisted of 4911 remaining patients who did not qualify for the LRG. In the LRG, losartan was superior to atenolol in reducing stroke: hazard ratio (HR), 0.72 (95% confidence interval [CI], 0.53 to 0.98); new-onset diabetes (HR, 0.74 [95% CI, 0.58 to 0.93]; and new-onset atrial fibrillation: HR, 0.69 (95% CI, 0.51 to 0.92), all P<0.05 but not composite end points or cardiovascular mortality (both P=NS). In the HRG, losartan was superior to atenolol in reducing composite end points: HR, 0.82 (95% CI, 0.71 to 0.94), P<0.01; cardiovascular mortality: HR, 0.77 (95% CI, 0.62 to 0.95), P<0.05; stroke: HR, 0.75 (95% CI, 0.61 to 0.92), P<0.01; new-onset diabetes: HR, 0.76 (95% CI, 0.60 to 0.96), P<0.05; and new-onset atrial fibrillation: HR, 0.71 (95% CI, 0.58 to 88), P<0.05. Test for interaction of treatment with LRG versus HRG was not significant for composite end point, stroke, or atrial fibrillation, but was for cardiovascular mortality (P=0.018). Achieved systolic BP reduction favored losartan over atenolol by -1.8 mm Hg in LRG (P=NS) and -0.7 mm Hg (P=0.001) in HRG, but no significant differences occurred in diastolic or mean BP in either group. In conclusion, losartan compared with atenolol reduces the risk of stroke, new-onset diabetes, and new-onset atrial fibrillation in the LRG and the HRG.     

Losartan benefits over atenolol in non-smoking hypertensive patients with left ventricular hypertrophy: the LIFE study

We studied the impact of smoking in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, which showed superiority of losartan over atenolol for reduction of composite risk of cardiovascular death, stroke and myocardial infarction in hypertensives with left ventricular hypertrophy. We compared hazard ratios in 4656 never-smokers, and 3033 previous and 1499 current smokers, adjusting for gender, age, alcohol intake, exercise and race. Composite endpoint rate was higher in previous (28/1000 years), as well as current (39/1000 years) smokers than in never-smokers (21/1000 years). Composite (hazard ratio 0.78, 95% CI 0.65-0.94, p < 0.01) and stroke (hazard ratio 0.61, 95% CI 0.47-0.80], p < 0.001) risks were lower with losartan than atenolol in never-smokers, but not significantly in previous smokers. Drug regimens did not differ in current smokers (composite hazard ratio 0.99, stroke hazard ratio 0.94). Smoking-treatment interactions were non-significant, but a borderline significant trend (p = 0.05) suggested decreasing benefit of losartan vs atenolol for stroke prevention from never- to previous to current smoking status. Smoking increased cardiovascular risk markedly in the LIFE study. The benefit of losartan vs atenolol is consistent with the overall conclusion of the LIFE study, although the treatment effect appeared largest in non-smokers.     

Sodium load increases renal angiotensin type 1 receptors and decreases bradykinin type 2 receptors.

The regulation of both angiotensin receptors and bradykinin receptors during sodium intake is poorly understood. We hypothesized that an altered balance between renal angiotensin type 1 (AT1) receptors and bradykinin type 2 (B2) receptors might contribute to an increase in blood pressure during periods of high-sodium intake. We studied the effects of high-sodium intake on renal AT1 receptors and B2 receptors in 5-6-week-old spontaneously hypertensive rats (SHR) receiving high-sodium chloride (6% NaCl) or mineral salts (10.5%, composition: 57% NaCl, 28% KCl, 12% MgSO4) compared to those receiving a low-sodium (NaCl 0.125%) diet for 10 weeks. Mineral salt intake was included due to its beneficial effects on blood pressure and cardiac hypertrophy. Receptor densities were measured by quantitative autoradiography. AT1 receptors were quantified using incubation with 125I-Sar1-Ile8-angiotensin II and displacement was measured with PD123319 (10 micromol/l), whereas B2 receptors were quantified using 125I-HPP-icatibant and displacement was measured with icatibant (3 micromol/l). Compared to the SHR controls, a further increase in blood pressure occurred after 2 weeks in the 6% NaCl group and after 6 weeks in the mineral salt group. AT1 receptor density increased in the renal cortex by 41% (p<0.01) in the 6% NaCl group and by 26% (p<0.05) in the mineral salt group. B2 receptor density decreased in the renal medulla by 26% (p<0.01) in the 6% NaCl group, and decreased even more i.e., by 45% (p<0.001), in the mineral salt group. It was shown that a 6% NaCl or a 10.5% mineral salt loading was capable of increasing renal AT1 receptor density and decreasing renal B2 receptor density. An altered balance between these receptors might be associated with hypertension under conditions of sodium loading.