School success in childhood and subsequent prodromal symptoms and psychoses in the Northern Finland Birth Cohort 1986.

BACKGROUND: Low IQ is a risk factor for psychosis, but the effect of high IQ is more controversial. The aim was to explore the association of childhood school success with prodromal symptoms in adolescence and psychoses in adulthood. METHODS: In the general population-based Northern Finland Birth Cohort 1986 (n = 8 229), we studied the relationship between teacher-assessed learning deficits, special talents and general school success at age 8 years and both prodromal symptoms (PROD-screen) at age 15-16 years and the occurrence of psychoses by age 30 years. RESULTS: More prodromal symptoms were experienced by those talented in oral presentation [boys: adjusted odds ratio (OR) 1.49; 95% confidence interval 1.14-1.96; girls: 1.23; 1.00-1.52] or drawing (boys: 1.44; 1.10-1.87). Conversely, being talented in athletics decreased the probability of psychotic-like symptoms (boys: OR 0.72; 0.58-0.90). School success below average predicted less prodromal symptoms with boys (OR 0.68; 0.48-0.97), whereas above-average success predicted more prodromal symptoms with girls (OR 1.22; 1.03-1.44). The occurrence of psychoses was not affected. Learning deficits did not associate with prodromal symptoms or psychoses. CONCLUSIONS: Learning deficits in childhood did not increase the risk of prodromal symptoms in adolescence or later psychosis in this large birth cohort. Learning deficits are not always associated with increased risk of psychosis, which might be due to, e.g. special support given in schools. The higher prevalence of prodromal symptoms in talented children may reflect a different kind of relationship of school success with prodromal symptoms compared to full psychoses.

Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease.

AIMS/HYPOTHESIS: Plasminogen activator inhibitor-1 (PAI-1, also known as serpin peptidase inhibitor, clade E [nexin, plasminogen activator inhibitor type 1], member 1 [SERPINE1]) plays a pathogenetic role in renal fibrosis. It is upregulated in experimental and human diabetic nephropathy. These studies assessed the effect of PAI-1 deficiency and overproduction on renal disease in experimental diabetes. MATERIALS AND METHODS: Diabetes was induced by injection of streptozotocin in 6-week-old PAI-1-deficient mice, transgenic mice overexpressing Pai-1 and control mice. Animals were killed after 24 weeks of diabetes or after observation alone. RESULTS: Pai-1 mRNA was upregulated in kidneys from genetically normal mice with diabetes and in non-diabetic Pai-1 transgenic mice. PAI-1 was not further increased in kidneys from Pai-1 transgenic mice with diabetes. Diabetes-associated albuminuria and glomerular injury, as well as renal alpha-smooth muscle actin production, were ameliorated in diabetic PAI-1-deficient mice, an amelioration associated with attenuated increases in renal matrix metallopeptidase-2 expression and activity. Diabetic Pai-1 transgenic mice did not develop increased albuminuria or glomerular injury, but the tubulointerstitial area was modestly enhanced. In addition to the findings in diabetic mice, abnormalities also developed in 30-week-old PAI-1-deficient and Pai-1 transgenic mice without diabetes. PAI-1 deficiency resulted in increased tubulointerstitial area, TGFB1 protein and alpha-smooth muscle actin. Non-diabetic 30-week-old Pai-1 transgenic mice developed similar renal abnormalities and increased matrix metallopeptidase-2 activity, together with a modest increase in serum glucose and HbA(1c). CONCLUSIONS/INTERPRETATION: These results demonstrate that endogenous PAI-1 deficiency protects mice from glomerular injury in longer term diabetes and that endogenous PAI-1 maintains normal renal interstitial structure in ageing not associated with diabetes.

Interaction of cyclosporine A and the renin-angiotensin system; new perspectives.

Despite extensive research, the exact mechanisms of cyclosporine A (CsA)-induced hypertension and nephrotoxicity remain obscure. Several lines of evidence suggest an involvement of the renin-angiotensin system (RAS) in CsA toxicity, but the issue is still controversial in more ways than one. Some interesting data of the interaction of CsA and RAS have been presented by us and others during the last years. In rats, activation of RAS by CsA is a consistent finding while the results from clinical studies show controversial results. The mechanisms of activation of RAS may be multifactorial. CsA increases renin release directly from juxtaglomerular cells. However, RAS activation may at least partly account for glomerular ischemia by vasoconstriction. A totally different view about the interaction of CsA and RAS has recently been presented. CsA antagonised the harmful effects of RAS over-expression on renal damage in double transgenic rats harbouring human renin and angiotensinogen genes. The protection was due to anti-inflammatory properties of CsA by inhibition of interleukin-6 and inducible nitric oxide synthase (iNOS) expression. Other studies have confirmed the inhibitory effect of CsA on iNOS. Calcium antagonists have been proposed to be the antihypertensive drugs of choice in treatment of CsA-induced hypertension because of their favourable haemodynamic effects on the kidneys. However, because angiotensin II plays a major role in the development of CsA-induced structural renal damage, pharmacological inhibition of RAS in CsA-treatment may have some beneficial effects beyond blood pressure control.

Cyclosporine induces myocardial connective tissue growth factor in spontaneously hypertensive rats on high-sodium diet.

BACKGROUND: The introduction of cyclosporine (CsA) has led to an improvement in the prognosis of solid organ transplantation. However, drug-induced hypertension and nephrotoxicity, associated with the development of atherosclerosis and coronary heart disease, still worsen the long-term outcome of CsA-treated patients. Whether the CsA-induced myocardial changes are associated with the induction of connective tissue growth factor (CTGF), a recently found polypeptide implicated in extracellular matrix synthesis, is not known. METHODS: Spontaneously hypertensive rats (8-9 weeks old) were treated with CsA (5 mg x kg(-1) x d(-1) subcutaneously) for 6 weeks. The influence of angiotensin-converting enzyme inhibition (enalapril 30 mg x kg(-1) x d(-1) orally) and angiotensin-1 receptor blockade (valsartan 3 and 30 mg x kg(-1) x d(-1) orally) on CsA toxicity was also investigated. Myocardial morphology was examined, and vascular lesions were scored. Localization and the quantitative expression of CTGF, as well as collagen I and collagen III, mRNA were evaluated by in situ hybridization and Northern blot. RESULTS: CsA-induced hypertension and nephrotoxicity were associated with myocardial infarcts and vasculopathy of the coronary arteries. CsA increased myocardial CTGF, collagen I, and collagen III mRNA expressions by 91%, 198%, and 151%, respectively. CTGF mRNA expression colocalized with the myocardial lesions. Blockade of the renin-angiotensin system prevented vascular damage and the CsA-induced CTGF, collagen I, and collagen III mRNA overexpressions in the heart. CONCLUSIONS: CsA increases CTGF, collagen I, and collagen III mRNA expressions in the heart. The induction of CTGF gene is mediated, at least in part, by angiotensin II.

Vascular changes in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.

Functional and morphological changes of blood vessels in cyclosporine A (CsA)-induced hypertension and nephrotoxicity were studied in spontaneously hypertensive rats (SHR). The role of the L-arginine-nitric oxide (NO) pathway and the importance of oxidative stress in CsA toxicity were also assessed. SHR (7-8 week old) on a high-sodium diet were treated with CsA (5 mg kg(-1) d(-1) s.c.) for 6 weeks. A proportion of the rats were treated concomitantly with the NO precursor L-arginine (1.7 g kg(-1)d(-1) p.o.). CsA elevated blood pressure and caused renal dysfunction and morphological nephrotoxicity. CsA also impaired mesenteric and renal arterial function and caused structural damage to intrarenal and extrarenal small arteries and arterioles. Medial atrophy of the mesenteric resistance vessels and decreased viability of smooth muscle cells of the thoracic aorta were observed. Renal and arterial damage was associated with the presence of inflammatory cells. CsA did not affect markers of the L-arginine-NO pathway (urinary cyclic GMP excretion or endothelial or inducible NO synthase expression in kidney, aorta or heart) or oxidative stress (urinary excretion of 8-isoprostaglandin F2alpha, plasma urate concentration or total radical trapping capacity). Concomitant L-arginine treatment did not affect CsA-induced changes in blood pressure or histological findings but tended to alleviate the arterial dysfunction. The renal and cardiovascular toxicity of CsA was associated with arterial dysfunction and morphological changes in small arteries and arterioles in SHR on a high-sodium diet. The findings did not support the role of oxidative stress or a defect in the L-arginine-NO pathway.

Comparison of enalapril and valsartan in cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on high-sodium diet.

1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.

Enalapril and valsartan improve cyclosporine A-induced vascular dysfunction in spontaneously hypertensive rats.

Cyclosporine A causes hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). In the present study, arterial function was investigated using in vitro vascular preparations after long-term treatment with cyclosporine A. SHR received cyclosporine A (5 mg kg(-1) day(-1) s.c.) and high-Na(+) diet for 6 weeks during the developmental phase of hypertension. Part of the rats were treated concomitantly either with the angiotensin converting enzyme inhibitor enalapril (30 mg kg(-1) day(-1) p.o.) or with an angiotensin AT(1) receptor antagonist valsartan (3 or 30 mg kg(-1) day(-1) p.o.). In renal arteries, contractile responses to noradrenaline and angiotensin II, as well as relaxation responses to acetylcholine (endothelium-dependent) and to sodium nitroprusside (endothelium-independent), were severely impaired by cyclosporine A-treatment. There was also a trend for the dysfunction of the mesenteric arteries, but the impairment did not reach statistical difference. Enalapril and valsartan improved the impaired renal arterial functions. Cyclosporine A-induced hypertension and nephrotoxicity seem to be associated with renal arterial dysfunction in SHR on high-Na(+) diet. Antagonism of the renin-angiotensin system protects from vascular toxicity of cyclosporine A.

Effects of ACE inhibition on cyclosporine A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats on a high-sodium diet.

Cyclosporine A (CsA)-induced hypertension has been shown to be dependent on the level of dietary salt. The present study assessed the role of the renin-angiotensin system in the development of CsA-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR) on a high-sodium diet. In addition, we examined whether ACE inhibition prevents the detrimental effects of CsA on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. Eight-week-old SHR were divided into three different groups (n = 8 in each group): (i) SHR control group receiving a high-sodium diet (Na 2.6% of the dry weight of the chow), (ii) CsA group (5 mg/kg s.c.) on a high-sodium diet and (iii) CsA + enalapril group (30 mg/kg p.o.) on a high-sodium diet. At the end of the six-week experimental period, systolic blood pressure in the CsA group was significantly higher compared to the control group (245+/-6 vs 208+/-9 mmHg, respectively, p < 0.05). Plasma renin activity was increased 20-fold by CsA treatment (p < 0.05 compared to controls). CsA increased serum creatinine by 22%, the 24-h urinary protein excretion by 190% and the 24-h urinary excretions of calcium, phosphorus and magnesium by 150%, 25% and 140%, respectively (p < 0.05 compared to controls). Histologically, the kidneys of CsA-treated SHR showed severe thickening of the media of the afferent arteriole and fibrinoid necrosis of the arteriolar wall. Interestingly, CsA induced vascular injury also in the small myocardial arteries. Enalapril treatment prevented CsA-induced hypertension and deterioration of kidney function as well as CsA-induced vascular injuries in the kidneys and myocardium. Enalapril also decreased left ventricular weight-to body weight ratio and prevented CsA-induced increases in urinary calcium and phosphorus excretions. Our findings indicate that CsA has a detrimental effect on blood pressure, kidney function and vascular morphology in SHR on high sodium intake. ACE inhibition prevents the CsA-induced hypertension, nephrotoxicity and vascular injuries. Our findings thus suggest that increased activity of the renin-angiotensin system is involved in the pathogenesis of CsA-induced hypertension and nephrotoxicity in SHR on a high-sodium diet.