Relationship of cyclosporin and sirolimus blood concentrations regarding the incidence and severity of hyperlipidemia after kidney transplantation

The influence of drug concentrations on the development of persistent posttransplant hyperlipidemia was investigated in 82 patients who received cyclosporin A (CsA) and prednisone plus sirolimus (SRL) (52) or azathioprine (AZA) (30) during the first year after transplantation. Blood levels of CsA and SRL, daily doses of AZA and prednisone, and cholesterol, triglyceride, and glucose concentrations were determined during each visit (pretransplant and 30, 60, 90, 120, 180, and 360 days posttransplant). Persistent hyperlipidemia was defined as one-year average steady-state cholesterol (CavCHOL) or triglyceride (CavTG) concentrations above 240 and 200 mg/dL, respectively. Mean cholesterol and triglyceride concentrations increased after transplantation (P < 0.01) and were higher in patients receiving SRL compared to AZA (P < 0.001). Patients receiving SRL showed a significantly higher number of cholesterol (>229 or >274 mg/dL) and triglyceride (>198 or >282 mg/dL) determinations in the upper interquartile ranges. CsA and SRL interquartile ranges correlated with cholesterol concentrations (P = 0.001) whereas only SRL interquartile ranges correlated with triglyceride concentrations (P < 0.0001). Only pretransplant cholesterol concentration >205 mg/dL was independently associated with development of persistent hypercholesterolemia (CavCHOL >240 mg/dL, relative risk (RR) = 20, CI 3.8-104.6, P = 0.0004) whereas pretransplant triglyceride concentration >150 mg/dL (RR = 7.2, CI 1.6-32.4, P = 0.01) or >211 mg/dL (RR = 19.8, CI 3.6-107.9, P = 0.0006) and use of SRL (RR = 3, CI 1.0-8.8, P = 0.0049) were independently associated with development of persistent hypertriglyceridemia (CavTG >200 mg/dL). Persistent hypercholesterolemia was more frequent among patients with higher pretransplant cholesterol concentrations and was dependent on both CsA and SRL concentrations. Persistent hypertriglyceridemia was more frequent among patients with higher pretransplant triglyceride concentrations and was dependent on SRL concentrations.

Activation of neural cholecystokinin-1 receptors induces relaxation of the isolated rat duodenum which is reduced by nitric oxide synthase inhibitors

Cholecystokinin (CCK) influences gastrointestinal motility, by acting on central and peripheral receptors. The aim of the present study was to determine whether CCK has any effect on isolated duodenum longitudinal muscle activity and to characterize the mechanisms involved. Isolated segments of the rat proximal duodenum were mounted for the recording of isometric contractions of longitudinal muscle in the presence of atropine and guanethidine. CCK-8S (EC50: 39; 95% CI: 4.1-152 nM) and cerulein (EC50: 58; 95% CI: 18-281 nM) induced a concentration-dependent and tetrodotoxin-sensitive relaxation. Nomeganitro-L-arginine (L-NOARG) reduced CCK-8S- and cerulein-induced relaxation (IC50: 5.2; 95% CI: 2.5-18 µM) in a concentration-dependent manner. The magnitude of 300 nM CCK-8S-induced relaxation was reduced by 100 µM L-NOARG from 73 ± 5.1 to 19 ± 3.5% in an L-arginine but not D-arginine preventable manner. The CCK-1 receptor antagonists proglumide, lorglumide and devazepide, but not the CCK-2 receptor antagonist L-365,260, antagonized CCK-8S-induced relaxation in a concentration-dependent manner. These findings suggest that CCK-8S and cerulein activate intrinsic nitrergic nerves acting on CCK-1 receptors in order to cause relaxation of the rat duodenum longitudinal muscle.

The decreased oxygen uptake during progressive exercise in ischemia-induced heart failure is due to reduced cardiac output rate

We tested the hypothesis that the inability to increase cardiac output during exercise would explain the decreased rate of oxygen uptake (VO2) in recent onset, ischemia-induced heart failure rats. Nine normal control rats and 6 rats with ischemic heart failure were studied. Myocardial infarction was induced by coronary ligation. VO2 was measured during a ramp protocol test on a treadmill using a metabolic mask. Cardiac output was measured with a flow probe placed around the ascending aorta. Left ventricular end-diastolic pressure was higher in ischemic heart failure rats compared with normal control rats (17 ± 0.4 vs 8 ± 0.8 mmHg, P = 0.0001). Resting cardiac index (CI) tended to be lower in ischemic heart failure rats (P = 0.07). Resting heart rate (HR) and stroke volume index (SVI) did not differ significantly between ischemic heart failure rats and normal control rats. Peak VO2 was lower in ischemic heart failure rats (73.72 ± 7.37 vs 109.02 ± 27.87 mL min-1 kg-1, P = 0.005). The VO2 and CI responses during exercise were significantly lower in ischemic heart failure rats than in normal control rats. The temporal response of SVI, but not of HR, was significantly lower in ischemic heart failure rats than in normal control rats. Peak CI, HR, and SVI were lower in ischemic heart failure rats. The reduction in VO2 response during incremental exercise in an ischemic model of heart failure is due to the decreased cardiac output response, largely caused by depressed stroke volume kinetics.

High incidence of adverse reactions to initial antiretroviral therapy in Brazil

A concurrent prospective study was conducted from 2001 to 2003 to assess factors associated with adverse reactions among individuals initiating antiretroviral therapy at two public referral HIV/AIDS centers in Belo Horizonte, MG, Brazil. Adverse reactions were obtained from medical charts reviewed up to 12 months after the first antiretroviral prescription. Cox proportional hazard model was used to perform univariate and multivariate analyses. Relative hazards (RH) were estimated with 95% confidence intervals (CI). Among 397 charts reviewed, 377 (95.0%) had precise information on adverse reactions and initial antiretroviral treatment. Most patients received triple combination regimens including nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors and protease inhibitors. At least one adverse reaction was recorded on 34.5% (N = 130) of the medical charts (0.17 adverse reactions/100 person-day), while nausea (14.5%) and vomiting (13.1%) were the most common ones. Variables independently associated with adverse reactions were: regimens with nevirapine (RH = 1.78; 95% CI = 1.07-2.96), indinavir or indinavir/ritonavir combinations (RH = 2.05; 95% CI = 1.15-3.64), female patients (RH = 1.93; 95% CI = 1.31-2.83), 5 or more outpatient visits (RH = 1.94; 95% CI = 1.25-3.01), non-adherence to antiretroviral therapy (RH = 2.38; 95% CI = 1.62-3.51), and a CD4+ count of 200 to 500 cells/mm³ (RH = 2.66; 95% CI = 1.19-5.90). An independent and negative association was also found for alcohol use (RH = 0.55; 95% CI = 0.33-0.90). Adverse reactions were substantial among participants initiating antiretroviral therapy. Specially elaborated protocols in HIV/AIDS referral centers may improve the diagnosis, management and prevention of adverse reactions, thus contributing to improving adherence to antiretroviral therapy among HIV-infected patients.

Wood biochemicals for the protection of health. Focus on hemicellulose, stilbenoids and lignans

Trees produce an enormous amount of compounds that are still scantly utilized.However, the results obtained from structurally similar biochemicals suggest that wood-derived compounds could be used for the protection of health in various applications. Polyphenols, for instance, could be extracted from wood in high quantities. Similar polyphenols to those in wood include resveratrol, found in grapes, and secoisolariciresinol, present in flaxseeds. Their consumption has been inversely associated with the incidence of various diseases, especially certain cancers and obesity-related disorders. The aim of this study was to determine the health-promoting effects of woodderived biochemicals. The effect of spruce hemicellulose on the growth of probiotic intestinal bacteria was studied. The results suggest that the bifidobacteria and lactobacilli can utilize hemicellulose and thus it has potential as a prebiotic compound. In particular, the efficacy of pine polyphenols to inhibit the growth of prostate cancer was our main interest. It was found that stilbenoids and lignans inhibited the proliferation of various cancer cells, and reduced the growth of prostate cancer xenografts in mice. The polyphenol rich pine knot extract was well tolerated in diet and extract-derived polyphenols were rapidly absorbed after intake. Furthermore, we determined the effect of the dietary pine knot extract on the weight gain and the expression of aromatase gene in reporter mouse expressing the promoter region of a human aromatase gene. It was found that dietary pine knot extract alleviated the obesity-induced inflammation in adipose tissue and downregulated the expression of a human aromatase gene. Taken together, several components of spruce and pine may have a future role as health-promoting compounds.

An extract of Polygonum multiflorum protects against free radical damage induced by ultraviolet B irradiation of the skin

Over the last decades, the incidence of ultraviolet B (UVB)-related skin problems has been increasing. Damages induced by UVB radiation are related to mutations that occur as a result of direct DNA damage and/or the production of reactive oxygen species. We investigated the anti-oxidant effects of a Polygonum multiflorum thumb extract against skin damage induced by UVB irradiation. Female SKH-1 hairless mice were divided into three groups: control (N = 7), distilled water- (N = 10), and P. multiflorum extract-treated (PM, N = 10) groups. The PM (10 g) was extracted with 100 mL distilled water, cryo-dried and 9.8 g was obtained. The animals received a topical application of 500 µL distilled water or PM extract (1, 2, 4, 8, and 16%, w/v, dissolved in distilled water) for 30 min after UVB irradiation (wavelength 280-320 nm, 300 mJ/cm²; 3 min) of the dorsal kin for 14 days, and skin immunohistochemistry and Cu,Zn-superoxide dismutase (SOD1) activity were determined. SOD1 immunoreactivity, its protein levels and activities in the skin were significantly reduced by 70% in the distilled water-treated group after UVB irradiation compared to control. However, in the PM extract-treated groups, SOD1 immunoreactivity and its protein and activity levels increased in a dose-dependent manner (1-16%, w/v, PM extract) compared to the distilled water-treated group. SOD1 protein levels and activities in the groups treated with 8 and 16%, w/v, PM extract recovered to 80-90% of the control group levels after UVB. These results suggest that PM extract strongly inhibits the destruction of SOD1 by UV radiation and probably contains anti-skin photoaging agents.

Incidence of heart failure in infarcted rats that die spontaneously

The present study reports for the first time the incidence of congestive heart failure (CHF) in previously infarcted rats that died spontaneously. Previously, pulmonary (PWC) and hepatic (HWC) water contents were determined in normal rats: 14 control animals were evaluated immediately after sacrifice, 8 placed in a refrigerator for 24 h, and 10 left at room temperature for 24 h. In the infarcted group, 9 rats died before (acute) and 28 died 48 h after (chronic) myocardial infarction. Thirteen chronic animals were submitted only to autopsy (N = 13), whereas PWC and HWC were also determined in the others (N = 15). Seven rats survived 48 h and died during anesthesia. Notably, PWC differed in normal rats: ambient (75.7 ± 1.3%) < control (77.5 ± 0.7%) < refrigerator (79.1 ± 1.4%) and there were no differences with respect to HWC. No clinical signs of CHF (dyspnea, lethargy or foot edema) were observed in infarcted rats before death. PWC was elevated in all chronic and anesthetized rats. HWC was increased in 48% of chronic and in all anesthetized rats. Our data showed that PWC needs to be evaluated before 24 h post mortem and that CHF is the rule in chronic infarcted rats suffering natural death. The congestive syndrome cannot be diagnosed correctly in rats by clinical signs alone, as previously proposed.

Incidence, risk factors and prognostic factors of acute renal failure in patients admitted to an intensive care unit

The objective of the present study was to assess the incidence, risk factors and outcome of patients who develop acute renal failure (ARF) in intensive care units. In this prospective observational study, 221 patients with a 48-h minimum stay, 18-year-old minimum age and absence of overt acute or chronic renal failure were included. Exclusion criteria were organ donors and renal transplantation patients. ARF was defined as a creatinine level above 1.5 mg/dL. Statistics were performed using Pearsons' chi2 test, Student t-test, and Wilcoxon test. Multivariate analysis was run using all variables with P < 0.1 in the univariate analysis. ARF developed in 19.0% of the patients, with 76.19% resulting in death. Main risk factors (univariate analysis) were: higher intra-operative hydration and bleeding, higher death risk by APACHE II score, logist organ dysfunction system on the first day, mechanical ventilation, shock due to systemic inflammatory response syndrome (SIRS)/sepsis, noradrenaline use, and plasma creatinine and urea levels on admission. Heart rate on admission (OR = 1.023 (1.002-1.044)), male gender (OR = 4.275 (1.340-13642)), shock due to SIRS/sepsis (OR = 8.590 (2.710-27.229)), higher intra-operative hydration (OR = 1.002 (1.000-1004)), and plasma urea on admission (OR = 1.012 (0.980-1044)) remained significant (multivariate analysis). The mortality risk factors (univariate analysis) were shock due to SIRS/sepsis, mechanical ventilation, blood stream infection, potassium and bicarbonate levels. Only potassium levels remained significant (P = 0.037). In conclusion, ARF has a high incidence, morbidity and mortality when it occurs in intensive care unit. There is a very close association with hemodynamic status and multiple organ dysfunction.

Noninvasive prognostic markers for cardiac death and ventricular arrhythmia in long-term follow-up of subjects with chronic Chagas' disease

The objective of the present study was to investigate clinical, echocardiographic and electrocardiographic (12-lead resting ECG, 24-h ambulatory ECG monitoring and signal-averaged ECG (SAECG)) parameters in subjects with chronic Chagas' disease in a long-term follow-up as prognostic markers for adverse outcomes. Fifty adult outpatients (34 to 74 years old, 31 females) staged according to Los Andes class I, II or III and complaining of palpitation were enrolled in a longitudinal study. SAECG was analyzed in time and frequency domains and the endpoint was a composite of cardiac death and ventricular tachycardia. During a follow-up of 84.2 ± 39.0 months, 34.0% of the patients developed adverse outcomes (9 cardiac deaths and 11 episodes of ventricular tachycardia). After optimal dichotomization, in a stepwise multivariate Cox-hazard regression model, apical aneurysm (HR = 3.7; 95% CI = 1.2-1.3; P = 0.02), left ventricular ejection fraction <62% (HR = 4.60; 95% CI = 1.39-15.24; P = 0.01) and incidence of ventricular premature contractions >614 per 24 h (hazard ratio = 6.1; 95% CI = 1.7-22.6; P = 0.006) were independent predictors of the composite endpoint. Although a high frequency content in SAECG demonstrated association with the presence of left ventricular dysfunction and myocardial fibrosis, its predictive value for the composite endpoint was not significant. Apical aneurysms, reduced left ventricular function and a high incidence of ventricular ectopic beats over a 24-h period have a strong predictive value for a composite endpoint of cardiac death and ventricular tachycardia in subjects with chronic Chagas' disease.

p53 immunostaining is correlated with reduced survival and is not correlated with gene mutations in resected pulmonary large cell carcinomas

Malignancy of pulmonary large cell carcinomas (LCC) increases from classic LCC through LCC with neuroendocrine morphology (LCCNM) to large cell neuroendocrine carcinomas (LCNEC). However, the histological classification has sometimes proved to be difficult. Because the malignancy of LCC is highly dependent on proteins with functions in the cell cycle, DNA repair, and apoptosis, p53 has been targeted as a potentially useful biological marker. p53 mutations in lung cancers have been shown to result in expression and protein expression also occurs in the absence of mutations. To validate the importance of both p53 protein expression (by immunostaining) and p53 gene mutations in lung LCC (by PCR-single strand conformational polymorphism analysis of exons 5, 6, 7, and 8) and to study their relationships with clinical factors and sub-classification we investigated the correlation of p53 abnormalities in 15 patients with LCC (5 classic LCC, 5 LCNEC, and 5 LCCNM) who had undergone resection with curative intent. Of these patients, 5/15 expressed p53 and none had mutant p53 sequences. There was a negative survival correlation with positive p53 immunostaining (P = 0.05). After adjustment for stage, age, gender, chemotherapy, radiotherapy, and histological subtypes by multivariate analysis, p53 expression had an independent impact on survival. The present study indicates that p53 assessment may provide an objective marker for the prognosis of LCC irrespective of morphological variants and suggests that p53 expression is important for outcome prediction in patients with the early stages of LCC. The results reported here should be considered to be initial results because tumors from only 15 patients were studied: 5 each from LCC, LCNEC and LCCNM. This was due to the rarity of these specific diseases.

Effect of 30 mCi radioiodine on multinodular goiter previously treated with recombinant human thyroid-stimulating hormone

Recombinant human thyroid-stimulating hormone (rhTSH) enhances 131I uptake, permitting a decrease in radiation for the treatment of multinodular goiter (MNG). Our objective was to evaluate the safety and efficacy of a single 0.1-mg dose of rhTSH, followed by 30 mCi 131I, in patients with MNG. Seventeen patients (15 females, 59.0 ± 13.1 years), who had never been submitted to 131I therapy, received a single 0.1-mg injection of rhTSH followed by 30 mCi 131I on the next day. Mean basal thyroid volume measured by computed tomography was 106.1 ± 64.4 mL. 131I 24-h uptake, TSH, free-T4, T3, thyroglobulin, anti-thyroid antibodies, and thyroid volume were evaluated at regular intervals of 12 months. Mean 131I 24-h uptake increased from 18.1 ± 9.7 to 49.6 ± 13.4% (P < 0.001), a median 2.6-fold increase (1.2 to 9.2). Peak hormonal levels were 10.86 ± 5.44 mU/L for TSH (a median 15.5-fold increase), 1.80 ± 0.48 ng/dL for free-T4, 204.61 ± 58.37 ng/dL for T3, and a median of 557.0 ng/mL for thyroglobulin. The adverse effects observed were hyperthyroidism (17.6%), painful thyroiditis (29.4%) and hypothyroidism (52.9%). Thyroid volume was reduced by 34.3 ± 14.3% after 6 months (P < 0.001) and by 46.0 ± 14.6% after 1 year (P < 0.001). Treatment of MNG with a single 0.1-mg dose of rhTSH, followed by a fixed amount of radioactivity of 131I, leads to an efficacious decrease in thyroid volume for the majority of the patients, with a moderate incidence of non-serious and readily treatable adverse effects.

Reduced plasma levels of angiotensin-(1-7) and renin activity in preeclamptic patients are associated with the angiotensin I- converting enzyme deletion/deletion genotype

The relationship between preeclampsia and the renin-angiotensin system (RAS) is poorly understood. Angiotensin I-converting enzyme (ACE) is a key RAS component and plays an important role in blood pressure homeostasis by generating angiotensin II (Ang II) and inactivating the vasodilator angiotensin-(1-7) (Ang-(1-7)). ACE (I/D) polymorphism is characterized by the insertion (I) or deletion (D) of a 287-bp fragment, leading to changes in ACE activity. In the present study, ACE (I/D) polymorphism was correlated with plasma Ang-(1-7) levels and several RAS components in both preeclamptic (N = 20) and normotensive pregnant women (N = 20). The percentage of the ACE DD genotype (60%) in the preeclamptic group was higher than that for the control group (35%); however, this percentage was not statistically significant (Fisher exact test = 2.86, d.f. = 2, P = 0.260). The highest plasma ACE activity was observed in the ACE DD preeclamptic women (58.1 ± 5.06 vs 27.6 ± 3.25 nmol Hip-His Leu-1 min-1 mL-1 in DD control patients; P = 0.0005). Plasma renin activity was markedly reduced in preeclampsia (0.81 ± 0.2 vs 3.43 ± 0.8 ng Ang I mL plasma-1 h-1 in DD normotensive patients; P = 0.0012). A reduced plasma level of Ang-(1-7) was also observed in preeclamptic women (15.6 ± 1.3 vs 22.7 ± 2.5 pg/mL in the DD control group; P = 0.0146). In contrast, plasma Ang II levels were unchanged in preeclamptic patients. The selective changes in the RAS described in the present study suggest that the ACE DD genotype may be used as a marker for susceptibility to preeclampsia.

Reduced folate carrier 1 (RFC1) is associated with cleft of the lip only

In this report, we have reanalyzed genotyping data in a collection of families from South America based on maternal origin. Genotyping analysis was performed at the Craniofacial Anomalies Research Center at the University of Iowa. These genotypes were derived from genomic DNA samples obtained from blood spots from children born with isolated orofacial clefts in 45 hospitals located in eight countries (Argentina, Bolivia, Brazil, Chile, Ecuador, Paraguay, Uruguay, and Venezuela) collaborating with ECLAMC (Latin American Collaborative Studies of Congenital Malformations) between January 1998 and December 1999. Dried blood samples were sent by regular mail to the Laboratory of Congenital Malformations, Federal University of Rio de Janeiro. Previous findings suggested that mitochondrial haplotype D is more commonly found among cleft cases born in South America. We hypothesized that association of certain genes may depend upon the ethnic origin, as defined by population-specific markers. Therefore, we tested if markers in MTHFR (5,10-methylenetetrahydrofolate reductase) and RFC1 (reduced folate carrier 1) were associated with oral clefts, depending on the maternal origin defined by the mitochondrial haplotype. Transmission distortion of alleles in MTHFR C677T and RFC1 G80A polymorphic variants was tested in 200 mother/affected child pairs taking into consideration maternal origin. RFC1 variation was over-transmitted to children born with cleft lip only (P = 0.017) carrying mitochondrial DNA haplotypes other than haplotype D. Our results provide a new indication that variation in RFC1 may contribute to cleft lip only. Future studies should investigate the association between oral clefts and RFC1 based on more discrete phenotypes.

Reduced cortical renal GLUT1 expression induced by angiotensin-converting enzyme inhibition in diabetic spontaneously hypertensive rats

Diabetes in spontaneously hypertensive rats is associated with cortical renal GLUT1 and GLUT2 overexpression. Our objective was to evaluate the effect of the angiotensin-converting enzyme blockade on cortical renal GLUT1 and GLUT2 expression, urinary albumin and urinary TGF-β1. Streptozotocin, 50 mg/kg, or citrate buffer (N = 16) was administered as a single injection into the tail vein in adult spontaneously hypertensive rats (~260 g). Thirty days later, these diabetic spontaneously hypertensive rats received ramipril by gavage: 0.01 mg·kg-1·day-1 (D0.01, N = 14), 1 mg·kg-1·day-1 (D1, N = 9) or water (D, N = 11) for 15 days. Albumin and TGF-β1 (24-h urine), direct arterial pressure, renal tissue angiotensin-converting enzyme activity (fluorometric assay), and GLUT1 and GLUT2 protein levels (Western blot, renal cortex) were determined. Glycemia and glycosuria were higher (P < 0.05) in the diabetic rats compared with controls, but similar between the diabetic groups. Diabetes in spontaneously hypertensive rats lowered renal tissue angiotensin-converting enzyme activity (40%), which was reduced further when higher ramipril doses were used. Diabetes associated with hypertension raised GLUT1 by 28% (P < 0.0001) and GLUT2 by 76% (P = 0.01), and both doses of ramipril equally reduced cortical GLUT1 (D vs D1 and vs D0.01, P ≤ 0.001). GLUT2 levels were reduced in D0.01 (P < 0.05 vs D). Diabetes increased urinary albumin and TGF-β1 urinary excretion, but the 15-day ramipril treatment (with either dose) did not reduce them. In conclusion, ramipril is effective in lowering renal tissue angiotensin-converting enzyme activity, as well as blocking cortical GLUT1 overexpression, which may be beneficial in arresting the development of diabetic nephropathy.