Gliotoxin causes apoptosis and necrosis of rat Kupffer cells in vitro and in vivo in the absence of oxidative stress: exacerbation by caspase and serine protease inhibition

BACKGROUND/AIMS: A potential application of gliotoxin therapy for liver fibrosis was suggested by its apoptotic effect on fibrogenic activated stellate cells. We investigated if gliotoxin exerts similar effects on hepatic macrophage Kupffer cells. METHODS: Effects of gliotoxin on Kupffer cells isolated from the normal liver and in vivo following its administration to CCl(4)-induced cirrhotic rats were studied. RESULTS: Gliotoxin caused apoptosis of cultured Kupffer cells, the effect being apparent at 0.3 microM concentration within 1h; longer incubation caused necrosis. This effect was associated with mitochondrial cytochrome c release, caspase-3 activation and ATP depletion. Interestingly, inhibition of caspase-3 and serine proteases accelerated and augmented gliotoxin-induced cell death via necrosis. Gliotoxin stimulated nuclear translocation of NFkappaB, and phosphorylation of p38, ERK1/2 and JNK MAP kinases, but these signaling molecules were not involved in gliotoxin-induced death of Kupffer cells. In vivo administration of gliotoxin to cirrhotic rats caused apoptosis of Kupffer cells, stellate cells and hepatocytes. In control rats, the effect was minimal on the nonparenchymal cells and not apparent on hepatocytes. CONCLUSIONS: In the fibrotic liver, gliotoxin nonspecifically causes death of hepatic cell types. Modification of gliotoxin molecule may be necessary for selective targeting and elimination of activated stellate cells.     

Genetic variations associated with echocardiographic left ventricular traits in hypertensive blacks

Echocardiographic measures of cardiac target organ damage, including left ventricular mass and relative wall thickness, are powerful predictors of heart disease morbidity and mortality. The aim of this study is to investigate whether single nucleotide polymorphisms in candidate genes for hypertension and heart disease have effects on quantitative measures of hypertensive cardiac target organ damage, independent of their actions on blood pressure levels, in a cohort of hypertensive black sibships. To detect replication of genetic effects across samples, this study took advantage of the affected sibling pair design and created 2 samples, each with 448 unrelated individuals. As part of the Genetic Epidemiology Network of Arteriopathy Study, subjects were screened using 2D echocardiography, and 395 single nucleotide polymorphisms in 80 candidate genes were genotyped. Linear regression was used to test for single nucleotide polymorphisms significantly associated with left ventricular mass index (g/m(2.7)) or relative wall thickness after adjusting for associated covariates. Significant single nucleotide polymorphisms were subsequently tested for consistent directionality in genotype-phenotype relationships across samples. Three single nucleotide polymorphisms, 1 each in the APOE, SCN7A, and SLC20A1 genes, were significantly associated in both samples with left ventricular mass index and had replicate genotype-phenotype relationships. One in the ADRB1 gene was significantly associated with relative wall thickness with replicate effects in both samples. We identified genetic variation that significantly influences left ventricular traits with replicable effects in a cohort of hypertensive, black siblings.     

Clinical implications of residual growth hormone (GH) response to provocative testing in adults with severe GH deficiency

CONTEXT: The diagnosis of GH deficiency (GHD) in adults is based on provocative tests of GH release, all influenced by clinical factors. It is unknown whether the amount of residual GH reserve under the cutoff value has any physiological implication. OBJECTIVES: We used a large pharmacoepidemiological database of adult GHD (KIMS) and tested the impact of confounding factors on GH release of no greater than 3 microg/liter after an insulin tolerance test (ITT) and evaluated its potential physiological role. DESIGN, SETTINGS, AND PATIENTS: A total of 1098 patients fulfilled the criteria of having a GH peak of no greater than 3 microg/liter during ITT as well as documented IGF-I levels. OUTCOMES: The impact of underlying hypothalamic-pituitary disease, age, gender, body weight, as well as treatment modalities such as irradiation on peak GH level to ITT was evaluated, and the correlations between GH peak and targets of GH action were analyzed. RESULTS: The GH response to ITT was regulated by gender, age, and the number of additional pituitary deficiencies. In a multivariate evaluation, the extent of hypothalamic-pituitary dysfunction was the most important single predictor of GH peak in ITT. GH peaks in ITT were positively related to IGF-I levels and high-density lipoprotein-cholesterol, as well as inversely to triglycerides. CONCLUSIONS: Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.     

Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls

CONTEXT: Peripubertal obesity is associated with abnormal sex steroid concentrations, but the timing of onset and degree of these abnormalities remain unclear. OBJECTIVE: The objective of the study was to assess the degree of hyperandrogenemia across puberty in obese girls and assess overnight sex steroid changes in Tanner stage 1-3 girls. DESIGN: This was a cross-sectional analysis. SETTING: The study was conducted at general clinical research centers. SUBJECTS: Thirty normal-weight (body mass index for age < 85%) and 74 obese (body mass index for age >or= 95%) peripubertal girls. INTERVENTION: Blood samples (circa 0500-0700 h) were taken while fasting. Samples from the preceding evening (circa 2300 h) were obtained in 23 Tanner 1-3 girls. MAIN OUTCOME MEASURES: Hormone concentrations stratified by Tanner stage were measured. RESULTS: Compared with normal-weight girls, mean free testosterone (T) was elevated 2- to 9-fold across puberty in obese girls, whereas fasting insulin was 3-fold elevated in obese Tanner 1-3 girls (P < 0.05). Mean LH was lower in obese Tanner 1 and 2 girls (P < 0.05) but not in more mature girls. In a subgroup of normal-weight Tanner 1-3 girls (n = 17), mean progesterone (P) and T increased overnight 2.3- and 2.4-fold, respectively (P 相似文献   

Effects of testosterone and nandrolone on cardiac function: a randomized, placebo-controlled study

BACKGROUND: Androgens have striking effects on skeletal muscle, but the effects on human cardiac muscle function are not well defined, neither has the role of metabolic activation (aromatization, 5alpha reduction) of testosterone on cardiac muscle been directly studied. OBJECTIVE: To assess the effects of testosterone and nandrolone, a non-amplifiable and non-aromatizable pure androgen, on cardiac muscle function in healthy young men. DESIGN: Double-blind, randomized, placebo-controlled, three-arm parallel group clinical trial. SETTING: Ambulatory care research centre. PARTICIPANTS: Healthy young men randomized into three groups of 10 men. INTERVENTION: Weekly intramuscular injections of testosterone (200 mg mixed esters), nandrolone (200 mg nandrolone decanoate) or matching (2 ml arachis oil vehicle) placebo for 4 weeks. MAIN OUTCOME MEASURES: Comprehensive measures of cardiac muscle function involving transthoracic cardiac echocardiography measuring myocardial tissue velocity, peak systolic strain and strain rates, and bioimpedance measurement of cardiac output and systematic vascular resistance. RESULTS: Left ventricular (LV) function (LV ejection fraction, LV modified TEI index), right ventricular (RV) function (ejection area, tricuspid annular systolic planar motion, RV modified TEI index) as well as cardiac afterload (mean arterial pressure, systemic vascular resistance) and overall cardiac contractility (stroke volume, cardiac output) were within age- and gender-specific reference ranges and were not significantly (P < 0.05) altered by either androgen or placebo over 4 weeks of treatment. Minor changes remaining within normal range were observed solely within the testosterone group for: increased LV end-systolic diameter (30 +/- 7 vs. 33 +/- 5 mm, P = 0.04) and RV end-systolic area (12.8 +/- 1.3 vs. 14.6 +/- 3.3 cm(2), P = 0.04), reduced LV diastolic septal velocity (Em, 9.5 +/- 2.6 vs. 8.7 +/- 2.0 cm/s, P = 0.006), increased LV filling pressure (E/Em ratio, 7.1 +/- 1.6 vs. 8.3 +/- 1.8, P = 0.02) and shortened PR interval on the electrocardiogram (167 +/- 13 vs. 154 +/- 12, P = 0.03). CONCLUSION: Four weeks of treatment with testosterone or nandrolone had no beneficial or adverse effects compared with placebo on cardiac function in healthy young men.     

Unique lipid a modifications in Pseudomonas aeruginosa isolated from the airways of patients with cystic fibrosis

Three structural features of lipid A (addition of palmitate [C16 fatty acid], addition of aminoarabinose [positively charged amino sugar residue], and retention of 3-hydroxydecanoate [3-OH C10 fatty acid]) were determined for Pseudomonas aeruginosa isolates from patients with cystic fibrosis (CF; n=86), from the environment (n=13), and from patients with other conditions (n=14). Among P. aeruginosa CF isolates, 100% had lipid A with palmitate, 24.6% with aminoarabinose, and 33.3% retained 3-hydroxydecanoate. None of the isolates from the environment or from patients with other conditions displayed these modifications. These results indicate that unique lipid A modifications occur in clinical P. aeruginosa CF isolates.     

Cutaneous human papillomaviruses found in sun-exposed skin: Beta-papillomavirus species 2 predominates in squamous cell carcinoma

BACKGROUND: A spectrum of cutaneous human papillomaviruses (HPVs) is detectable in nonmelanoma skin cancers, as well as in healthy skin, but the significance that the presence of these types of HPV DNA has for the pathogenesis of skin cancer remains unclear. METHODS: We studied 349 nonimmunosuppressed patients with skin lesions (82 with squamous cell carcinomas, 126 with basal cell carcinomas, 49 with actinic keratoses, and 92 with benign lesions). After superficial skin had been removed by tape, paired biopsy samples--from the lesion and from healthy skin from the same patient--were tested for HPV DNA. Risk factors for HPV DNA were analyzed in multivariate models. RESULTS: Overall, 12% of healthy skin samples were positive for HPV DNA, compared with 26% of benign lesions, 22% of actinic keratoses, 18% of basal cell carcinomas, and 26% of squamous cell carcinomas. HPV DNA was associated with sites extensively exposed to the sun, both for the lesions (odds ratio [OR], 4.45 [95% confidence interval {CI}, 2.44-8.11]) and for the healthy skin samples (OR, 3.65 [95% CI 1.79-7.44]). HPV types of Beta-papillomavirus species 2 predominate in squamous cell carcinomas (OR, 4.40 [95% CI, 1.92-10.06]), whereas HPV types of Beta-papillomavirus species 1 are primarily found in benign lesions (OR, 3.47 [95% CI, 1.72-6.99]). CONCLUSIONS: Cutaneous HPV types are primarily detected at sites extensively exposed to the sun. HPV types of Beta-papillomavirus species 2, but not of species 1, are associated with squamous cell carcinoma.     

Subclinical self-harm: range of behaviors, extent, and associated characteristics

This study examined characteristics associated with mildly injurious (fingernail biting, skin picking, etc.) and more injurious (cutting, burning, etc.) self-harm (SH) in an undergraduate sample (N = 280); 31% reported mildly injurious SH within the past 3 years with no more injurious SH, whereas 20% reported more injurious SH within the past 3 years. SH was not associated with significant general negative affect or history of physical or sexual abuse, although more injurious SH was associated with a history of emotional abuse. A portion of both groups reported negative affect regarding their histories of SH. Both types of SH were associated with other impulsive and disordered eating behaviors, some obsessive-compulsive characteristics, and more somatic symptoms. Similarities and differences with clinical SH are discussed, as well as implications for further research and treatment. Arguments for and against a continuum view of self-harm, as ranging from mild to severe in injuriousness or clinical significance, are also discussed.