Effects of gender and age on hypothalamic-pituitary-adrenal reactivity after pharmacological challenge with low-dose 1-µg ACTH test: a prospective study in healthy adults.

OBJECTIVE: Τhe aim of this study was to observe cortisol responses to a pharmacological challenge with 1 µg ACTH as a function of age and gender. PATIENTS: Twenty-one young (13 women and 8 men; mean age: 43∙48 ± 10∙52 years) and forty elderly (20 women and 20 men; mean age: 79 ± 6∙76 years) volunteers without overt acute or chronic disease participated in this study. MEASUREMENTS: Basal serum cortisol levels were measured, and cortisol values were obtained at 30 and 60 min after administration of 1 µg ACTH. Free thyroxine, triiodothyronine, thyrotrophin, prolactin, dehydroepiandrosterone sulphate (DHEAS), insulin-like growth factor-1, follicle stimulating hormone, luteinizing hormone, oestradiol levels in women and total testosterone levels in men were also measured at baseline. RESULTS: No differences were observed between the groups of older and younger individuals in baseline plasma cortisol levels and mean cortisol responses at 30 and 60 min postchallenge. In the elderly subjects, statistically lower cortisol responses were observed in men at 30 and 60 min after 1-µg ACTH challenge (540∙17 ± 112∙28 vs 670∙11 ± 146∙49 nmol/l in women, P = 0∙003 at 30 min, and 482∙24 ± 108∙14 vs 568∙04 ± 135∙73 nmol/l in women, P = 0∙03 at 60 min). Furthermore, significant lower values in PRL, IGF-1, DHEAS and T3 were detected in older subjects when compared to the younger age group. Interestingly, a higher incidence of individuals who did not achieve normal responses to 1-µg ACTH test (>497 nmol/l) was noted in the group of elderly male subjects. CONCLUSION: This study documents a marked gender effect in the elderly, in the cortisol response levels to 1-µg ACTH stimulation. Elderly men demonstrate a decreased responsiveness compared to women in the same age range.

The acute effect of cigarette smoking on the respiratory function and FENO production among young smokers.

INTRODUCTION: Smoking is known to have a long-term impact on lung function; however, the acute physiological response of smoking a single cigarette and the influential role of pack years and cigarettes per day on pulmonary indices remains an area of interest, especially among young smokers. METHODS: 50 naive smokers (ages: 18-26, 24 males: mean pack years 3.8) participated in this experimental study. Respiratory resistance (R), reactance (X), and impedance (Z) were assessed through impulse oscillometry. The participants' fraction of exhaled nitric oxide (FENO) was measured. All tests were performed immediately before and after smoking one single cigarette. RESULTS: Smoking a single cigarette was found to immediately increase airway impedance (Z 5 Hz) by 0.024 kPa/(L/s) (P = .002), airway resistance at R 5 Hz, R 10 Hz, and R 20 Hz by 0.024 kPa/(L/s)(P < .001), 0.016 kPa/(L/s)(P = .019), and 0.023 kPa/(L/s) (P = .007), respectively, after adjusting for BMI, age, gender, and pack years. FENO concentrations also decreased from 11.70 ppb to 9.85 ppb, P < .001. Sensitivity analyses indicated that the participants' number of pack years and cigarettes per day influenced pulmonary reactance at 10 Hz and 20 Hz, however only at baseline with these differences found to disappear immediately after smoking. CONCLUSIONS: The present study indicates that the consumption of a single cigarette may alter lung mechanics and FENO production among young smokers. Further research is needed to assess the mechanisms and washout period after which these parameters return to normal.

Extracellular matrix-associated (GAGs, CTGF), angiogenic (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in type 1 diabetes mellitus nephropathy.

BACKGROUND: The aim of the present study was to evaluate the role of extracellular matrix-associated glycosaminoglycans (GAGs), connective tissue growth factor (CTGF), angiogenic vascular endothelial growth factor (VEGF) and inflammatory factors (MCP-1, CD40, IFN-γ) in the development of diabetic nephropathy in type 1 diabetes (T1DM). METHODS: Plasma and urine samples from 30 T1DM patients and 20 healthy controls were used to measure the levels of CTGF, VEGF, MCP-1, CD40 and IFN-γ by ELISA. Plasma and urine GAGs were measured using a spectrophotometric method. RESULTS: Plasma levels of GAGs, CD40 and MCP-1 and urine levels of GAGs and CTGF were significantly elevated in normoalbuminuric T1DM patients. A tendency to higher plasma VEGF levels was found in patients compared to controls. The urine/plasma GAGs ratio of T1DM patients was almost similar to that of healthy subjects (HS), whereas the urine/plasma CTGF ratio was about three times greater in diabetic patients compared to HS. CONCLUSIONS: Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria.

Design and study protocol of the maternal smoking cessation during pregnancy study, (M-SCOPE).

BACKGROUND: Maternal smoking is the most significant cause of preventable complications during pregnancy, with smoking cessation during pregnancy shown to increase birth weight and reduce preterm birth among pregnant women who quit smoking. Taking into account the fact that the number of women who smoke in Greece has increased steadily throughout the previous decade and that the prevalence of smoking among Greek females is one of the highest in the world, smoking cessation should be a top priority among Greek health care professionals. METHODS/DESIGN: The Maternal Smoking Cessation during Pregnancy Study (M-SCOPE), is a Randomized Control Trial (RCT) that aims to test whether offering Greek pregnant smokers a high intensity intervention increases smoking cessation during the third trimester of pregnancy, when compared to a low intensity intervention. Prospective participants will be pregnant smokers of more than 5 cigarettes per week, recruited up to the second trimester of pregnancy. Urine samples for biomarker analysis of cotinine will be collected at three time points: at baseline, at around the 32nd week of gestation and at six months post partum. The control group/low intensity intervention will include: brief advice for 5 minutes and a short leaflet, while the experimental group/intensive intervention will include: 30 minutes of individualized cognitive-behavioural intervention provided by a trained health professional and a self-help manual especially tailored for smoking cessation during pregnancy, while counselling will be based on the ''5 As.'' After childbirth, the infants' birth weight, gestational age and any other health related complications during pregnancy will be recorded. A six months post-partum a follow up will be performed in order to re-assess the quitters smoking status. DISCUSSION: If offering pregnant smokers a high intensity intervention for smoking cessation increases the rate of smoking cessation in comparison to a usual care low intensity intervention in Greek pregnant smokers, such a scheme if beneficial could be implemented successfully within clinical practice in Greece. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01210118.

Dose-related shortening of ventricular tachycardia cycle length after administration of the KATP channel opener bimakalim in a 4-day-old chronic infarct anesthetized pig model.

Potassium channel openers are known to act on potassium ATP-dependent channels in cardiac tissue. Such agents may exacerbate acceleration of acute ischemia-induced ventricular repolarization and aggravate arrhythmias. To test whether activation of K( ATP) channels during the healing period of myocardial infarction (MI) can still influence the electrophysiologic properties and the type of inducible arrhythmias, we investigated the effects of bimakalim (BIM) on sustained ventricular tachycardia (VT) 4 days after ligation of the left anterior descending (LAD) coronary artery in pigs. Programmed stimulation was performed to elicit VT prior to and after intravenous (IV) BIM. Combination monophasic action potential (MAP)/PACING catheters were used to enable simultaneous ventricular MAP recording and pacing. Ventricular effective refractory period (ERP) and MAP duration determined at 50% and 90% repolarization were measured prior to and after BIM. After completion of baseline measurements, BIM was consecutively given at 0.5, 1, and 3 mg/kg bolus followed by 0.025, 0.05, and 0.1 mg/kg per minute maintenance infusion, respectively. From a total of 23 pigs subjected to LAD ligation, 4 animals succumbed to infarction and the remaining 19 animals were studied by programmed stimulation. Only animals that exhibited reproducible and hemodynamically stable monomorphic VTs during control stimulation were selected for evaluation (n = 14). After the first, second, and third dose of BIM, the mean VT rate was increased by 6%, 14% (P <. 01), and 47% (P < .001) compared to control values, respectively. Ventricular ERP and repolarization were significantly shortened only by the second and third dose of BIM. Of 14 pigs receiving the highest BIM dosage, 3 revealed polymorphic VTs degenerating into ventricular fibrillation (VF). Our data suggest that high BIM doses may lead to faster and more aggressive pacing-induced reentrant VTs after subacute MI. This is consistent with the drug-induced acceleration of ventricular repolarization with shortening of MAP duration and refractoriness.

Assessment of local atrial repolarization in a porcine acetylcholine model of atrial flutter and fibrillation.

OBJECTIVES: Progressive electrical alternans followed by conduction block and fibrillatory conduction have been suggested to precede disorganization of atrial flutter (Afl) to atrial fibrillation (AF). The purpose of the present study was to investigate patterns of local repolarization in the high and low right atrium to determine the site with pronounced propensity to action potential disorganization during Afl and AF. METHODS: Combination pacing/recording contact monophasic action potential (MAP) catheters were utilized to evaluate repolarization from the upper and low atrial endocardium in 16 pigs. To induce sustained atrial flutter (Afl) or fibrillation (AF), programmed atrial stimulation was carried out prior to and during intravenous acetylcholine (ACh) infusion at a dosage rate of 2.7 mg/min. Atrial repolarization was measured at 30, 50, and 90% of total MAP duration. RESULTS: Two main types of atrial MAPs were distinguished: MAPs originated from high atrial regions showing a prominent notch and longer duration and MAPs recorded from the lower atrium displaying a much slower slope of phase I repolarization and shorter duration. Control stimulation did not elicit any significant atrial tachyarrhythmias. After ACh all animals developed reproducibly induced sustained and non-sustained whole Afl or AF during programmed stimulation. A total of 40 sustained arrhythmia episodes were selected for evaluation: fourteen episodes of primary AF and 26 episodes of Afl. Whole Afl and AF in all animals were associated with MAPs of almost regular morphology in lower parts of atrium and disorganized activation in higher atrial regions. ACh significantly reduced (P < 0.001) both high and low atrial effective refractory periods as well as MAP duration determined at 30, 50, and 90% repolarization. CONCLUSIONS: ACh facilitated the induction of Afl more than AF in this experimental model. MAPs recorded from high atrial regions revealed discordant repolarization during Afl or AF, whereas low atrial MAPs maintained their baseline regular morphology. These findings may help expand knowledge about mechanisms underlying instability and perpetuation of these arrhythmias.

The Role and Predictive Value of Cytokines in Atherosclerosis and Coronary Artery Disease.

Atherosclerosis is currently regarded as a chronic inflammatory disease that is mediated by several types of cells and molecules. Emphasis has been placed on the role of cytokines and the way they act and interact to initiate and sustain inflammation in the microenvironment of an atherosclerotic plaque. Cytokines are invariably expressed by all cells involved in the pathogenesis of atherosclerosis, act on a variety of targets exerting multiple effects and are largely responsible for the crosstalk among endothelial, smooth muscle cells, leukocytes and other vascular residing cells. In the present paper our aim is to review current information on the role of the most commonly discussed cytokines in the process of atherogenesis and to discuss the prognostic significance of these cytokines in atherosclerosis and coronary artery disease.

Expression of clock genes in patients with colorectal cancer.

Recent studies have demonstrated the influence of clock genes in cell cycle regulation, cell proliferation, apoptosis and DNA damage recognition and repair. There is evidence suggesting the implication of clock genes in colorectal cancer (CRC) development and progression. The aim of this study is to evaluate the expression levels of clock genes in CRC and correlate them with patients' prognosis. Forty-two CRC samples (from 24 males and 18 females), their paired noncancerous tissues and 8 biopsies from healthy individuals were included. Quantitative real-time PCR was used to examine the expression levels of CLOCK1, BMAL1, PER1, PER2 and PER3 genes in all the samples. In the cancerous tissues CLOCK1 (p<0.0001) and BMAL1 (p<0.0001) expression levels were higher, while PER1 (p<0.0024) and PER3 (p<0.0001) expression levels were lower compared to matched healthy tissues. No difference was observed in the expression levels of PER2 (p=0.99). No correlation was found between clock gene expression and patients' clinicopathological characteristics or prognosis. The results suggest abnormal expression of CLOCK1, BMAL1, PER1 and PER3 genes in CRC but no correlation with patients' prognosis.

The antioxidant effect of angiotensin II receptor blocker, losartan, in streptozotocin-induced diabetic rats.

We determined the effect of a short-term angiotensin II signaling blockade on vascular endothelial growth factor (VEGF), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide (NO), and malondialdehyde (MDA) (index of lipid peroxidation) levels in the systemic circulation and on peroxynitrite generation and insulitis development in the streptozotocin (STZ) diabetic rats' pancreas. Diabetes was induced in Wistar rats by intraperitoneal STZ injection. Diabetic rats were treated for 1 week with losartan (20 mg/kg/body weight/day in the drinking water), and pancreas and blood were collected for histochemical, immunohistochemical, and biochemical studies. Diabetic rats showed greater VEGF, sICAM-1, NO, and MDA levels, a high score of insulitis, increased nitrotyrosine staining, and markedly reduced pancreatic insulin content when compared with controls. Losartan treatment suppressed the excessive NO and lipid peroxidation production systemically without restoring them to that of healthy subjects and reduced VEGF levels while leaving sICAM-1 levels unchanged. The insulitis score and nitrotyrosine staining were reduced, whereas the pancreatic islets and the beta-cell area were increased significantly in the treated group, indicating the reduction of inflammation and nitrosative stress and an early regeneration of beta-cell mass in the pancreas. Conclusively, in the STZ diabetic rat model, even a short-term losartan treatment improves oxidative and nitrosative stress systemically and locally, improving the islets' environment and accelerating beta-cell regeneration.