Early short-term versus prolonged low-dose methylprednisolone therapy in acute lung injury

The present study compared the effects of early short-term with prolonged low-dose corticosteroid therapy in acute lung injury (ALI). In total, 120 BALB/c mice were randomly divided into five groups. In the control group, saline was intratracheally (i.t.) instilled. In the ALI group, mice received Escherichia coli lipopolysaccharide (10 mu g i.t.). ALI animals were further randomised into four subgroups to receive saline (0.1 mL i.v.) or methylprednisolone (2 mg center dot kg(-1) i.v.) at 6 h, 24 h or daily (for 7 days, beginning at day 1). At 1, 3 and 8 weeks, in vivo and in vitro lung mechanics and histology (light and electron microscopy), collagen and elastic fibre content, cytokines in bronchoalveolar lavage fluid and the expression of matrix metalloproteinase (MMP)-9 and -2 were measured. In vivo (static elastance and viscoelastic pressure) and in vitro (tissue elastance and resistance) lung mechanics, alveolar collapse, cell infiltration, collagen and elastic fibre content and the expression of MMP-9 and MMP-2 were increased in ALI at 1 week. Methylprednisolone led to a complete resolution of lung mechanics, avoided fibroelastogenesis and the increase in the expression of MMP-9 and MMP-2 independent of steroid treatment design. Thus, early short-term, low-dose methylprednisolone is as effective as prolonged therapy in acute lung injury.

Preoperative respiratory muscle dysfunction is a predictor of prolonged invasive mechanical ventilation in cardiorespiratory complications after heart valve surgery

Objective: To verify whether preoperative respiratory muscle strength and ventilometric parameters, among other clinically relevant factors, are associated with the need for prolonged invasive mechanical ventilation (PIMV) due to cardiorespiratory complications following heart valve surgery. Methods: Demographics, preoperative ventilometric and manometric data, and the hospital course of 171 patients, who had undergone heart valve surgery at Hospital das Clinicas da Faculdade de Medicina de Ribeirao Preto, were prospectively collected and subjected to univariate analysis for identifying the risk factors for PIMV. Results: The hospital mortality was 7%. About 6% of the patients, who had undergone heart valve surgery required PIMV because of postoperative cardiorespiratory dysfunction. Their hospital mortality was 60% (vs 4%, p < 0.001). Univariate analysis revealed that preoperative respiratory muscle dysfunction, characterized by maximal inspiratory and expiratory pressure below 70% of the predicted values combined with respiratory rate above 15 rpm during ventilometry, was associated with postoperative PIMV (p = 0.030, odds ratio: 50, 95% confidence interval (CI): 1.2-18). Postoperative PIMV was also associated with: (1) body mass index (BMI) < 18.5 (odds ratio: 7.2, 95% CI: 1.5-32), (2) body weight < 50 kg (odds ratio: 6.5, 95% CI: 1.6-25), (3) valve operation due to acute endocarditis (odds ratio: 5.5, 95% CI: 0.98-30), and (4) concomitant operation for mitral and tricuspid valve dysfunction (p = 0.047, odds ratio: 5.0, 95% CI: 1.1-22). Conclusion: Our results have demonstrated that respiratory muscle dysfunction, among other clinical factors, is associated with the need for PIMV due to cardiovascular or pulmonary dysfunction after heart valve surgery. (C) 2010 European Association for Cardio-Thoracic Surgery. Published by Elsevier B. V. All rights reserved.

Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge

Leptin resistance and desensitization of hypophagia during prolonged inflammatory challenge. Am J Physiol Endocrinol Metab 300: E858-E869, 2011. First published February 22, 2011; doi: 10.1152/ajpendo.00558.2010.-Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.

Escitalopram prolonged fear induced by simulated public speaking and released hypothalamic-pituitary-adrenal axis activation

Simulated public speaking (SPS) test is sensitive to drugs that interfere with serotonin-mediated neurotransmission and is supposed to recruit neural systems involved in panic disorder. The study was aimed at evaluating the effects of escitalopram, the most selective serotonin-selective reuptake inhibitor available, in SPS. Healthy males received, in a double-blind, randomized design, placebo (n = 12), 10 (n = 17) or 20 (n = 14) mg of escitalopram 2 hours before the test. Behavioural, autonomic and neuroendocrine measures were assessed. Both doses of escitalopram did not produce any effect before or during the speech but prolonged the fear induced by SPS. The test itself did not significantly change cortisol and prolactin levels but under the higher dose of escitalopram, cortisol and prolactin increased immediately after SPS. This fear-enhancing effect of escitalopram agrees with previously reported results with less selective serotonin reuptake inhibitors and the receptor antagonist ritanserin, indicating that serotonin inhibits the fear of speaking in public.

Obesity due to Melanocortin 4 Receptor (MC4R) Deficiency Is Associated with Increased Linear Growth and Final Height, Fasting Hyperinsulinemia, and Incompletely Suppressed Growth Hormone Secretion

Context: Melanocortin receptor 4 (MC4R) deficiency is characterized by increased linear growth greater than expected for the degree of obesity. Objective: The objective of the investigation was to study the somatotroph axis in obese MC4R-deficient patients and equally obese controls. Patients and Methods: We obtained anthropometric measurements and insulin concentrations in 153 MC4R-deficient subjects and 1392 controls matched for age and severity of obesity. We measured fasting IGF-I, IGF-II, IGF binding protein (IGFBP)-1, IGFBP-3, and acid-labile subunit levels in a subset of 33 MC4R-deficient patients and 36 control subjects. We examined pulsatile GH secretion in six adult MC4R-deficient subjects and six obese controls. Results: Height so score was significantly greater in MC4R-deficient children under 5 yr of age compared with controls (mean +/- SEM: 2.3 +/- 0.06 vs. 1.8 +/- 0.04, P < 0.001), an effect that persisted throughout childhood. Final height (cm) was greater in MC4R-deficient men (mean +/- SEM 173 +/- 2.5 vs. 168 +/- 2.1, P < 0.001) and women (mean 165 +/- 2.1 vs. 158 +/- 1.9, P < 0.001). Fasting IGF-I, IGF-II, acid-labile subunit, and IGFBP-3 concentrations were similar in the two groups. GH levels were markedly suppressed in obese controls, but pulsatile GH secretion was retained in MC4R deficiency. The mean maximal GH secretion rate per burst (P < 0.05) and mass per burst (P < 0.05) were increased in MC4R deficiency, consistent with increased pulsatile and total GH secretion. Fasting insulin levels were markedly elevated in MC4R-deficient children. Conclusions: In MC4R deficiency, increased linear growth in childhood leads to increased adult final height, greater than predicted by obesity alone. GH pulsatility is maintained in MC4R deficiency, a finding consistent with animal studies, suggesting a role for MC4R in controlling hypothalamic somatostatinergic tone. Fasting insulin levels are significantly higher in children carrying MC4R mutations. Both of these factors may contribute to the accelerated growth phenotype characteristic of MC4R deficiency. (J Clin Endocrinol Metab 96: E181-E188, 2011)

The effect of temperature and fasting period on the viability of free-living females of Rhipicephalus sanguineus (Acari : Ixodidae) under laboratory conditions

Little is known about the effect of temperature on viability of free-living phases of the life cycle of Rhipicephalus sanguineus (Latreille, 1806) despite of its importance as vector of several pathogens. Knowledge of the effect of abiotic factors on the capacity of a given tick species to infest new hosts is important for routine experimental activities under laboratory conditions, and may be relevant to understand the transmission of pathogens. The study evaluates the viability of R. sanguineus females held at 18 +/- 1, 27 +/- 1 and 32 +/- 1 degrees C and 80 +/- 5% RH (saturation deficits of 3.0, 5.3 and 7.2 mmHg, respectively) for three fasting periods (3 and 20 days and the day when female mortality reached approximately 50% after ecdysis), under laboratory conditions. In general, the best result on viability was obtained when rabbits were infested with unfed female ticks after three or 20 fasting days at both 27 +/- 1 and 32 +/- 1 degrees C and 80 +/- 5% RH.

Effect of prolonged application times on the durability of resin-dentin bonds

Objectives. To examine the effect of prolonged application time on the early and 3-year resin-dentin microtensile bond strength. Methods. Water/ethanol (Single Bond [SB]) and acetone-based systems (One Step [OS]) were employed. A flat superficial dentin surface was exposed in third human molars by wet abrasion. The adhesives were applied to a delimited area of 52 mm(2) on wet surfaces, for 40, 90, 150 and 300s. Four teeth were assigned for each experimental condition. Composite build-ups were constructed incrementally After water storage at 37 degrees C for 24 h, teeth were sectioned to obtain sticks with cross-sectional areas of 0.8 mm(2) to be tested in tension (0.5 mm/min) either immediately (IM) or after 3 years (3Y) of water storage. The microtensile bond strength (mu TBS) values were analyzed by two way repeated measures ANOVA and Tukey`s test (alpha = 0.05). Results. The 90- and 150-s groups achieved the highest IM mu TBS for OS (p < 0.01). For SB, the highest IM mu TBS values were observed after 300-s application (p < 0.01). Significant decreases in mu TBS were observed for OS in the 40- and 90-s groups after 3Y, except for the 150-s group. With regard to SB, after 3Y significant drops in mu TBS values were observed for the 40- and 150-s groups, except for the 300-s group. Significance. Prolonged application times can increase the immediate LTBS of two-step etch-and-rinse adhesive systems and make the adhesive layer more stable over time. (c) 2007 Academy of Dental Materials. Published by Elsevier Ltd. All rights reserved.

Effect of prolonged erosive pH cycling on different restorative materials

This in vitro study evaluated the effect of a prolonged erosive pH cycling on the superficial microhardness change (SMHC) and the erosive wear of different restorative materials. Eighty enamel specimens with prepared cavities of 1.5 x 1.5 mm were randomly divided into eight groups according to the restorative materials used for the fillings (RMGI - resin-modified glass-ionomer, CGI - conventional glass-ionomer, CR- composite resin, A - amalgam) and immersion media used (ERO - erosive medium or SAL - artificial saliva). During 35 days, half of the specimens were immersed in a cola drink (ERO), for 5 min, three times a day, and they remained in SAL between the erosive cycles. The other half of the specimens was immersed in SAL only, for the entire experimental period (control). Data were tested for significant differences by anova and Tukey`s tests (P < 0.05). Scanning electron microscopy images were made to illustrate the enamel erosive wear and restorative materials alterations. The mean SMHC (%) and mean erosive wear (mu m) of the materials were: RMGI-ERO (30/0.5); CGI-ERO (37/0.5); CR-ERO (-0.3/0.3); A-ERO (-4/0.3); RMGI-SAL (4/0.4); CGI-SAL (-6/0.4); CR-SAL (-3/0.2) and A-SAL (2/0.4). Scanning electron microscopy images showed pronounced enamel erosive wear on groups submitted to erosive pH cycling when compared with groups maintained in saliva. In conclusion, the prolonged pH cycling promoted significantly higher alterations (SMHC and erosive wear) on the glass-ionomer cements than the CR and amalgam.

A twin study of the etiology of prolonged fatigue and immune activation

Risk factors to prolonged fatigue syndromes (PFS) are controversial. Pre-morbid and/or current psychiatric disturbance, and/or disturbed cell-mediated immunity (CMI), have been proposed as etiologic factors. Self-report measures of fatigue and psychologic distress and three in vitro measures of CMI were collected from 124 twin pairs. Crosstwincrosstrait correlations were estimated for the complete monozygotic (MZ; 79 pairs) and dizygotic (DZ; 45 pairs) twin groups. Multivariate genetic and environmental models were fitted to explore the patterns of covariation between etiologic factors. For fatigue, the MZ correlation was more than double the DZ correlation (0.49 versus 0.16) indicating strong genetic control of familial aggregation. By contrast, for in vitro immune activation measures MZ and DZ correlations were similar (0.49–0.69 versus 0.42–0.53) indicating the etiologic role of shared environments. As small univariate associations were noted between prolonged fatigue and the in vitro immune measures (r = −0.07 to −0.12), multivariate models were fitted. Relevant etiologic factors included: a common genetic factor accounting for 48% of the variance in fatigue which also accounted for 4%, 6% and 8% reductions in immune activation; specific genetic factors for each of the in vitro immune measures; a shared environment factor influencing the three immune activation measures; and, most interestingly, unique environmental influences which increased fatigue but also increased markers of immune activation. PFS that are associated with in vitro measures of immune activation are most likely to be the consequence of current environmental rather than genetic factors. Such environmental factors could include physical agents such as infection and/or psychologic stress.

Prolonged retention after aggregation into secretory granules of human R183H-growth hormone (GH), a mutant that causes autosomal dominant GH deficiency type II

Human R183H-GH causes autosomal dominant GH deficiency type II. Because we show here that the mutant hormone is fully bioactive, we have sought to locate an impairment in its progress through the secretory pathway as assessed by pulse chase experiments. Newly synthesized wild-type and R183H-GH were stable when expressed transiently in AtT20 cells, and both formed equivalent amounts of Lubrol-insoluble aggregates within 40 min after synthesis. There was no evidence for intermolecular disulfide bond formation in aggregates of wild-type hormone or the R183H mutant. Both wildtype and R183H-GH were packaged into secretory granules, assessed by the ability of 1 mm BaCl2 to stimulate release and by immunocytochemistry. The mutant differed from wildtype hormone in its retention in the cells after packaging into secretory granules; 50% more R183H-GH than wild-type aggregates were retained in AtT20 cells 120 min after synthesis, and stimulated release of R183H-GH or a mixture of R183H-GH and wild-type that had been retained in the cell was reduced. The longer retention of R183H-GH aggregates indicates that a single point mutation in a protein contained in secretory granules affects the rate of secretory granule release.

The value of the Widal test in the diagnosis of Prolonged Septicemic Salmonellosis

Twenty patients with prolonged septicemic salmonellosis (Group 1) and 20 with schistosomiasis mansoni (Group 2) were selected for this study. In both groups, the Widal test was done using antigens of the sample Ty 901 (S. typhi). The test was also applied in 6 group 1 patients with antigens prepared from salmonellae isolated from these patients (autoantigens). Titres over 1:200 were considered significant. Ten group 1 patients (50%) were positive for antigen "H" and 5 (25%) were positive for antigen "O". Three patients with negative "H" and "O" reactions became positive with high titres when using autoantigens. Two other cases maintained the same positive titres and one case showed a fourfold increase in titres when the test was done 'with antigens of the Salmonella isolated. The Widal test was positive in most patients infected with group D Salmonellae. Considering titres above 1:200, all cases were negative in Group 2. The authors conclude that the Widal test has low positivity in prolonged septicemic salmonellosis. The test may be valuable in the diagnosis of this disease when using S. paratyphi "A" and "B" antigens and a mixture of Salmonella antigens taken from other groups.

Renal involvement in prolonged salmonella bacteremia: the role of schistosomal glomerulopathy

Renal involvement has been well documented in patients with hepatosplenic schistosomiasis and in patients with prolonged salmonella bacteremia (PSB). Whether there is a specific renal lesion related to PSB or the chronic bacterial infection aggravates a pre-existing schistosomal glomerulopathy has been a matter of controversy. To analyze the clinical manifestations and histopathological findings of the renal involvement, 8 patients with hepatosplenic schistosomiasis and PSB (group I) were compared with 8 patients with schistosomal glomerulopathy (group II) matched by sex and glomerular disease. The mean age in group I was 17.7 years. All patients presented with hematuria, in 4 cases associated with non-nephrotic proteinuria. In group II the mean age was 23 years; nephrotic syndrome was the clinical presentation in 7 of the 8 patients in the group. All patients in group I experienced remission of the clinical and laboratory abnormalities as the salmonella infection was cured; in group II the patients had persistent, steroid-resistant, nephrotic syndrome. On histological examination, no difference was noted between the two groups, except for pronounced glomerular hypercellularity and interstitial mononuclear cell infiltration in group I. These observations strongly suggest that PSB exacerbates a pre-existing sub-clinical schistosomal glomerulopathy by the addition of active lesions directly related to the prolonged bacteremia

The prolonged use of niclosamide as a molluscicide for the control of Schistosoma mansoni

Applications of niclosamide at three-monthly intervals were undertaken for 14 years in foci of Biomphalaria glabrata in the water sources of Peri-Peri (Capim Branco, MG). All the residents of the area were submitted to an annual fecal examination (Kato/Katz) and those individuals eliminating Schistosoma mansoni eggs were treated with oxamniquine. A malacological survey was undertaken at three-monthly intervals by means of ten scoops with a perforated ladle each ten metres along the two banks of the ditches and streams of the region. Where snails were found, molluscicide was applied by means of dripping or aspersion using a 3 ppm aqueous suspension of niclosamide. Initially, a mean of 14.3% of snails in the region were found to be eliminating cercariae. Following the first four applications of molluscicide, this was reduced to 0.0% and maintained at about 1.5% throughout the program. Thus, there was a continued possibility of schistosomiasis transmission in the area and it was observed that the population of snails reestablished itself within three months of molluscicide application. The results obtained in this study do not encourage the continual use of niclosamide as the only method of control of schistosomiasis.

Detrimental role of prolonged sleep deprivation on adult neurogenesis

Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis.