Primary Adenocarcinoma of the Vagina of Mesonephric Pattern

Summary: A case of primary vaginal adenocarcinoma of probable mesonephric origin is presented and a review of the literature with reference to the condition is made.     

Bactericidal activity response of blood neutrophils from critically ill patients to in vitro granulocyte colony-stimulating factor stimulation

OBJECTIVE: Neutrophil function impairment is common in nonneutropenic critically ill patients. Whether granulocyte colony-stimulating factor (G-CSF) may be useful for preventing nosocomial infection in these patients is debated. The response of blood neutrophils from critically ill patients to G-CSF was investigated in vitro. DESIGN AND SETTING: Prospective study, laboratory investigation in two intensive care units. PATIENTS: 52 critically ill patients without immunosuppression. MEASUREMENTS: Neutrophils obtained from 52 patients on the 5th day of their intensive care unit stay were incubated with and without G-CSF (1, 10, 100 ng/ml). Reactive oxygen species (ROS) release and bactericidal activity against Staphylococcus aureus and Pseudomonas aeruginosa were evaluated. Plasma cytokines (interleukin 10, tumor necrosis factor alpha, and G-CSF) were measured. RESULTS: Median values (25th-75th percentiles) indicated no stimulatory effect of G-CSF on neutrophil bactericidal activity against either organism: S. aureus, 100% (95-109) of the unstimulated condition with 1 ng/ml G-CSF, and P. aeruginosa, 102% (98-109) with 1 ng/ml G-CSF. However, wide interindividual variability was found, ranging from marked inhibition to marked stimulation. Similar variability was found for ROS release. No correlations were found between ROS release and bactericidal activities against either bacterial strain. Inhibition of neutrophil bactericidal activity by G-CSF was associated with significantly higher plasma interleukin 10 concentrations. Plasma G-CSF levels were significantly higher in patients whose neutrophil bactericidal activity was unresponsive to G-CSF, suggesting G-CSF receptor downregulation. CONCLUSIONS: The effect of G-CSF on in vitro neutrophil bactericidal activity varied widely, depending on endogenous levels of G-CSF and was not predictable based on severity scores.     

Beneficial effect of an inhibitor of leukocyte elastase (EPI-hNE-4) in presence of repeated lung injuries

Persistence of alveolar neutrophil influx and activation may enhance the fibrotic process after acute lung injury. On the other hand, elastase has an antimicrobial activity and could participate in neutrophil migration, both events being critically important in host defense, explaining the controversial issue of therapeutic elastase inhibition in the setting of acute lung injury. We assessed the effect of a neutrophil elastase inhibitor, EPI-hNE-4, in single (bleomycin, 1.2 mg/rat intratracheally) and repeated (bleomycin, 1.2 mg/rat plus endotoxin and 1 mg/kg intratracheally 24 h later) lung injuries to assess the role of neutrophil in fibrosis. Subsequently, the effect of EPI-hNE-4 on bacterial clearance was evaluated during Pseudomonas aeruginosa-induced pneumonia. In the single injury model, despite a dramatic reduction of alveolar neutrophil influx with EPI-hNE-4 treatment, no significant inhibition of the decrease in respiratory system compliance, an index of lung fibrosis, was demonstrated at day 14. In the repeated injury model, EPI-hNE-4 treatment afforded a significant protective effect on compliance and alveolar inflammation at day 14. During bacterial pneumonia, EPI-hNE4 did not modify alveolar neutrophil recruitment or bacterial clearance from bronchoalveolar lavage fluid and lung homogenate. In conclusion, EPI-hNE-4, a specific inhibitor of leukocyte elastase, afforded a partial protective effect on the respiratory system compliance during repeated lung injuries, and had no detrimental effect during a gram-negative bacterial pneumonia.     

The antihyperglycemic effect of curcumin in high fat diet fed rats. Role of TNF-α and free fatty acids

This study was conducted to investigate the effect of curcumin, obtained from Curcuma longa, in comparison with rosiglitazone on the progression of insulin resistance and type 2 diabetes mellitus (T2DM) and the mechanisms underlying this effect. Insulin resistance and T2DM was induced in male Sprague Dawley rats by high fat diet (HFD) feeding for 60 and for 75 days representing two regimens of the study, protection and treatment. Prophylactic oral administration of curcumin (80 mg/kg), rosiglitazone (1 mg/kg), their combination, or vehicle (in control groups) was started along with HFD feeding in different groups. Treatment is achieved by oral administration of the previously mentioned agents in the last 15 days of HFD feeding after induction of insulin resistance and T2DM in rats.Curcumin showed an anti-hyperglycemic effect and improved insulin sensitivity, and this action may be attributed at least in part to its anti-inflammatory properties as evident by attenuating TNF-α levels in HFD fed rats, and its anti-lipolytic effect as evident by attenuating plasma free fatty acids. The curcumin effects are comparable to those of rosiglitazone, which indicate that they may act similarly. Finally we can say that, curcumin could be a beneficial adjuvant therapy in patients with T2DM.     

Differential expression of cyclin-dependent kinase inhibitors and apoptosis-related proteins in endocervical lesions

The development of neoplasia is associated with abnormalities of cell cycle control and apoptosis. In this study, a panel of cyclin-dependent kinase inhibitors (CDKIs) and apoptosis-related proteins (p16, p21, p53, Bcl2 and hsp27) was analysed by immunohistochemistry in 91 glandular cervical lesions. A significant increase in p21 and p53 expression occurred from normal cervix (n=11) through endometriosis/tubo-endometrioid metaplasia (TEM) (n=19) and cervical glandular intraepithelial neoplasia (CGIN)/adenocarcinoma in situ (AIS) (n=33) to invasive adenocarcinoma (n=28). p16 showed diffuse strong expression in CGIN/AIS and invasive adenocarcinoma compared with focal expression in some TEM/endometriosis lesions and no expression in normal cervix. Bcl2 was highly expressed in TEM/endometriosis compared with CGIN/AIS and adenocarcinoma. p16 immunostaining discriminated accurately between neoplastic and non-neoplastic cervical lesions, provided that diffuse strong positivity was present. Similarly, diffuse expression of Bcl2 distinguished endometriosis/TEM from CGIN/AIS. These data demonstrate that analysis of CDKIs and apoptosis-related proteins provides useful information in the diagnostic assessment of glandular lesions of the cervix.     

Physical activity and bronchial hyperresponsiveness: European Community Respiratory Health Survey II

BACKGROUND: Identification of the risk factors for bronchial hyperresponsiveness (BHR) would increase the understanding of the causes of asthma. The relationship between physical activity and BHR in men and women aged 28.0-56.5 years randomly selected from 24 centres in 11 countries participating in the European Community Respiratory Health Survey II was investigated. METHODS: 5158 subjects answered questionnaires about physical activity and performed BHR tests. Participants were asked about the frequency and duration of usual weekly exercise resulting in breathlessness or sweating. BHR was defined as a decrease in forced expiratory volume in 1 s of at least 20% of its post-saline value for a maximum methacholine dose of 2 mg. RESULTS: Both frequency and duration of physical activity were inversely related to BHR. The prevalence of BHR in subjects exercising or=4 times a week was 14.5%, 11.6% and 10.9%, respectively (p<0.001). The corresponding odds ratios were 1.00, 0.78 (95% CI 0.62 to 0.99) and 0.69 (95% CI 0.50 to 0.94) after controlling for potential confounding factors. The frequency of BHR in subjects exercising <1 h, 1-3 h and >or=4 h a week was 15.9%, 10.9% and 10.7%, respectively (p<0.001). The corresponding adjusted odds ratios were 1.00, 0.70 (95% CI 0.57 to 0.87) and 0.67 (95% CI 0.50 to 0.90). Physical activity was associated with BHR in all studied subgroups. CONCLUSIONS: These results suggest that BHR is strongly and independently associated with decreased physical activity. Further studies are needed to determine the mechanisms underlying this association.     

Volume therapy with colloid solutions preserves intestinal microvascular perfusion in endotoxaemia

Colloid solutions have been suggested to improve microvascular perfusion due to their anti-inflammatory properties. Whether this also applies for the gut, an important immunological organ vulnerable to hypoperfusion is unknown. This study investigated intestinal microcirculation of endotoxaemic rats after volume therapy with colloid solutions such as hydroxyethyl starch (HES) and gelatin or isotonic saline (NaCl). In addition intestinal oxygenation and morphology as well as mesenteric leukocyte-endothelium interaction were quantified. Rats were anaesthetised with urethane and ketamine, mechanically ventilated, and monitored haemodynamically. Normotensive endotoxaemia was induced by a continuous intravenous infusion of Escherichia coli lipopolysaccharide (LPS, 1.5 mg kg(-1) h(-1)). After 1 h of LPS infusion either 6% HES (16 ml kg(-1)), 4% gelatin (16 ml kg(-1)) or 0.9% NaCl (64 ml kg(-1)) were infused for 1 h. Using intravital microscopy, functional capillary density (FCD) and red blood cell velocity (RBCV) were measured in the mucosa of the terminal ileum at baseline and 3 h after volume therapy. In another set of animals, mesenteric leukocyte-endothelium interaction was determined 3 h after volume therapy. In all animals intestinal lactate/pyruvate ratio and intestinal morphology were assessed. Three hours after volume therapy, FCD decreased in NaCl (808 [749/843] cm(-1); median [quartiles] P<0.05 versus baseline) but not in HES (995 [945/1036] cm(-1)) and gelatin (988 [867/1193] cm(-1)) groups. RBCV, lactate/pyruvate ratio and intestinal morphology did not differ among groups. Also mesenteric leukocyte-endothelium interaction was not significantly influenced by either treatment. In conclusion, early volume therapy with HES or gelatin, but not with NaCl, preserved gut microvascular perfusion during endotoxaemia but did not have a significant effect on tissue oxygenation nor morphological appearance in this experimental model. An anti-inflammatory effect of colloid solutions was not seen and fails to explain the changes in intestinal microcirculation.     

PSNCBAM-1, a novel allosteric antagonist at cannabinoid CB1 receptors with hypophagic effects in rats

BACKGROUND AND PURPOSE: Rimonabant (Acomplia, SR141716A), a cannabinoid CB1 receptor inverse agonist, has recently been approved for the treatment of obesity. There are, however, concerns regarding its side effect profile. Developing a CB1 antagonist with a different pharmacological mechanism may lead to a safer alternative. To this end we have screened a proprietary small molecule library and have discovered a novel class of allosteric antagonist at CB1 receptors. Herein, we have characterized an optimized prototypical molecule, PSNCBAM-1, and its hypophagic effects in vivo. EXPERIMENTAL APPROACH: A CB1 yeast reporter assay was used as a primary screen. PSNCBAM-1 was additionally characterized in [35S]-GTPgammaS, cAMP and radioligand binding assays. An acute rat feeding model was used to evaluate its effects on food intake and body weight in vivo. KEY RESULTS: In CB1 receptor yeast reporter assays, PSNCBAM-1 blocked the effects induced by agonists such as CP55,940, WIN55212-2, anandamide (AEA) or 2-arachidonoyl glycerol (2-AG). The antagonist characteristics of PSNCBAM-1 were confirmed in [35S]-GTPgammaS binding and cAMP assays and was shown to be non-competitive by Schild analyses. PSNCBAM-1 did not affect CB2 receptors. In radioligand binding assays, PSNCBAM-1 increased the binding of [3H]CP55,940 despite its antagonist effects. In an acute rat feeding model, PSNCBAM-1 decreased food intake and body weight. CONCLUSIONS AND IMPLICATIONS: PSNCBAM-1 exerted its effects through selective allosteric modulation of the CB1 receptor. The acute effects on food intake and body weight induced in rats provide a first report of in vivo activity for an allosteric CB1 receptor antagonist.