Roles of endogenous opioid peptides in modulation of nocifensive response to formalin.

Roles of endogenous opioid peptides and their receptors in modulation of the nocifensive responses to formalin in mice were studied. Mice were pretreated i.c.v. or intrathecally (i.t.) with selective opioid receptor antagonists or intrathecally with antisera against endogenous opioid peptides and the nocifensive licking responses to intraplantar injection of formalin (0.5%, 25 microl) were then observed. Pretreatment with the epsilon-opioid receptor antagonist beta-endorphin(1-27) or the selective mu-opioid receptor antagonist D-Phe-Cys-Tyr-Orn-Thr-Pen-Thr-NH(2) (CTOP) given i.c.v. dose dependently enhanced the second, but not the first phase of the nocifensive response. However, i.c.v. pretreatment with the selective delta-receptor antagonist naltrindole or kappa-receptor antagonist nor-binaltrophimine did not affect the nocifensive responses. Intrathecal pretreatment with selective delta(1)-opioid antagonist 7-benzylidene naltrexamine significantly enhanced both the first and second phases of nocifension. Intrathecal pretreatment with CTOP also increased the second but not the first phase of the nocifension. However, i.t. pretreatment with the selective delta(2)-receptor antagonist naltriben or nor-binaltrophimine did not affect the second phase of the nocifension. Intrathecal pretreatment with antiserum against Leu-enkephalin, Met-enkephalin, or dynorphin A(1-17), but not beta-endorphin, enhanced only the second phase of nocifensive response to formalin. It is concluded that the blockade of epsilon- and mu-receptors, but not delta- or kappa-receptors, at the supraspinal sites enhanced the second phase of formalin-induced nocifension. In the spinal cord, Leu-enkephalin, and to a lesser extent, Met-enkephalin and dynorphin A(1-17) and mu- and delta(1)-opioid receptors, but not delta(2)- or kappa-opioid receptors, are involved in modulating the feedback inhibition of the second phase of formalin-induced nocifension.     

Functional Profile of the Isolated Uremic Nephron: IMPAIRED WATER PERMEABILITY AND ADENYLATE CYCLASE RESPONSIVENESS OF THE CORTICAL COLLECTING TUBULE TO VASOPRESSIN

Resistance of the chronically diseased kidney to vasopressin has been proposed as a possible explanation for the urinary concentrating defect of uremia. The present studies examined the water permeability and adenylate cyclase responsiveness of isolated cortical collecting tubules (CCT) from remnant kidneys of uremic rabbits to vasopressin. In the absence of vasopressin the CCTs of both normal and uremic rabbits were impermeable to water. At the same osmotic gradient, addition of a supramaximal concentration of vasopressin to the peritubular bathing medium led to a significantly lower net water flux per unit length (and per unit luminal surface area) in uremic CCTs than in normal CCTs. Transepithelial osmotic water permeability coefficient, P(f), was 0.0232 +/-0.0043 cm/s in normal CCTs and 0.0059+/-0.001 cm/s in uremic CCTs (P < 0.001). The impaired vasopressin responsiveness of the uremic CCTs was observed whether normal or uremic serum was present in the bath.Basal adenylate cyclase activity per microgram protein was comparable in normal and uremic CCTs. Stimulation by NaF led to equivalent levels of activity in both, whereas vasopressin-stimulated activity was 50% lower in the uremic than in the normal CCTs (P < 0.025).The cyclic AMP analogue, 8-bromo cyclic AMP, produced an increase in the P(f) of normal CCTs closely comparable to that observed with vasopressin. In contrast, the P(f) of uremic CCTs was only minimally increased by this analogue and was not further stimulated by theophylline.These studies demonstrate an impaired responsiveness of the uremic CCT to vasopressin. This functional defect appears to be a result, at least in part, of a blunted responsiveness of adenylate cyclase to vasopressin. The data further suggest that an additional defect in the cellular response to vasopressin may exist, involving a step (or steps) subsequent to the formation of cyclic AMP.A unifying concept of the urinary concentrating defect of uremia is proposed which incorporates a number of hitherto unexplained observations on the concentrating and diluting functions of the diseased kidney.     

Comparison of differences in outcome after percutaneous coronary intervention in men versus women <40 years of age

We evaluated the outcomes of 177 consecutive patients (43 women, 134 men) <40 years of age with premature atherosclerosis who underwent percutaneous coronary intervention. Women were younger, had more diabetes mellitus (37% vs 10%; p <0.001), but less hyperlipidemia (58% vs 75%; p <0.001) compared with men. In-hospital vascular complications and 1-year mortality rate or Q-wave myocardial infarction (7.9% vs 0.08%, p <0.01) were higher in women. By multivariable regression analysis, female gender was the only independent predictor of vascular complications (odds ratio, 14.1; 95% confidence intervals, 1.59 to 125, p = 0.01) and of 1-year mortality rate or nonfatal myocardial infarction (odds ratio, 12.5; 95% confidence interval, 1.14 to 111, p = 0.03). Women with premature coronary disease had a distinctive risk factor profile relative to men, with a predominance of diabetes and hypercholesterolemia, and were at higher risk of developing vascular and ischemic complications after percutaneous coronary intervention, warranting aggressive risk factor modification and vigilance in this population.     

Usefulness of tumor markers in serum and bronchoalveolar lavage of patients undergoing fiberoptic bronchoscopy

To evaluate the diagnostic usefulness of simultaneous determinations of 4 tumor markers (carcinoembryonic antigen, calcitonin, creatinine kinase-BB, and DNA), we studied 31 patients with lung cancer, 22 with benign lung disease, and 15 normal volunteers as control subjects. The measurements were made by radioimmunoassay in bronchoalveolar lavage (BAL) and in serum obtained on the same day. The results showed that in serum, only CEA levels were significantly higher in malignancy; in lavage fluids, all 4 markers were abnormally high in cancer patients when compared with control subjects (p less than 0.05); there was no correlation between the levels in lavage and those in the bloodstream. When the mean levels in lavage of the normal control subjects were designated as the limits for a positive test, significant association was found between malignancy and abnormally elevated marker concentration (p less than 0.01). The particular combination of CEA-BAL greater than 35 ng/mg, CEA-serum greater than 4 ng/ml, and calcitonin-BAL greater than 120 pg/mg taken together with the results of bronchoscopy (histologic and cytologic) showed the highest discriminating power between malignant and benign lung disease. The sensitivity of the bronchoscopy procedure increased from 50 to 89%, with at least 2 positive markers, and had a specificity of 71%. When both bronchoscopy and all 3 markers were negative, the results showed a negative predictive value of 100%. We conclude that tumor marker levels in lavage are a useful aid in the diagnosis of malignancy in patients undergoing bronchoscopy.     

Mild cognitive impairment--beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment

The First Key Symposium was held in Stockholm, Sweden, 2-5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired.     

Frequency of visceral leishmaniasis relapses in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy

There are contradictory data about whether highly active antiretroviral therapy (HAART) prevents visceral leishmaniasis (VL) relapses in human immunodeficiency virus type 1 (HIV-1)-infected patients. The aim of this study was to assess the frequency of VL relapses in individuals receiving HAART. Thirty-one patients who received HAART after developing VL were included in a retrospective cohort study. Ten of them received secondary chemoprophylaxis and the rest did not. Eight (38%) patients without secondary chemoprophylaxis showed a VL relapse. None of the seven subjects with VL relapses and 6 of 11 without recurrence (P = 0.038), in whom all scheduled data were available, showed an increase of more than 100 CD4+ cells/mm(3) during the follow-up. Patients with relapse showed higher levels of HIV RNA viral load at their last visit (P = 0.047). The frequency of VL relapses in patients receiving HAART is high. Relapses of VL are observed only in individuals with uncontrolled HIV replication and/or poor immunologic responses.