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We have studied the most representative functions of lymphocytes such as adherence to substrate, mobility directed to a chemoattractant gradient (chemotaxis), proliferative response to mitogens and antibody-dependent cellular cytotoxicity (ADCC), as well as natural killer (NK) activity in peripheral blood cells from the turtle Mauremys caspica, and the seasonal changes of these functions in both female and male animals. The plasma levels of steroid hormones were determined to study their relationship with the immune functions. Our results show high chemotaxis, lymphoproliferative response and ADCC as well as NK activity in winter when the levels of corticosterone, testosterone and 17-beta-estradiol were depleted. Proliferative responses to phytohaemagglutinin (PHA), concanavalin A (Con A) and pokeweed mitogen (PWM) were increased in spring correlating with low levels of corticosterone and testosterone in middle and late spring. In summer, the proliferative response was decreased but adherence, chemotaxis, ADCC and NK activity were increased, although steroid hormones showed high plasma levels. In autumn, a depletion of both the hormone levels and the immune response were found except for adherence to substrate. The immune functions studied were strikingly influenced by the seasonal cycle, which induced a different pattern of response depending on the function analyzed. Moreover, these immune cells showed a different degree of dependence on steroids in relation to the function and the season considered, suggesting the existence of other factors that modulate the immune response studied.

The potential antinociceptive effects of the S(+)- and R(-)-enantiomers of flurbiprofen (SFB and RFB, respectively) were investigated when given intravenously to rats using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. Groups of 6 rats received either vehicle or the enantiomer in turn and antinociception was determined by evaluating the dose-response curves over time. Although SFB and RFB produced dose-dependent effects with similar efficacy (SFB: 277.4 +/- 29.9 au and RFB: 293.5 +/- 20.1 au), the R(-)-enantiomer was unable to produce any antinociceptive action when assessed at the same dose ranges as SFB. It was necessary to increase the dose of RFB by 100 times to produce similar antinociception. Accordingly, S(+)-flurbiprofen was 100-fold more potent (ED50 = 0.33 +/- 0.13 mg/kg) than its antipode R(-)-(ED50 = 30.0 +/- 1.7 mg/kg). SFB generated from metabolic inversion (> 1%) after i.v. dosage of RFB, as well as impurities of SFB present in RFB preparations, tend to confirm the hypothesis that the efficacy of RFB achieved at 100 mg/kg, similar to that observed with 1 mg/kg of SFB, is attributable to SFB.

Objective: To determine the clinical and immunological characteristics of primary Sjögren's syndrome (SS) in men from a large series of unselected patients with this condition., Methods: We studied 223 consecutive patients (204 women and 19 men; mean age at onset 53 y, range 15-87 y, mean disease duration 77 months) with primary SS visited in our units. All these patients fulfilled 4 or more of the diagnostic criteria for SS proposed by the European Community Study Group in 1993., Results: Nineteen (9%) patients were men and they represent the male group described in this paper. Extraglandular manifestations during the course of their disease were present in 10 (53%) of our male patients with primary SS: articular involvement in 4 (21%) patients, interstitial pneumopathy in 3 (16%) and peripheral neuropathy in 2 (11%). ANA were positive in 13 (68%) patients, RF in 5 (31%), anti-Ro/SS-A in 3 (16%) and cryoglobulins in 1/14 (7%). When compared with women, men with primary SS presented a lower prevalence of articular involvement (21 percent; vs 46%, P=0.03, OR 0.32, CI 0.07-0.97)., Conclusion: Although primary SS is typically a disease of middle-aged women, clinicians should note that it may be diagnosed in male patients. Except for a lower prevalence of articular involvement, we could no find any notable differences in clinical and immunological characteristics between male and female patients with primary SS.

Cystic fibrosis (CF) is caused by mutations in the secretory Cl(-) channel CFTR (cystic fibrosis transmembrane conductance regulator). Variation in the severity of disease has been attributed to mutations in the CFTR gene that cause different degrees of dysfunction of the CFTR Cl(-) channel. However, studies of mouse models of CF indicate that the severity of intestinal pathology is not correlated with activity of the CFTR chloride channel. This observation suggests that other 'environmental' factors might be important in determining the severity of disease. In this respect, we have identified and characterised an additional cellular defect in intestinal epithelial cells of CF mice, the inability of these cells to regulate their volume after hypotonic challenge. Here, we review the function of murine CFTR as both a Cl(-) channel and as a regulator of volume-dependent homeostatic cell mechanisms., (Copyright 2000 S. Karger AG, Basel.)

Acetylcholinesterase (AChE) catalyses the hydrolysis of the neurotransmitter acetylcholine and it has been implicated in several non-cholinergic actions, including neurite outgrowth and amyloid formation. We have studied the trophic function of brain AChE on neuronal cell metabolism and proliferation as well as the enzyme domain involved in such effects. Low AChE concentrations (0.1-2.5 nM) stimulated neurite outgrowth and induced cell proliferation as measured by MTT reduction and [3H]thymidine incorporation. The action of AChE was not affected by edrophonium and tacrine both active site inhibitors, but it was abolished by propidium and gallamine, two peripheral anionic binding site (PAS) ligands. We conclude that the PAS domain of AChE is involved in the neurotrophic activity of the enzyme.

This work studied the proliferation activity in cultures of vascular smooth muscle cells (SMC) from individuals of different ages. The cells derived from arteries of 12 donors of both sexes from 45 to 91 years of age. The main parameter considered was the 'proliferation rate' (cells grown per day in the different culture passages) taking into account the age of the donor. No significant relationship between age of the donor and the cell life in proliferation was found. On the contrary, the mean time of passage duration for reaching the maximum of proliferation as well as its 'efficiency' (maximum of proliferation rate registered/mean time of passage duration) show a statistically significant dependence on the age of the donor. Furthermore, the proliferation rate measured in each passage is statistically significant related to donor age. The regressions obtained show a similar negative slope (VC 4%). Considering the first five culture passages, the regression crosses the x-axis at the age of 105.6+/-11.7 years. This age in which no proliferative activity of human SMC would be expected lies near the limit of maximum life potential for human beings. Our results suggest that with advancing donor age there is an increasing number of senescent SMC either primarily transferred or appeared in the culture. Vascular SMC of individuals whose life is near the end would almost be all senescent and therefore show extremely low proliferation rates in the culture. If the proliferative activity of arterial SMC is a condition for atherogenesis, the proportion of senescent cells would be inversely related to the propensity of developing the atheroma because of the inability of these cells to divide.

Caffeine potentiation of ketorolac-induced antinociception in the pain-induced functional impairment model in rats was assessed. Caffeine alone was ineffective, but increased the effect of ketorolac without affecting its pharmacokinetics. Intra-articular administration of adenosine and N6-cyclohexyladenosine (CHA, an adenosine A1 receptor agonist), but not 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS-21680, an adenosine A2A receptor agonist), significantly increased ketorolac antinociception. This effect was not local, as contralateral administration was also effective. Ipsilateral and contralateral administration of adenosine and CHA also increased antinociception by ketorolac-caffeine. Intra-articular 8-Bromo-adenosine cyclic 3',5'-hydrogen phosphate sodium or 8-Bromo-guanosine-3',5'-cyclophosphate sodium (cGMP) given ipsilaterally or contralaterally did not affect ketorolac-induced antinociception. Nevertheless, ipsilateral, but not contralateral, administration of 8-Br-cGMP significantly increased antinociception by ketorolac-caffeine, suggesting a local effect. The results suggest that caffeine potentiation of ketorolac antinociception is mediated, at least partially, by a local increase in cGMP and rule out the participation of adenosine receptor blockade.

This work addresses the differential effects of several oxidative insults on two neuronal cell lines, PC12 and Neuro 2a cells, extensively used as neuronal models in vitro. We measured cellular damage using the cytotoxic assays for MTT reduction and LDH release and found that acetylcholinesterase (AChE)-amyloid-beta-peptide (Abeta) complexes, Abeta25-35 fragment, glutamate and H2O2 were over 200-fold more toxic to PC12 than to Neuro 2a cells. 17alpha and 17beta estradiol were able to protect both cell types from damage caused by H2O2 or glutamate. By contrast, other insults not related to oxidative stress, such as those caused by the nonionic detergent Triton X-100 and serum deprivation, induced a similar level of damage in both PC12 and Neuro 2a cells. Considering that the Abeta peptide, H2O2 and glutamate are cellular insults that cause an increase in reactive oxygen species (ROS), the intracellular levels of the antioxidant compound, glutathione were verified. Neuro 2a cells were found to have 4- to 5-fold more glutathione than PC12 cells. Our results suggest that Neuro 2a cells are less susceptible to exposure to AChE-Abeta complexes, Abeta25-35 fragment, glutamate and H2O2 than PC12 cells, due to higher intracellular levels of antioxidant defense factors.

Purpose: This study was conducted to determine the incidence of intraocular uveal microexplosions ("pops") during contact diode laser transscleral cyclophotocoagulation (cyclodiode) and to analyze the influence of pop occurrence on results and postoperative complications., Methods: Cyclodiode treatment (1.5-2 W x 2 seconds over 270 degrees) was performed in 43 consecutive patients (43 eyes) with uncontrolled glaucoma who had not undergone previous ciliary ablation. Mean duration of follow-up evaluation was 12.7 months (range, 9-18 months). These eyes included 31 seeing eyes, in which intraocular pressure (IOP) reduction was indicated to preserve visual acuity (therapeutic group) and 12 blind eyes, in which IOP reduction was advisable to relieve pain (palliative group). Success was defined as a final IOP > or = 5 mmHg and < or = 21 mmHg in seeing eyes, and as the resolution of pain in blind eyes. Potential factors evaluated for intraoperative pop occurrence included patient age, gender, iris color, glaucoma diagnosis, preoperative IOP, and number of previous surgical procedures used to treat glaucoma., Results: In the group receiving therapeutic treatment, mean +/- standard deviation (SD) IOP was 41.8 +/- 12.7 mmHg before surgery and 19.2 +/- 8.3 mmHg after surgery; the success rate in this group was 83.9%. In the group receiving palliative treatment, mean IOP was 55.4 +/- 13.7 mmHg before surgery and 21.1 +/- 13.4 mmHg after surgery; success rate was 83.3% in this group. Intraoperative microdisruptions occurred in 48.8% of the cases during the first laser application; 67.5% of these occurred in the superior half of the eye. No significant difference in rate of intraoperative pop was observed between patients after one cyclodiode session and those eyes that underwent additional sessions. Mean baseline IOP was significantly higher in patients with intraoperative occurrence of pops. An audible pop was more common in the group undergoing palliative treatment. Intraoperative occurrence of pops was associated with a greater severity of postoperative iridocyclitis. All patients with postoperative hyphema also had pops during surgery. No significant difference in the success rate was found between patients in whom intraoperative pops did and did not occur., Conclusion: Choroidal vaporization is significantly more common in patients with higher baseline IOP. Occurrence of pops also is associated with more severe postoperative inflammation and with a greater risk of postoperative hyphema.

Alzheimer's disease (AD) is a neurodegenerative disorder whose hallmark is the presence of senile plaques and neurofibrillary tangles. Senile plaques are mainly composed of amyloid beta-peptide (Abeta) fibrils and several proteins including acetylcholinesterase (AChE). AChE has been previously shown to stimulate the aggregation of Abeta1-40 into amyloid fibrils. In the present work, the neurotoxicity of different amyloid aggregates formed in the absence or presence of AChE was evaluated in rat pheochromocytoma PC12 cells. Stable AChE-Abeta complexes were found to be more toxic than those formed without the enzyme, for Abeta1-40 and Abeta1-42, but not for amyloid fibrils formed with AbetaVal18-Ala, a synthetic variant of the Abeta1-40 peptide. Of all the AChE-Abeta complexes tested the one containing the Abeta1-40 peptide was the most toxic. When increasing concentrations of AChE were used to aggregate the Abeta1-40 peptide, the neurotoxicity of the complexes increased as a function of the amount of enzyme bound to each complex. Our results show that AChE-Abeta1-40 aggregates are more toxic than those of AChE-Abeta1-42 and that the neurotoxicity depends on the amount of AChE bound to the complexes, suggesting that AChE may play a key role in the neurodegeneration observed in Alzheimer brain.

The senile plaques present in Alzheimer's disease (AD) are composed of a core of amyloid beta-peptide (Abeta) plus several proteins including acetylcholinesterase (AChE). Recently we found that AChE forms complexes with the Abeta peptide in vitro and that these are more cytotoxic than Abeta fibrils alone. Considering that estrogen has been reported to act as a protective agent against Abeta-induced cytotoxicity, the effect of 17beta-estradiol was studied in rat pheochromocytoma (PC12) and mouse neuroblastoma (Neuro 2a) cells exposed to either Abeta alone or AChE-Abeta complexes. Estrogen showed a powerful protective effect in response to the challenge of AChE-Abeta complexes as well as with Abeta fibrils. This was also the case for other cytotoxic agents such as glutamate and H2O2. Our results suggest a common mechanism for cellular protection by estrogen against the toxicity of both Abeta fibrils and AChE-Abeta complexes, likely avoiding the free radical apoptotic pathway.

We investigated the antinociceptive properties of dexketoprofen trometamol [S(+)-ketoprofen tromethamine salt; SKP], a new analgesic, antiinflammatory drug, using the pain-induced functional impairment model in the rat (PIFIR), an animal model of arthritic pain. SKP was compared with racemic ketoprofen tromethamine salt (rac-KP), R(-)-ketoprofen tromethamine salt (RKP), ketorolac (KET), and morphine (MOR). We also assessed the effects of flurbiprofen (rac-FB) and its enantiomers (SFB and RFB) in the same model. Groups of six rats received either vehicle or analgesic drug and antinociception was evaluated by evaluating the dose-response curves over time. SKP was an effective antinociceptive drug in this model and was almost equally potent by either oral or intracerebroventricular administration. The oral potency of SKP was similar to that of oral KET and greater than that of oral MOR. No significant differences were observed between racemic ketoprofen and its enantiomers when administered orally. In the rat, significant bioinversion of RKP to SKP occurs when RKP is given orally. After oral administration of RKP, SKP was detectable in 30 min and surpassed the concentration of RKP after 3 h. Nevertheless, when the compounds were given intracerebroventricularly, some stereoselectivity in favor of SKP was observed. Stereoselectivity was observed with flurbiprofen, an analogue of ketoprofen that does not undergo significant metabolic inversion. Whereas SFB was an effective antinociceptive, RFB had no antinociceptive effect at the doses tested when given either orally or intracerebroventricularly.

The relationship between the pharmacokinetics and the antinociceptive effect of tolmetin was characterized by an indirect model using a population approach. Animals received an intra-articular injection of uric acid in the right hindlimb to induce its dysfunction. Once dysfunction was complete, rats received an oral tolmetin dose of 1, 3.2, 10, 31.6, 56.2 or 100 mg/kg and antinociceptive effect and blood tolmetin concentration were simultaneously evaluated. Tolmetin produced a dose-dependent recovery of functionality, which was not directly related to blood concentration. An inhibitory indirect response model was used based on these response patterns and the fact that tolmetin reduced nociception by inhibiting prostaglandin synthesis. Pharmacokinetic (PK) and pharmacodynamic (PD) data were simultaneously fitted using nonlinear mixed effects modeling (NONMEM) to the one-compartment model and indirect response model. The individual time courses of the response were described using Bayesian analysis with population parameters as a priori estimates. There was good agreement between the predicted and observed data. Population analysis yielded a maximal inhibition of the nociceptive response of 76% and an IC50 of 9.22 micrograms/ml. This IC50 is similar to that for tolmetin-induced prostaglandin synthesis inhibition in vitro (3.0 micrograms/ml). The present results demonstrate that mechanism-based PK-PD analysis using a population approach is useful for quantitating individual responses as well as reflecting the actual mechanism of action of a given drug in vivo.

Objective: To describe the clinical and histopathological manifestations of a case of pseudoepitheliomatous, keratotic and micaceous balanitis and review the literature on this rare condition., Methods: A case of pseudoepitheliomatous, keratotic and micaceous balanitis in a 63-year-old man is presented. The lesion appeared a few months after undergoing circumcision due to phimosis and recurrent inflammatory balanitis., Results: The lesion relapsed after topical treatment with 5-FU, cryotherapy and shaving-biopsy plus electrocoagulation. It was finally diagnosed as epidermoid carcinoma and surgically excised., Conclusions: The clinical and histopathological features, course and relationship between micaceous balanitis and carcinoma of the penis are reviewed.

Serotonin (5-hydroxytryptamine; 5-HT) elicits external carotid vasoconstriction in vagosympathectomized dogs via 5-HT1B/1D receptors and a mechanism unrelated to the 5-HT1, 5-HT2, 5-HT3 and 5-HT4 types. In order to further explore the nature of this novel mechanism, the canine external carotid effects of 2-(2-aminoethyl)-quinoline (D-1997), a novel 5-HT1 receptor agonist, were analyzed and compared with those of 5-HT and sumatriptan. Intracarotid (i.c.) infusions of 5-HT, D-1997 and sumatriptan to vagosympathectomized dogs dose-dependently decreased external carotid conductance, the rank order of agonist potency being 5-HT > sumatriptan > D-1997. The effects to D-1997 were resistant to intravenous (i.v.) pretreatment with 5-HT2 and 5-HT3/5-HT4 receptor antagonists. Remarkably, the effects induced by lower (10-100 microg/min), but not higher (300-1000 microg/min), doses of D-1997 were blocked by high doses of methiothepin (1 and 3 mg/kg, i.v.), as previously shown with 5-HT. In addition, GR-127935 (1-10 microg/kg, i.v.), partially and dose-dependently antagonized D-1997-induced responses. However, the effects of D-1997 remained unaltered after blockade of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, or inhibition of 5-HT-uptake or cyclo-oxygenase, depletion of biogenic amines or blockade of Ca2+ channels. These results may support our previous contention that lower doses of 5-HT elicit external carotid vasoconstriction in vagosympathectomized dogs by activation of 5-HT1B/1D receptors, whilst higher doses of 5-HT stimulate a novel vasoconstrictor mechanism.

A cDNA clone, CanTUB, encoding a putative beta-tubulin protein was isolated from a cDNA library constructed from 5-day old chickpea (Cicer arietinum) epicotyls. Analysis of its deduced amino acid sequence showed all the typical structural motifs of plant beta-tubulins. Putative sequences for autoregulation and tubulin mRNA stability, GTP and Ca2+/MAPs (microtubule-associated proteins) binding sites were present. Southern blot analysis of chickpea genomic DNA revealed that there are multiple beta-tubulin genes. The level of expression of beta-tubulin genes was correlated with the rate of growth in either seedlings and adult plants. The transcript levels of beta-tubulin genes were higher in actively elongating tissues such as etiolated epicotyls, roots and stem tissues of adult plants. Brassinolide-induced growth in chickpea epicotyls was accompanied by promotion of the expression of the gene coding for beta-tubulin.

Introduction: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The Intercellular Adhesion Molecule plays a fundamental part in the migration of T cells to the inflammed tissues. It is known that there is an increase in the expression of endothelial cells and other cells found in lesions of the central nervous system of MS patients. ICAM-I may be detected in its soluble form in serum and it is of interest to understand its behaviour in this liquid since it is easily accessible., Material and Methods: We studied the concentration of soluble ICAM-I in the serum of patients with MS: one group which had clinical attacks were studied whilst in remission; another had the chronic progressive clinical form and a third group had optic neuritis as the probable initial sign of the disorder. Within the different clinical forms, some patients received treatment with beta-interferon or azathioprine and others did not., Results and Conclusions: We found a significant increase in the levels of soluble ICAM-I in patients with inactive, untreated MS as compared with normal persons, with no difference found between the different clinical types.

Brain acetylcholinesterase (AChE) forms stable complexes with amyloid-beta peptide (Abeta) during its assembly into filaments, in agreement with its colocalization with the Abeta deposits of Alzheimer's brain. The association of the enzyme with nascent Abeta aggregates occurs as early as after 30 min of incubation. Analysis of the catalytic activity of the AChE incorporated into these complexes shows an anomalous behavior reminiscent of the AChE associated with senile plaques, which includes a resistance to low pH, high substrate concentrations, and lower sensitivity to AChE inhibitors. Furthermore, the toxicity of the AChE-amyloid complexes is higher than that of the Abeta aggregates alone. Thus, in addition to its possible role as a heterogeneous nucleator during amyloid formation, AChE, by forming such stable complexes, may increase the neurotoxicity of Abeta fibrils and thus may determine the selective neuronal loss observed in Alzheimer's brain.

Two cDNAs, CanST-1 and CanST-2, encoding two different growth-related organ-specific sequences have been isolated from a cDNA library from growing epicotyls of Cicer arietinum. An intriguing property of these two clones is the presence in their coding region of a repeated sequence which is highly conserved except for the number of repeats. The corresponding genes of CanST-1 and CanST-2 encode for proteins related to elongation processes. CanST-1 and CanST-2 are up-regulated during epicotyl growth, the transcript levels of both clones decrease when the growth of epicotyls is inhibited by several treatments and their expression increases when epicotyls resume growth. Furthermore, clones CanST-1 and CanST-2 are tissue-specific and are only expressed in epicotyls, mesocotyls, roots and stem tissues whose cells undergo elongation processes. Neither clone was found to be expressed in other organs such as cotyledons, leaves, flowers, pods and immature seeds. The results of auxin (IAA) and brassinolides (BR) treatments suggest that the processes in which the proteins encoded by CanST-1 and CanST-2 are involved are not mediated by these hormones.

The relationship between the pharmacokinetics and the antinociceptive effect of diclofenac was evaluated using the pain-induced functional impairment model in the rat. Male Wistar rats were injected with uric acid in the knee joint of the right hind limb, which induced its dysfunction. Once the dysfunction was complete, animals received a p.o. dose of 0.56, 1, 1.8, 3.2, 5.6 or 10 mg/kg of sodium diclofenac, and the antinociceptive effect and drug blood concentration were simultaneously evaluated at selected times for a period of 6 h. Diclofenac produced a dose-dependent antinociceptive effect, measured as a recovery of the functionality of the injured limb. However, the onset of the antinociceptive effect was delayed with respect to blood concentrations. Moreover, the effect lasted longer than expected from pharmacokinetic data. Therefore, when functionality index was plotted against diclofenac blood concentration, an anticlockwise hysteresis loop was observed for all doses. Hysteresis collapse was achieved using the effect-compartment model, and the plot of functionality index against diclofenac concentration in the effect-compartment data was well fitted by the sigmoidal Emax model. Our data suggest slow equilibrium kinetics between diclofenac concentration in blood and at its site of action, which leads to a delayed onset of the antinociceptive effect as well as a longer duration of the response resulting from drug accumulation in synovial fluid.

Objective: To determine the prevalence and clinical significance of antiphospholipid antibodies (aPL) in a cohort of patients with primary Sjögren's syndrome (SS)., Methods: Eighty patients with primary SS were studied prospectively. The prevalence of aPL and characteristics of the clinical and laboratory features of these patients were compared with those of the following groups of patients: (i) 50 patients with SS associated with systemic lupus erythematosus (SLE); (ii) 100 patients with SLE without SS; and (iii) 100 healthy blood donors from the blood bank of our hospital., Results: Only 11 (14%) patients with primary SS were found to have aPL (anticardiolipin antibodies or lupus anticoagulant, or both) in their sera, but anti beta 2-glycoprotein I antibodies were not detected in any patient. In contrast, aPL were detected in 12 (24%) patients with SS secondary to SLE and in 21 (21%) patients with SLE without SS. None of the healthy controls presented aPL in their sera. Patients with primary SS presented a lower prevalence of thrombocytopenia (p < 0.05) and livedo reticularis (p < 0.01) compared with the other two groups of patients. No patient with primary SS was diagnosed as having an antiphospholipid syndrome (APS), while 4 (8%) patients with secondary SS and 9 (9%) with SLE without SS were found to have APS (p < 0.05)., Conclusion: In patients with primary SS, aPL are present in a lower percentage than in patients with SS secondary to SLE or in patients with SLE without SS. The presence of aPL in these primary SS patients is not associated with the clinical events of APS.

Background: To determine the clinical and immunologic characteristics of a large cohort of patients with primary Sjörgen's syndrome (SS) and to asses if the sex, the age at onset, the time of evolution and the immunologic pattern define different subsets with specific characteristics., Patients and Methods: We included 80 patients (76 female and 4 male) that were prospectively studied at our Unit. All patients fulfilled the European Community criteria proposed in 1993 for the diagnosis of SS., Results: Mean age of patients was 62 years with a mean disease duration of 8 years. The most frequently observed clinical manifestations were xerostomia (96%), xerophthalmia (94%) and parotidomegaly (46%). The main extraglandular manifestations were arthritis (45%), Raynaud's phenomenon (20%) and liver involvement (19%). The immunologic study showed antinuclear antibodies in 82% of patients, rheumatoid factor in 45%, anti-Ro/SS-A in 40% and anti-La/SS-B in 20%. In patients with an onset of disease before the age of 40 years, a higher prevalence of parotidomegaly, peripheral neuropathy, cutaneous vasculitis, rheumatoid factor, anti-Ro/SS-A and anti-La/SS-B antibodies was observed. A disease duration longer than 10 years was associated with a higher prevalence of pulmonary involvement and more focus of mononuclear cells in the minor salivary glands. Clinical manifestations associated to any one or more immunologic marker (rheumatoid factor, anti-Ro/SS-A and/or anti-La/SS-B) were Raynaud's phenomenon, arthritis, thyroid disease, cutaneous vasculitis and peripheral neuropathy., Conclusions: Primary SS is an autoimmune disease characterized by a marked heterogeneity in the clinical presentation and evolution, thus allowing the definition of several subsets of patients with their own clinical and immunological characteristics.

Contribution of a case report of vesical small cell carcinoma (SCC) seen at our Centre and managed with partial cystectomy and systemic chemotherapy (CMT) with M-VAC. SCC is an uncommon neoplasia of the bladder usually associated with an aggressive behaviour. The effectiveness of radical surgery has not been demonstrated, so a conservative treatment was chosen which has allowed to preserve a high quality of life until now, 36 months after diagnosis. The studies of local and distant relapses show no signs of residual disease.

We determined the prevalence and relationship with clinical manifestations of antibodies to thromboplastin (aTP) in 92 patients with systemic lupus erythematosus (SLE). Thirty-two (35%) patients had aTP: 13 (14%) were positive for IgG aTP, 13 (14%) for IgM aTP, and 6 (7%) for both. Patients with aTP had an increased incidence of thrombosis (p = 0.01), thrombocytopenia (p < 0.001), hemolytic anemia (p < 0.001), and fetal losses (p = 0.03). When the IgG and IgM aTP isotypes were analysed separately, the IgG aTP were found to be associated with thrombosis (p < 0.001), thrombocytopenia (p < 0.001), and fetal losses (p = 0.02). The IgM aTP were associated with hemolytic anemia (p < 0.001). A correlation was found between the titers of aTP and those of anticardiolipin antibodies, in both IgG (p < 0.01, r = 0.6) and IgM (p < 0.01, r = 0.64) isotypes, and between the titers of IgG aTP and the diluted Russell's viper venom time used to detect the lupus anticoagulant (p < 0.001, r = 0.42). This test is a reliable, reproducible and sensitive assay for the detection of antiphospholipid antibodies, specially in those patients under anticoagulant therapy.

Objective: To determine the prevalence and correlation with clinical manifestations of the IgG and IgM isotypes of antibodies to cardiolipin (aCL), phosphatidic acid (aPA), phosphatidylinositol (aPI) and phosphatidylserine (aPS) in patients with systemic lupus erythematosus (SLE)., Methods: Clinical and laboratory features of 92 consecutive unselected patients with SLE were prospectively studied over two years. aCL, aPA, aPI and aPS were determined by ELISA., Results: aCL were detected in 34 (37%) patients, aPA in 26 (28%), aPI in 22 (24%), and aPS in 29 (32%). A significant association was found between the appearance of thrombosis and the presence of IgG aCL (p < 0.001) and IgG aPS (p < 0.05). A significant association was also found between thrombocytopenia and the presence of IgG aCL (p < 0.001), IgG aPA (p < 0.01), IgG aPI (p < 0.05), and IgG aPS (p < 0.001). The development of hemolytic anemia was associated with the detection of IgM aCL (p < 0.001), IgM aPA (p < 0.05), IgM aPI (p < 0.001), and IgM aPS (p < 0.01)., Conclusion: We found a relatively high prevalence of aCL, aPA, aPI and aPS in our SLE population and confirmed the presence of a correlation between the IgG isotype of these antibodies and thrombosis and thrombocytopenia, and also between the IgM isotype and hemolytic anemia. These results demonstrate the variety of antiphospholipid antibodies that can be detected in SLE patients, as well as their association with the clinical manifestations of the antiphospholipid syndrome.

The effects of caffeine and nitric oxide synthesis inhibition on the antinociceptive action of ketorolac were assessed using the pain-induced functional impairment model in the rat. Nociception was induced by the intra-articular injection of uric acid. Ketorolac, but not caffeine, produced an antinociceptive effect which was reduced by NG nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis. Caffeine coadministration potentiated the ketorolac effect. L-NAME induced a dose-dependent reduction of this potentiation. The results suggest the participation of the L-arginine-nitric oxide-cyclic GMP pathway in the caffeine potentiation of ketorolac-induced antinociception.

The urinary C-peptide excretion was measured in a healthy standardized population sample of 160 subjects from 20 to 90 years of age, homogeneously distributed by age and sex. Urinary C-peptide excretion corresponded to 7% of the total amount released. The daily C-peptide excretion was 61.23 +/- 2.2 (S.E.) microg in the whole sample which corresponds to 41.9 +/- 1.5 IU of insulin secreted/day (I(CP)d), without sex differences. There is an increase of the I(CP)d value from the young to the healthy middle-aged person, but when the results were corrected for standard amounts of excreted creatinine (1 g) and urea (22 g) the age-dependent increase is to be observed during the whole adult life span. Assuming that cross-sectionally observed data are representative of the individual changes, it is concluded that age alone increases insulin secretion. The results which may be useful as reference values for clinical application were as follows: (A) in 5 diabetes type II patients in which the I(CP)d value was measured several times a week, the intraindividual variation coefficient was 10.9 +/- 7.2%;(B) in a sample of 47 type II diabetic patients of both sexes, between 51 and 70 years of age, a clear correlation was found between I(CP)d and the results of the glucagon stimulation test, mainly regarding the relationship between I(CP)d and the planimetrically measured area under the curve (r = 0.7, P < 0.0001); (C) in 7 obese non-diabetic individuals of similar ages the influence of the hypocaloric diet on the I(CP)d value was more evident than the use of C-peptide blood determinations before or after glucagon. Finally, the I(CP)d values of type II diabetes patients with insulin requirement (n = 27) were significantly lower than in the healthy control group (31.1 +/- 24.0 vs. 45.0 +/- 20.4), while diabetic patients without insulin requirement showed significantly higher values (73.0 +/- 33.0) (n = 27). These clinical studies primarily focused on the physiology of human ageing justify the measurement of C-peptide urinary excretion for evaluating daily insulin secretion in patients with type II diabetes.

1. 5-Hydroxytryptamine (5-HT) can produce vasodilatation or vasoconstriction of the canine external carotid bed depending upon the degree of carotid sympathetic tone. Hence, external carotid vasodilatation to 5-HT in dogs with intact sympathetic tone is primarily mediated by prejunctional 5-HT1-like receptors similar to the 5-HT1D subtype, which inhibit the carotid sympathetic outflow. The present investigation is devoted to the pharmacological analysis of the receptors mediating external carotid vasoconstriction by 5-HT in vagosympathectomized dogs. 2. Intracarotid (i.c.) infusions for 1 min of 5-HT (0.3, 1, 3, 10, 30 and 100 micrograms) resulted in dose-dependent decreases in both external carotid blood flow and the corresponding conductance; both mean arterial blood pressure and heart rate remained unchanged during the infusions of 5-HT. These responses to 5-HT were resistant to blockade by antagonists at 5-HT2 (ritanserin) and 5-HT3/5-HT4 (tropisetron) receptors, but were partly blocked by the 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (0.3 mg kg-1); higher doses of methiothepin (1 and 3 mg kg-1) caused little, if any, further blockade. These methiothepin (3 mg kg-1)-resistant responses to 5-HT were not significantly antagonized by MDL 72222 (0.3 mg kg-1) or tropisetron (3 mg kg-1). 3. The external carotid vasoconstrictor effects of 5-HT were mimicked by the selective 5-HT1-like receptor agonist, sumatriptan (3, 10, 30 and 100 micrograms during 1 min, i.c.), which produced dose-dependent decreases in external carotid blood flow and the corresponding conductance; these effects of sumatriptan were dose-dependently antagonized by methiothepin (0.3, 1 and 3 mg kg-1), but not by 5-HT1D-like receptor blocking doses of metergoline (0.1 mg kg-1). 4. The above vasoconstrictor effects of 5-HT remained unaltered after administration of phentolamine, propranolol, atropine, hexamethonium, brompheniramine, cimetidine and haloperidol, thus excluding the involvement of alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors. Likewise, inhibition of either 5-HT-uptake (with fluoxetine) or cyclo-oxygenase (with indomethacin), depletion of biogenic amines (with reserpine) or blockade of calcium channels (with verapamil) did not modify the effects of 5-HT. 5. Taken together, the above results support our contention that the external carotid vasoconstrictor responses to 5-HT in vagosympathectomized dogs are mainly mediated by activation of sumatriptan-sensitive 5-HT1-like receptors. It must be emphasized, notwithstanding, that other mechanisms of 5-HT, including an interaction with a novel 5-HT receptor (sub)type and/or an indirect action that may lead to the release of a known (or even unknown) neurotransmitter substance cannot be categorically excluded.

We have performed this prospective study to address the question of whether there is an association between the outcome following cataract surgery and the distance from the patient's home to the place of surgery. Three hundred and forty consecutive out-patient extracapsular cataract extractions were evaluated. According to the distance, the cases were grouped into two categories, 183 cases in the nearest group (Group 1) and 157 cases in the farthest group (Group 2). A best corrected visual acuity of 0.5 or better was achieved in 90% of patients, 6 between the groups. No significant differences in rates for operative and postoperative complications were identified. This study does not show that the distance from the patient's home to the surgical site has had any adverse effect of surgical outcome or in rates of complications.

The analgesic effects of acetaminophen, p.o., (ACE) and d-propoxyphene, s.c., (PROP) administered either separately or in 24 different combinations were determined in a model of pain-induced functional impairment in the rat. This allowed us to detect the analgesic interaction profile of the combinations. Furthermore, we set out to determine the optimal degree of enhancement obtained with a specific combination of the above drugs by means of the surface of synergistic interaction (SSI) of the combinations. This parameter was calculated from the total analgesic effect produced by the combination after having subtracted the analgesic effect produced by each drug alone. The ED50s for ACE and PROP were 286.1 +/- 1.4 mg/kg and 66.3 +/- 1.2 mg/kg, respectively. Over the dose ranges used, the analgesic activities of both ACE and PROP tended to be smaller than those of their respective combinations. Furthermore, 11 combinations showed various degrees of enhancement (p<0.01), while the others (13) exhibited additive analgesic effects. The combination of ACE (562.3 mg/kg) and PROP (56.2 mg/kg) produced the maximum analgesic effect. However,5 combinations of ACE with PROP (177.8-56.2, 316.2-10.0, 316.2-17.8, 316.2-56.2 and 562.3-10.0 mg/kg) produced the highest enhancement. The SSI clearly showed which combination of these analgesic drugs produced the highest degree of enhancement in the rat. This study shows that a specific combination ratio of analgesic drugs can produce optimum enhancement of their analgesic effects.

The possibility that activation of opioid receptors is involved in the analgesic activity of ketorolac was explored. The analgesic effects of ketorolac, of ketocyclazocine, the prototype kappa-agonist, and of morphine, the prototype mu-agonist, were assayed in the pain-induced functional impairment model in the rat. All three drugs induced a significant analgesic effect in this model. Naloxone was able to antagonize the effects of ketocyclazocine and morphine. However, the effect of ketorolac was not blocked by naloxone, although a high dose, 3.2 mg kg-1, capable of blocking kappa-receptors was used. It is concluded that activation of mu- or kappa-opioid receptors, by either a direct or an indirect mechanism, does not play a role in the analgesic activity of ketorolac.

The involvement of nitric oxide in the antinociception produced by ketorolac was assessed using the pain-induced functional impairment model in the rat: 800 micrograms of NG-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthesis, or saline was injected intra-articularly in a hind limb joint previously injured with uric acid. Animals then received ketorolac, dipyrone or no drug. Ketorolac and dipyrone produced a significant antinociceptive effect which was reduced by pretreatment with NG-nitro-L-arginine methyl ester, but not with saline. It is concluded that the antinociceptive effect of both drugs involves the local participation of nitric oxide.

We present a 6-month-old girl with the unusual combination of microphthalmos, facial capillary hemangioma and Dandy-Walker malformation. This is the fourth case with such an association reported in the literature. On the basis of the experience with our patient and with those previously reported, we stress the importance of performing brain-imaging studies on all infants with large facial hemangiomas, or if unusual ophthalmic findings are present.

We present the two first Spanish cases about the endodermic heterotopia of the atrioventricular node. This is an infrequent and probably congenital lesion, with a not well known histogenesis and associated with heart blocks and sudden death, which affects women in most cases. The first observation attaches a 55 years-old woman with an acute leukemia who died during the first chemotherapy treatment. The second observation affects a 25 years-old woman, with previous heart blocks, who died suddenly. A complete post-mortem study was done in both cases (including cardiac conduction system) with conventional histopathological study and extensive immunohistochemical panel. Ultrastructural study of first case was done. In both cases a multicystic and tubular lesion was found in the atrioventricular node region. It was lined by two or more cubic and polyhedral cell layers. In the cystic lumina an eosinophilic material, which corresponded to acid and neutral mucosubstances was found. The maximal lesion's diameter were: 0.9 and 1.3 cm, respectively. Immunohistochemically it was detected in both cases strong positivity for cytoqueratines, EMA, CEA and focally for chromogranin A and calcitonin. The immunohistochemical results in both cases express and endodermic differentiation (with neuroendocrine fenotipe).

5-Hydroxytryptamine (5-HT) inhibits contractile responses to adrenergic nerve stimulation in several blood vessels and organs. We have now investigated the potential ability of 5-HT to inhibit the pressor responses caused by preganglionic sympathetic stimulation (T7-T9) in pithed rats. Sympathetic stimulation (0.03, 0.1, 0.3, 1 and 3 Hz) resulted in frequency-dependent increases in diastolic blood pressure; these effects were augmented after i.v. treatment with desipramine (50 micrograms/kg). During continuous infusions of 5-HT (1.8, 3.1, 5.6 and 10 micrograms/kg.min, i.v.), but not of saline, the pressor responses were dose-dependently inhibited in both control and desipramine-pretreated rats; this inhibitory effect of 5-HT was significantly more pronounced at lower frequencies of stimulation. In contrast, the above infusions of 5-HT did not inhibit the pressor responses induced by i.v. bolus injections of exogenous norepinephrine (up to 3 micrograms/kg). Taken together, the above findings suggest an operative 5-HT-induced prejunctional inhibition of sympathetic nerve activity on the systemic vasculature in vivo.

Intelligent organizations (IO) represent a valuable tool to organize and guide dengue fever surveillance, prevention and control interventions. IO entail state of the art technology in managerial science to generate behavioral frameworks of organizational structures and policies. They present a systematic description of problems and construct computerized models to develop systemic thinking; they produce a shared vision and build progressive mental learning and advancement models. Also, IO promote team building and personal control skills. Scientific-technological advances have produced a wealth of information in medicine, with the corresponding growth of organizations and difficulty of responses because of sudden and incessant change. This new environment calls for the application of IO know-how. This article is oriented to prove the usefulness of the IO technology in the ordering and systematization of the reports about the medical sciences facts. Dengue was chosen to exemplify the use of IO technology as it represents an increasing health problem in America, as well as in Mexico; it is so complex that it can evolve to a more serious problem, besides it can be analyzed within a systemic method.

The noradrenergic innervation of the rat thymus during pregnancy and the post partum period was examined by a sucrose glyoxylic acid method for catecholamines, and by high pressure liquid chromatography. Fluorescent nerves decreased in number throughout pregnancy when there was an overall loss in thymic weight due to cortical involution. These changes are maximal by parturition. There was a dramatic increase in nerves between d 21 of pregnancy and d 1 after parturition, especially in the capsule and around blood vessels in the connective tissue septa. The neonates were removed at parturition and thymic weight was rapidly regained. The increased numbers of nerves remained throughout this post partum period. Noradrenaline levels in the thymus altered in a similar pattern throughout pregnancy and the post partum period, but did not parallel thymic weight changes. The mean noradrenaline concentration in the virgin thymus was 1063 +/- 107 pg/mg protein. Levels remained similar during early pregnancy and increased significantly at d 16. Virgin levels were regained by d 21. Values peaked after parturition but rapidly decreased over the next 3 days, and remained at or below virgin levels to d 28 except for a transient rise at d 10 post partum. Adrenaline values were consistently below detection levels. This study shows that there are variations in both nerves visualised, and in neurotransmitter (noradrenaline) content in the thymus during the course of pregnancy and the post partum period. Thus thymic function could be influenced by central events (levels of catecholamines in peripheral blood) as well as local events mediated by transmitter changes in nerves.

Ten prevalences of disease or functional affections due to degenerative processes that statistically show a significant age-dependent behaviour were taken as variables for a biological aging study of a population living in a district of Madrid. The cross-sectional procedure consisted in grouping the disease prevalences by age decades and calculating aging by the vector-analytical mathematical method in which the age-dependent prevalence was the result of one of the total of 10 vector components. The progressive accumulative increase of the vector distances from the origin as well as the distances among the vectors in relation to the population age was considered as biological aging. On the basis of similar mathematical models the results were compared with those obtained from other populations in which different indicators were used; the results are concurrent, but show here a greater aging acceleration than when the population was composed solely of healthy individuals. This is considered a logical consequence due to the sample composition. The presented procedure, focussed epidemiologically, can be useful in comparing aging of populations.

The ability of caffeine to potentiate the analgesic effect of aspirin was studied in the pain-induced functional impairment model in the rat. Female Wistar rats received an intra-articular injection of 30% uric acid in the right hind limb, inducing its dysfunction. Once the dysfunction was complete, animals received aspirin oral doses of 0, 0.55, 0.98, and 1.74 mmol/kg with and without 0.17 mmol/kg of caffeine, and the recovery of functionality over time was considered as an expression of analgesia. Blood samples were drawn simultaneously with hind limb functionality determinations, and plasma concentrations of aspirin, salicylic acid, and gentisic acid were measured by high-performance liquid chromatography. Aspirin induced a dose-dependent analgesic effect. Caffeine alone was ineffective. However, caffeine significantly increased the analgesic effect of aspirin at all doses, without modifying aspirin, salicylic acid, or gentisic acid plasma levels. It is concluded that caffeine potentiates the analgesic effect of aspirin by a pharmacodynamic, but not by a pharmacokinetic mechanism.

1. The present study was designed to analyse the effect of the centrally-acting sympatho-inhibitory drugs, prazosin and ketanserin, on the increase in external carotid blood flow (external CBF) produced by 5-hydroxytryptamine (5-HT) in pentobarbital-anaesthetized dogs. 2. Intracarotid (i.c.) infusions of 5-HT (10 micrograms min-1 during 1 min) produced an increase in external CBF without changes in mean arterial blood pressure or heart rate. This response to 5-HT was dose-dependently blocked by intravenous (i.v.) administration of prazosin (1, 3, 10, 30 and 100 micrograms kg-1) or ketanserin (10, 30, 100 and 300 micrograms kg-1). 3. Furthermore, 5-HT-induced increase in external CBF was inhibited by either the ganglionic blocking agent, mecamylamine (0.03, 0.1, 0.3, 1, 3 and 10 mg kg-1), the mixed 5-HT1-like and 5-HT2 receptor antagonist, methiothepin (3, 10 and 30 micrograms kg-1) or the 5-HT1A ligand, spiroxatrine (10, 30, 100 and 300 micrograms kg-1). In contrast, the selective 5-HT2 and 5-HT1C receptor antagonist, ritanserin (30 and 100 micrograms kg-1, i.v.), was unable to block the above response to 5-HT. 4. It is concluded that the inhibition of 5-HT-induced increase in external CBF by prazosin, ketanserin, mecamylamine and spiroxatrine is due to a reduction in the sympathetic tone and not to a blockade of 5-HT receptors.