Combined anti CXC receptors 1 and 2 therapy is a promising anti-inflammatory treatment for respiratory diseases by reducing neutrophil migration and activation.

Neutrophil infiltration and activation in the lung are important pathophysiological features in COPD, severe asthma and bronchiectasis mostly mediated by CXCL8 and CXCL1 via CXCR1 and CXCR2. No thorough study to date has been performed to compare the anti-inflammatory effect profile of dual CXCR1/2 vs. selective CXCR2 antagonists in relevant human neutrophil assays and pulmonary inflammation models. Dual CXCR1/2 (SCH527123, diaminocyclobutandione-1) and selective CXCR2 (SB265610, thiopyrimidine-1) antagonist activity and receptor residence time were determined by [(35)S]GTPγS binding in human (h)- and guinea pig (gp)-CXCR1 and CXCR2 overexpressing membranes. h-neutrophil chemotaxis, degranulation and ROS production were established using CXCL8 or CXCL1 to evaluate dual CXCR1/2- or selective CXCR2-dependent activities. LPS-induced lung inflammation in gp was selected to assess in vivo potency. Dual CXCR1/2 antagonists blocked both CXCL8 and CXCL1-induced h-neutrophil functions and [(35)S]GTPγS binding. In contrary, selective CXCR2 antagonists displayed significantly reduced potency in CXCL8 -mediated h-neutrophil responses despite being active in CXCR2 assays. Upon LPS challenge in gp, administration of SCH527123 inhibited the increase of neutrophils in BALF, modestly reduced blood neutrophils and induced minor neutrophil accumulation in bone marrow. Differentiation of CXCR1/2 vs. CXCR2 antagonists could not be extended to in vivo due to differences in CXCR1 receptor homology between h and gp. Dual CXCR1/2 therapy may represent a promising anti-inflammatory treatment for respiratory diseases reducing more effectively neutrophil migration and activation in the lung than a CXCR2 selective treatment. However, the in vivo confirmation of this claim is still missing due to species differences in CXCR1.

House dust mite induces direct airway inflammation in vivo: implications for future disease therapy?

House dust mite (HDM) is the major source of allergen in house dust and is strongly associated with the development of asthma. HDM can evoke a direct, nonallergic inflammatory reaction in vitro. We aimed to determine whether this apparent nonallergic, inflammatory response can be observed in a more complex in vivo setting. Vehicle, Alum or HDM (Dermatophagoides pteronyssinus 5 microg, i.p. with Alum) sensitised Brown-Norway rats were challenged intratracheally with vehicle (saline), HDM (Der p 10 microg) or heat-inactivated HDM on day 21. Lung function changes and the associated inflammatory response were evaluated. Tissue and bronchoalveolar lavage from Alum sensitised Der p challenged animals exhibited strong eosinophilia and neutrophilia associated with an early release of pro-inflammatory cytokines (interleukin-13 and 1beta, eotaxin and thymus and activation-regulated chemokine). This response was not attenuated by removal of HDM-associated protease activity. Interestingly, the vehicle sensitised group (no Alum) lacked this inflammatory response. HDM allergen evokes nonallergic airways inflammation with an inflammatory profile similar to that of the asthmatic airway. This response, independent of the protease activity of the HDM extract, appeared to be linked to prior administration of the adjuvant Alum and the subsequent increase in total immunoglobulin E. This finding could have important implications in the development of future asthma therapies.

Inferring genetic parameters of lactation in Tropical Milking Criollo cattle with random regression test-day models.

This study inferred genetic and permanent environmental variation of milk yield in Tropical Milking Criollo cattle and compared 5 random regression test-day models using Wilmink's function and Legendre polynomials. Data consisted of 15,377 test-day records from 467 Tropical Milking Criollo cows that calved between 1974 and 2006 in the tropical lowlands of the Gulf Coast of Mexico and in southern Nicaragua. Estimated heritabilities of test-day milk yields ranged from 0.18 to 0.45, and repeatabilities ranged from 0.35 to 0.68 for the period spanning from 6 to 400 d in milk. Genetic correlation between days in milk 10 and 400 was around 0.50 but greater than 0.90 for most pairs of test days. The model that used first-order Legendre polynomials for additive genetic effects and second-order Legendre polynomials for permanent environmental effects gave the smallest residual variance and was also favored by the Akaike information criterion and likelihood ratio tests.

Event-related brain potentials in reading disabled children during an inverse serial digit detection task.

It has been reported that limitations in different components of working memory could underlie reading disabilities. In addition, reading-disabled (RD) children seem to perform worse when digit name processing is required. With the purpose to explore further these assumptions one inverse serial digit detection task was evaluated using event-related brain potentials in fifteen 8-year-old RD children and a control group (CG). CG obtained significantly more correct responses than RD, but had similar reaction times. The experimental task performance significantly correlated with the performance on reading tests. Difference event-related potentials showed a voltage component peaking at 160 ms over frontocentral leads (P160d) that reached significantly higher amplitude in RD group, and was interpreted as an index of the amount of neural resources involved in visual working memory load. The amplitude of P160d significantly correlated with reading speed, the backward digit span and with the experimental task performance. Present results point out that highly demanding working memory tasks reveal behavioral and electrophysiological differences in RD children with respect to healthy controls.

Time reproduction disturbances in ADHD children: an ERP study.

Sixteen ADHD children and a control group were asked to reproduce the varying time duration of successively presented visual stimuli. Time estimation was poorer in ADHD children, who showed more impulsive errors. ERPs exhibited similar grand-mean waveforms for both groups during the estimating period, but they were significantly different during the reproducing stage, when an early positive wave over frontal regions characterized the control group, interpreted as memory-guided motor output, followed by a slow negativity probably reflecting an inhibitory motor closure process, both probably involving central executive networks that seem to be improperly activated in ADHD children.

Inducible nitric oxide synthase is involved in the mechanisms of cocaine enhanced neuronal apoptosis induced by HIV-1 gp120 in the neocortex of rat.

Cocaine, often abused by human immunodeficiency virus (HIV) infected patients, has been suggested to worsen the HIV associated dementia via unknown mechanisms. Here we report that subchronic treatment with a dose of cocaine (30 mg/kg i.p.), unable per se to cause neuronal death, increases the number of apoptotic cells typically observed in the neocortex of rats treated with HIV-1 gp120 (100 ng given i.c.v.). A pre-treatment with MK801 (0.3 mg/kg i.p.), a NMDA receptor antagonist, L-NAME (10 mg/kg i.p.) and 7-nitroindazole (50 mg/kg i.p.), two specific inhibitors of NOS, or with 1400 W (1 mg/kg s.c.), a selective inhibitor of inducible NOS (iNOS), minimized neurotoxicity by combined administration of cocaine and gp120 thus implicating iNOS. This conclusion is supported by the evidence that cocaine increases brain neocortical citrulline, the co-product of NO synthesis.

Event-related brain potentials during a continuous performance test (CPT) task in normal children.

BACKGROUND: Continuous Performance Test (CPT) is a commonly used paradigm to assess attention disorders that could involve working memory processes. METHODS: Event-related potentials (ERPs) during a CPT (X-AX) test were obtained in 16 healthy male students, with ages ranging from 9 to 11 years (X = 10.3). In grouped averaged ERPs, an endogenous slow positive potential was recorded in the first task (infrequent letter detection); maximum was at 460 msec with a slight lateralization tendency toward left parietal area. In the second task (target detection with an A as warning signal), an early (maximum at 330 msec) and more acute peak was detected without evidence of any lateralization. RESULTS: Reaction times were significantly shorter for the second task. Electrophysiologic differences between both target conditions showed an early, remarkable, and statistically significant component located at the parietal area at 340 msec. CONCLUSIONS: These ERPs findings could be interpreted as correlates with working memory processes in children.

[Gestational diabetes mellitus and congenital malformations]. / Diabetes mellitus gestacional y malformaciones congénitas.

INTRODUCTION: Maternal diabetes mellitus affects approximately 5% of all pregnancies. Pregestational diabetes mellitus has been associated with a high risk of spontaneous abortions and congenital malformations during the first trimester of pregnancy then is considered teratogenic. This frequency of birth defects is three to fivefold increased compared with general population. Although an association of gestational diabetes mellitus (GDM) with an increase of congenital malformations has not been demonstrated, some clinical and epidemiological studies of this possible association have reported the presence of GDM in mothers of children with congenital malformations. THE OBJECTIVE: Of this study was to compare the prevalence of congenital malformations associated with GDM in relation to pregestational diabetes mellitus and general population. MATERIALS AND METHODS: In the present study 3 groups were compared: the group I was integrated by 112 new born of mothers with GDM; in the group 2, there were 30 new born from women with gestational diabetes mellitus. 103 new born from healthy women integrated the group 3. All patients were recruited consecutively during a period of 18 months. RESULTS: A total of 24 cases with congenital malformations were detected. The group with the higher prevalence was the group 2 (30%). We found a tendency to a higher risk of congenital malformations on the cases exposed to GDM (group 1) compared with the group not exposed (group 3). The analysis of the mothers background of the children from group 2 with congenital malformations showed a significant difference in the antecedent of previous macrosomic product in comparison with the antecedents of the mothers of the same group that bear healthy babies. COMMENT: The results of the analysis in the studied population did not show an association between GDM and congenital malformations, although there is a tendency to a higher prevalence in comparison with not exposed population. This could be due to the heterogeneity of the GDM; an entity usually detected late in pregnancy, but probably present since the first weeks of gestation when the teratogenic effect could occur. CONCLUSION: In the present study we found that the antecedent of previous macrosomic products is an important risk factor, therefore, such women require a close vigilance of the glucose levels before and during the first weeks of pregnancy in order to prevent congenital malformations, one of the principal causes of death in the new born.

Transitory cognitive impairment in epileptic children during a CPT task.

EEGs and behavioral responses were studied in two sex matched groups of 58 epileptic and 20 healthy children between 8 and 12 years of age, during the execution of a go-no go CPT (X; A-X) task to determine transitory cognitive impairment (TCI) incidence. Paroxysmal discharges were found on 87.9% and 5% of the EEGs in the epileptic and control groups respectively, with no differences related to sex. The predominant EEG findings with respect to paroxysmal discharges were the association of two or more types of paroxysms with frequency higher than 5/minute, an average duration less than 0.5 second and topographical distribution over temporal-parietal-occipital areas without significant interhemispheric differences. TCI was detected in 36.2% of epileptic children. The epileptic group showed significantly higher numbers of behavioral errors and longer reaction times (RTs) in relation to the control group. Analyzing RTs on the two blocks of the task, linear discriminant analysis showed an acceptable classification of TCI incidence between groups.

[Usefulness of cholinesterase determination in ascitic fluid in the differential diagnosis of ascites]. / Utilidad de la determinación de la colinesterasa en líquido ascítico en el diagnóstico diferencial de la ascitis.

BACKGROUND: Cholinesterase is an enzyme mainly synthesized in the liver that might play a role in the differential diagnosis of ascites. We prospectively compared the sensitivity, specificity and diagnostic usefulness of the ascites cholinesterase and the classical parameters, ascites total protein concentration and serum-ascites albumin gradient in the differential diagnosis of ascites. In addition, we evaluated the relationship between those parameters and the degree of liver failure. METHODS: A total of 91 patients with ascites were analyzed. According the final diagnosis, patients were classified in two groups, patients with signs of portal hypertension [n = 78] (60 with chronic liver disease, 5 chronic liver disease and hepatocellular carcinoma, 3 chronic liver disease and spontaneous bacterial peritonitis, 3 chronic liver disease and secondary peritonitis, 7 malignancy with liver involvement) and patients with no signs of portal hypertension [n = 13] (12 patients with peritoneal neoplasia without liver involvement and 1 tuberculous peritonitis). RESULTS: The sensitivity of the test for detecting portal hypertensive ascites was lowest for ascites cholinesterase less than 600 U/L (71.7%); intermediate with ascites total protein concentration less than 25 g/l (87.2%) and highest with serum-ascites albumin gradient at least 11 g/l (93.6%). The specificity for ruling out portal hypertensive ascites was 100 percent for ascites total protein > or = 25 g/l and ascites cholinesterase > or = 600 U/L and, 76.9 percent for serum-ascites albumin gradient < 11 g/l). Diagnostic efficiency (percentage of patients accurately classified) was greater for serum-ascitis albumin gradient (91.2%; IC95: 83-95.8), and lower for ascites total protein content (89%, IC95: 80.3-94.3) and, ascites cholinesterase (75.8%; IC95: 65.5-83.9). Ascites cholinesterase showed a significant relationship (p = 0.007) with the degree of liver failure measured by Pugh's classification. CONCLUSION: Serum-ascites albumin gradient was the test with best performance characteristics to identify patients with ascites related with portal hypertension. Our results suggest that ascites cholinesterase is more associated with the degree of liver failure than with the presence of portal hypertension.

Predictors of condom use in Mexican migrant laborers.

The purpose of this study was to explore predictors of condom use with occasional sex partners and regular sex partners, as well as carrying condoms in a new high-risk group for HIV infection, Mexican migrant laborers. This study extends previous findings by (1) exploring additional predictors not previously examined, (2) utilizing a large sample of male and female Mexican migrant laborers, (3) carefully controlling for the effects of various demographic and lifestyle variables related to condom use, and (4) assessing the interactive effects of gender on predictors of condom use. Snowball sampling was used to survey 501 adult Mexican migrant laborers. Results revealed that condom use with occasional sex partners was predicted by carrying condoms and condom self-efficacy and that women were more likely to use condoms with occasional partners when both men and women knew someone with HIV/AIDS. Condom use with regular sex partners was predicted by procondom social norms, less negative attitudes toward condoms, not knowing someone with HIV/AIDS, and condom self-efficacy. Carrying condoms was predicted by procondom social norms, less negative attitudes toward condoms, condom self-efficacy, worry about contracting HIV/AIDS, and women were more likely than men to carry condoms when both men and women were married. Understanding these findings, future research directions, and implications for condom promotion strategies with Mexican migrant laborers are discussed.

Mechanisms of the neuroprotective effect of aspirin after oxygen and glucose deprivation in rat forebrain slices.

Acetylsalicylic acid (ASA, Aspirin) is an anti-inflammatory drug with a wide spectrum of pharmacological activities and multiple sites of action. Apart from its preventive actions against stroke due to its antithrombotic properties, recent data in the literature suggest that high concentrations of ASA also exert direct neuroprotective effects. We have used an in vitro model of brain ischaemia using rat forebrain slices deprived of oxygen and glucose to test ASA neuroprotective properties. We have found that ASA inhibits neuronal damage at concentrations lower than those previously reported (0.1-0.5 mM), and that these effects correlate with the inhibition of excitatory amino acid release, of NF-kappaB translocation to the nucleus and iNOS expression caused by ASA. All of these three mechanisms may mediate the neuroprotective effects of this drug. Our results also show that the effects of ASA are independent of COX inhibition. Taken together, our present findings show that ASA is neuroprotective in an in vitro model of brain ischaemia at doses close to those recommended for its antithrombotic effects.

Use of brain slices in the study of pathogenic role of inducible nitric oxide synthase in cerebral ischemia-reperfusion.

We have recently demonstrated that inducible nitric oxide synthase (iNOS) is expressed in rat forebrain slices exposed to oxygen and glucose deprivation (OGD). Now, we have found that the expression of iNOS after OGD is time-dependent since 20 min of OGD produces the appearance of iNOS at earlier times than 10 min of OGD. OGD also causes neurotoxicity in this model, as revealed by the increase in excitatory amino acid, neuron specific enolase and lactate dehydrogenase (LDH) efflux to the incubation solution. Finally, the administration of the NMDA receptor antagonist MK-801 (100 nM) inhibits both the expression of iNOS and the release of LDH. Our findings demonstrate that this method may be considered an useful in vitro model of ischemia-reperfusion to determine the therapeutic role of neuroprotective tools.

Down-regulation of neuronal nitric oxide synthase by nitric oxide after oxygen-glucose deprivation in rat forebrain slices.

The precise role that nitric oxide (NO) plays in the mechanisms of ischemic brain damage remains to be established. The expression of the inducible isoform (iNOS) of NO synthase (NOS) has been demonstrated not only in blood and glial cells using in vivo models of brain ischemia-reperfusion but also in neurons in rat forebrain slices exposed to oxygen-glucose deprivation (OGD). We have used this experimental model to study the effect of OGD on the neuronal isoform of NOS (nNOS) and iNOS. In OGD-exposed rat forebrain slices, a decrease in the calcium-dependent NOS activity was found 180 min after the OGD period, which was parallel to the increase during this period in calcium-independent NOS activity. Both dexamethasone and cycloheximide, which completely inhibited the induction of the calcium-independent NOS activity, caused a 40-70% recovery in calcium-dependent NOS activity when compared with slices collected immediately after OGD. The NO scavenger oxyhemoglobin produced complete recovery of calcium-dependent NOS activity, suggesting that NO formed after OGD is responsible for this down-regulation. Consistently, exposure to the NO donor (Z)-1-[(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-iu m-1,2-diolate (DETA-NONOate) for 180 min caused a decrease in the calcium-dependent NOS activity present in control rat forebrain slices. Furthermore, OGD and DETA-NONOate caused a decrease in level of both nNOS mRNA and protein. In summary, our results indicate that iNOS expression down-regulates nNOS activity in rat brain slices exposed to OGD. These studies suggest important and complex interactions between NOS isoforms, the elucidation of which may provide further insights into the physiological and pathophysiological events that occur during and after cerebral ischemia.

Mexican use of lead in the treatment of empacho: community, clinic, and longitudinal patterns.

This paper discusses research designed to investigate community, clinic, and longitudinal patterns in use of lead as a treatment for empacho, a folk illness manifest by gastrointestinal symptoms. The same questionnaire used in a clinic-based study seven years previously in Guadalajara, Mexico, was used to interview a randomly selected community sample: in addition, the study was repeated at the same clinic sites that had been studied previously. The goals were to investigate: (1) What are community wide prevalences of empacho and use of lead based remedies? (2) To what extent are current patterns of use of lead for treatment of empacho in clinic-based samples similar to those seven years ago. The attributable risk to the population as a whole from use of lead based remedies was found to be 11% of the households of Guadalajara. Essentially this same estimate was seen for the 1987 and 1994 clinic populations. Interestingly, while percentages of lead users have declined since 1987, twice as great a percentage of informants reported treating empacho. Other patterns originally identified in 1987 persisted in 1994; lead use continues to be associated with lower levels of parental education and income.

Protective effect of N-(3-(aminomethyl)benzyl) acetamidine, an inducible nitric oxide synthase inhibitor, in brain slices exposed to oxygen-glucose deprivation.

It has been suggested that large amounts of nitric oxide (NO) produced by inducible NO synthase are involved in the mechanisms of neurotoxicity after cerebral ischaemia. We have recently demonstrated that inducible NO synthase was expressed within hours after rat forebrain slices were exposed to oxygen-glucose deprivation. Therefore, we sought to determine whether NO produced by inducible NO synthase contributes to tissue damage in this model, by using a new, highly selective, inhibitor of inducible NO synthase, N-(3-(aminomethyl)benzyl)acetamidine (1400W). We found that incubation with 1400W from the start of the oxygen-glucose deprivation period until the end of the experiment decreases tissue damage determined as lactate dehydrogenase (LDH) efflux 4 h after the oxygen-glucose deprivation period, the time at which inducible NO synthase expression is maximal in this model. This effect may be a result of direct inhibition of inducible NO synthase activity, raising the possibility of a clinical use of selective inhibitors of this NO synthase isoform in the management of cerebral ischaemia.

Neuronal expression of inducible nitric oxide synthase after oxygen and glucose deprivation in rat forebrain slices.

Nitric oxide (NO) overproduction has been postulated to contribute significantly to ischaemia-reperfusion neurotoxicity. Inducible or type II NO synthase (iNOS) synthesizes NO in large quantities for long periods of time. Therefore we investigated the expression and localization of iNOS after oxygen and glucose deprivation in rat forebrain slices. In this experimental model, calcium-independent NOS activity reached a maximum 180 min after the end of a 20 min oxygen-glucose deprivation period. During the same period of time, the calcium-independent activity was absent in control forebrain slices. To test whether this calcium-independent NOS activity was due to the expression of iNOS, the effects of the addition of dexamethasone, cycloheximide and pyrrolidine dithiocarbamate were determined. All of them inhibited the induction of the calcium-independent NOS activity measured in the rat forebrain slices after oxygen and glucose deprivation. Furthermore, oxygen and glucose deprivation caused the expression of the gene encoding iNOS in rat forebrain slices, as assessed by the detection of iNOS message and protein in these samples. A sixfold increase in the iNOS mRNA levels was observed at 180 min and the time-course of the expression of iNOS mRNA was in agreement with the temporal profile of iNOS enzymatic activity. Immunohistochemistry analysis revealed that iNOS was highly expressed in neurones, astrocytes and microglial cells. These results demonstrate for the first time that iNOS is expressed in neurones after oxygen and glucose deprivation, and that this expression occurs in short periods of time. These findings suggest that NO can play an important pathogenic role in the tissue damage that occurs after cerebral ischaemia.

Granulomatous amebic encephalitis due to Balamuthia mandrillaris (Leptomyxiidae): report of four cases from Mexico.

In this report, we describe four cases of granulomatous amebic encephalitis caused by Balamuthia (Leptomyxid ameba) in four previously healthy Mexican patients. All four cases were characterized by focal neurologic signs, increased intracranial pressure, and cerebral hyperdense lesions in computed tomography scans of the head. These patients underwent craniotomies for evaluation of mass lesions for possible brain tumors. Granulomatous chronic inflammatory reaction and amebic trophozoites were found in brain biopsies. At autopsy, areas of hemorrhagic encephalomalacia were located in both basal frontal lobes, right parieto-occipital lobes, and, less often, in the brainstem and cerebellum. Angiitis, necrotizing granulomatous encephalitis, and large numbers of amebic trophozoites in perivascular spaces were present. Amebic trophozoites were seen in the left adrenal gland in one of the cases. The amebas in all four cases were identified as Balamuthia mandrillaris (Leptomyxiidae) based on their reactivity with the anti-Balamuthia (Leptomyxiidae) serum in an immunofluorescence test.

Survey of condom-related beliefs, behaviors, and perceived social norms in Mexican migrant laborers.

This study reports findings from a survey of condom-related beliefs, behaviors, and perceived social norms in Mexican migrant laborers that live and work in the United States for extended periods of time. Snowball sampling was used to recruit 501 Mexican migrants from five "sending towns" in Jalisco, Mexico, with historically high rates of out-migration to the United States. Results showed that subjects reported few negative beliefs about condom use and high efficacy to use condoms in challenging sexual situations but social norms sanctioning condoms were limited. Results also revealed mixed knowledge of HIV transmission, poor knowledge of condom use, and higher condom use with occasional versus regular sex partners. Forty-four percent of male migrants reported sex with prostitutes while in the U.S., with married men reporting less condoms use with prostitutes than single men. It was concluded that condom promotion efforts with Mexican migrants should concentrate on men to encourage consistent use with occasional sex partners, including prostitutes. AIDS prevention education should be provided with sensitivity to the language needs, limited education, and extreme social and geographic marginality of this highly underresearched Latino population.