Silent brain infarct in migraine: Systematic review and meta-analysis.

BACKGROUND: While migraine, particularly migraine with aura, is a recognized risk factor for ischemic stroke, the association of migraine with silent brain infarction is a matter of debate, as studies on this topic have yielded conflicting results. METHODS: A systematic review of the literature was conducted of studies reporting migraine and silent brain infarction, assessed by magnetic resonance imaging, between January 1980 and April 2022, by consulting Medline and Embase databases. Studies with a control group were included in a meta-analysis of population-based studies. An exploratory meta-analysis of both population-based and clinical-based studies was further performed to test the association between migraine with aura and silent brain infarction. RESULTS: A total of 2,408 articles were identified, among which 24 were included in the systematic review and 10 in the meta-analysis. The meta-analysis of population-based studies showed no association of migraine with silent brain infarction (odds ratio (OR)=1.32 [95% CI 0.92;1.90], P=0.13) and migraine with aura with silent brain infarction (OR=1.56 [0.74;3.30], P=0.24). However, in the exploratory meta-analysis of population-based and clinical-based studies, migraine with aura was significantly associated with silent brain infarction (OR=1.91 [1.02;3.59], P=0.04) and to silent cerebellar infarcts (OR=2.57 [1.01;6.56], P=0.05). CONCLUSION: In this updated systematic review and meta-analysis of population-based studies, migraine and migraine with aura were not associated with silent brain infarction.

Ondas de choque. Evidencias y recomendaciones SETOC (Sociedad Española de Tratamientos con Ondas de Choque) / Current evidences in shockwave treatment. SETOC (Spanish Society of Shockwave Treatment) recommendations

El documento consenso SETOC muestra la evidencia científica de la tecnología en ondas de choque extracorpóreas (OCE) y ondas de presión radial (OPR) en diversidad de patologías musculoesqueléticas, cutáneas, espasticidad, urológicas, etc. Las OCE y las OPR son un tratamiento eficaz, seguro, no invasivo, coste-efectivo, bien tolerado por el paciente, sin necesidad de anestesia, que reduce la necesidad de cirugía, con menor riesgo de complicaciones y menor tiempo de recuperación que una cirugía. Por todo ello, las OCE y las OPR deberían ser la primera opción terapéutica de las patologías crónicas mencionadas, cuando las alternativas conservadoras hayan fallado, teniendo en cuenta las recomendaciones de este artículo, de las sociedades científicas y de la evidencia para cada tecnología (AU)

This SETOC consensus document shows the scientific evidence of the technology in shockwaves (SW) and radial pressure waves (RPW) in a variety of spasticity disorders, musculoskeletal, skin, urological diseases, etc. SW and RPW, without anesthesia, are an effective, safe, non-invasive, cost-effective treatment, which reduces the need for surgery, lower risk of complications, faster recovery and greater acceptability to patients than surgery. Consequently, SW and RPW should be the first therapeutic option in the aforementioned chronic pathologies, when conservative alternatives have failed. SETOC advises to follow the recommendations given in this article, including the ones given by SW scientific societies and best evidence for each technology as well (AU)

Clinical factors associated with discontinuation of ts/bDMARDs in rheumatic patients from the BIOBADASER III registry.

Biologic and targeted synthetic disease-modifying antirheumatic drugs (ts/bDMARDs) play a pivotal role in the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Persistence of therapy provides an index of a drug's overall effectiveness. The objective of the study was to identify factors associated with discontinuation of ts/bDMARDs in a real-world dataset. The study population comprised patients diagnosed with RA, PsA, and AS included in the BIOBADASER registry for whom follow-up data were available until November 2019. Patient features and treatment data were included in the analysis. The Kaplan-Meier method was used to study survival of the different drugs according to the reason for discontinuation. Factors associated with discontinuation were studied using Cox regression models and bivariate and multivariate analyses. P values of less than 0.05 were regarded as statistically significant. The study population comprised 4,752 patients who received a total of 8,377 drugs, of which 4,411 (52.65%) were discontinued. The Kaplan-Meier curves showed that survival for first-line treatment was greater in all 3 groups (p < 0.001). Patients with RA had a greater risk of discontinuation if they were younger (HR, 0.99; 95% CI 0.99-1.00), if they were receiving anti-TNFα agents (HR, 0.61; 95% CI 0.54-0.70), and if they had more comorbid conditions (HR, 1.09; 95% CI 1.00-1.17). Patients with PsA had a higher risk if they were women (HR, 1.36; 95% CI 1.15-1.62) and if they were receiving other ts/bDMARDs (HR, 1.29; 95% CI 1.05-1.59). In patients with AS, risk increased with age (HR, 1.01; 95% CI 1.00-1.02), as did the number of comorbid conditions (HR, 1.27; 95% CI 1.12-1.45). The factors that most affected discontinuation of ts/bDMARDs were line of treatment, age, type of drug, sex, comorbidity and the year of initiation of treatment. The association with these factors differed with each disease, except for first-line treatment, which was associated with a lower risk of discontinuation in all 3 diseases.

[Current evidences in shockwave treatment. SETOC (Spanish Society of Shockwave Treatment) recommendations]. / Ondas de choque. Evidencias y recomendaciones SETOC (Sociedad Española de Tratamientos con Ondas de Choque).

This SETOC consensus document shows the scientific evidence of the technology in shockwaves (SW) and radial pressure waves (RPW) in a variety of spasticity disorders, musculoskeletal, skin, urological diseases, etc. SW and RPW, without anesthesia, are an effective, safe, non-invasive, cost-effective treatment, which reduces the need for surgery, lower risk of complications, faster recovery and greater acceptability to patients than surgery. Consequently, SW and RPW should be the first therapeutic option in the aforementioned chronic pathologies, when conservative alternatives have failed. SETOC advises to follow the recommendations given in this article, including the ones given by SW scientific societies and best evidence for each technology as well.

Effectiveness of ustekinumab in patients with psoriatic arthritis in a real-world, multicenter study.

OBJECTIVE: To assess the effectiveness and survival of ustekinumab (UST) among patients with psoriatic arthritis (PsA) treated under routine clinical care. METHODS: Multicenter study. Epidemiological and clinical data was collected through electronic medical records of all patients with PsA who started UST in 15 hospitals of Spain. RESULTS: Two hundred and one patients were included, 130 (64.7%) with 45 mg and 71 (35.3%) with 90 mg. One hundred and thirty one patients (65.2%) had previously received another biological therapy. The median baseline DAS 28 ESR was 3.99, and Psoriasis Area and Severity Index (PASI) was 3. Overall, there was a significant decrease in DAS66/68 CRP, swollen joint count (SJC), tender joint count (TJC), and PASI in the first month of treatment, with earlier improvement in skin (PASI) than joints outcomes. Survival was numerically lower in patients with UST 45 mg (58.1%) than 90 mg (76.1%), although significant differences were not found (p = 0.147). When comparing naïve and < 1 TNF blocker versus > 2 TNF blocker-experienced patients, a significantly earlier response was seen in the former group regarding SJC (p = 0.029) at 1 month. Fifty-one patients (25.3%) stopped UST due to joint inefficacy and 4 patients due to adverse events (1.9%). Drug survival was significantly better in patients with fewer lines of previous biological agents (p = 0.003 for < 1 TNF blocker versus > 2 TNF blocker users). CONCLUSIONS: UST was effective in PsA patients in a routine clinical care setting. Patients with UST 90 mg and fewer lines of previous biologics achieved better and faster responses. Key Points • Largest cohort of patients with PsA in treatment with UST with specific rheumatological indication. • First cohort of patients with PsA comparing effectiveness of UST according to 45/90 mg dose.

Effect of low dose metronomic therapy on MCF-7 tumor cells growth and angiogenesis. Role of muscarinic acetylcholine receptors.

The non-neuronal cholinergic system refers to the presence of acetylcholine, choline acetyltransferase, acetylcholinesterase and cholinergic receptors, nicotinic and muscarinic (mAChRs) expressed in non-neuronal cells. The presence of mAChRs has been detected in different type of tumor cells and they are linked with tumorigenesis. We had previously documented the expression of mAChRs in murine and human mammary adenocarcinomas and the absence of these receptors in normal mammary cells of the same origins. We also demonstrated that mAChRs are involved in breast cancer progression, pointing to a main role for mAChRs as oncogenic proteins. Since the long term treatment of breast cancer cells with the muscarinic agonist carbachol promoted cell death, here we investigated the ability of low doses of this agonist combined with paclitaxel (PX), a taxane usually administered to treat breast cancer, to inhibit the progression of human MCF-7 tumor cells. We demonstrated that PX plus carbachol reduced cell viability and tumor growth in vitro probably due to a down-regulation in cancer stem cells population and in the expression of ATP "binding cassette" G2 drug extrusion pump; also a reduction in malignant-induced angiogenesis was produced by the in vivo administration of the mentioned combination in a metronomic schedule to MCF-7 tumor-bearing NUDE mice. Our results confirm that mAChRs could be considered as therapeutic targets for metronomic therapy in breast cancer as well as the usefulness of a muscarinic agonist as repositioning drug in the treatment of this type of tumors.

Differences in clinical manifestations and increased severity of systemic lupus erythematosus between two groups of Hispanics: European Caucasians versus Latin American mestizos (data from the RELESSER registry).

BACKGROUND: Systemic lupus erythematosus (SLE) is regarded as a prototype autoimmune disease because it can serve as a means for studying differences between ethnic minorities and sex. Traditionally, all Hispanics have been bracketed within the same ethnic group, but there are differences between Hispanics from Spain and those from Latin America, not to mention other Spanish-speaking populations. OBJECTIVES: This study aimed to determine the demographic and clinical characteristics, severity, activity, damage, mortality and co-morbidity of SLE in Hispanics belonging to the two ethnic groups resident in Spain, and to identify any differences. METHODS: This was an observational, multi-centre, retrospective study. The demographic and clinical variables of patients with SLE from 45 rheumatology units were collected. The study was conducted in accordance with Good Clinical Practice guidelines. Hispanic patients from the registry were divided into two groups: Spaniards or European Caucasians (EC) and Latin American mestizos (LAM). Comparative univariate and multivariate statistical analyses were carried out. RESULTS: A total of 3490 SLE patients were included, 90% of whom were female; 3305 (92%) EC and 185 (5%) LAM. LAM patients experienced their first lupus symptoms four years earlier than EC patients and were diagnosed and included in the registry younger, and their SLE was of a shorter duration. The time in months from the first SLE symptoms to diagnosis was longer in EC patients, as were the follow-up periods. LAM patients exhibited higher prevalence rates of myositis, haemolytic anaemia and nephritis, but there were no differences in histological type or serositis. Anti-Sm, anti-Ro and anti-RNP antibodies were more frequently found in LAM patients. LAM patients also had higher levels of disease activity, severity and hospital admissions. However, there were no differences in damage index, mortality or co-morbidity index. In the multivariate analysis, after adjusting for confounders, in several models the odds ratio (95% confidence interval) for a Katz severity index >3 in LAM patients was 1.45 (1.038-2.026; p = 0.02). This difference did not extend to activity levels (i.e. SLEDAI >3; 0.98 (0.30-1.66)). CONCLUSION: SLE in Hispanic EC patients showed clinical differences compared to Hispanic LAM patients. The latter more frequently suffered nephritis and higher severity indices. This study shows that where lupus is concerned, not all Hispanics are equal.

Relationship between damage and mortality in juvenile-onset systemic lupus erythematosus: Cluster analyses in a large cohort from the Spanish Society of Rheumatology Lupus Registry (RELESSER).

OBJECTIVES: To identify patterns (clusters) of damage manifestation within a large cohort of juvenile SLE (jSLE) patients and evaluate their possible association with mortality. METHODS: This is a multicentre, descriptive, cross-sectional study of a cohort of 345 jSLE patients from the Spanish Society of Rheumatology Lupus Registry. Organ damage was ascertained using the Systemic Lupus International Collaborating Clinics Damage Index. Using cluster analysis, groups of patients with similar patterns of damage manifestation were identified and compared. RESULTS: Mean age (years) ±â€¯S.D. at diagnosis was 14.2 ±â€¯2.89; 88.7% were female and 93.4% were Caucasian. Mean SLICC/ACR DI ±â€¯S.D. was 1.27 ±â€¯1.63. A total of 12 (3.5%) patients died. Three damage clusters were identified: Cluster 1 (72.7% of patients) presented a lower number of individuals with damage (22.3% vs. 100% in Clusters 2 and 3, P < 0.001); Cluster 2 (14.5% of patients) was characterized by renal damage in 60% of patients, significantly more than Clusters 1 and 3 (P < 0.001), in addition to increased more ocular, cardiovascular and gonadal damage; Cluster 3 (12.7%) was the only group with musculoskeletal damage (100%), significantly higher than in Clusters 1 and 2 (P < 0.001). The overall mortality rate in Cluster 2 was 2.2 times higher than that in Cluster 3 and 5 times higher than that in Cluster 1 (P < 0.017 for both comparisons). CONCLUSIONS: In a large cohort of jSLE patients, renal and musculoskeletal damage manifestations were the two dominant forms of damage by which patients were sorted into clinically meaningful clusters. We found two clusters of jSLE with important clinical damage that were associated with higher rates of mortality, especially for the cluster of patients with predominant renal damage. Physicians should be particularly vigilant to the early prevention of damage in this subset of jSLE patients with kidney involvement.

Glacier mass loss. Dynamic thinning of glaciers on the Southern Antarctic Peninsula.

Growing evidence has demonstrated the importance of ice shelf buttressing on the inland grounded ice, especially if it is resting on bedrock below sea level. Much of the Southern Antarctic Peninsula satisfies this condition and also possesses a bed slope that deepens inland. Such ice sheet geometry is potentially unstable. We use satellite altimetry and gravity observations to show that a major portion of the region has, since 2009, destabilized. Ice mass loss of the marine-terminating glaciers has rapidly accelerated from close to balance in the 2000s to a sustained rate of -56 ± 8 gigatons per year, constituting a major fraction of Antarctica's contribution to rising sea level. The widespread, simultaneous nature of the acceleration, in the absence of a persistent atmospheric forcing, points to an oceanic driving mechanism.

Treatment with LPS plus INF-γ induces the expression and function of muscarinic acetylcholine receptors, modulating NIH3T3 cell proliferation: participation of NOS and COX.

BACKGROUND AND PURPOSE: LPS and IFN-γ are potent stimuli of inflammation, a process in which fibroblasts are frequently involved. We analysed the effect of treatment with LPS plus IFN-γ on the expression and function of muscarinic acetylcholine receptors in NIH3T3 fibroblasts with regards to proliferation of these cells. We also investigated the participation of NOS and COX, and the role of NF-κB in this process. EXPERIMENTAL APPROACH: NIH3T3 cells were treated with LPS (10 ng·mL(-1)) plus IFN-γ (0.5 ng·mL(-1)) for 72 h (iNIH3T3 cells). Cell proliferation was evaluated with MTT and protein expression by Western blot analysis. NOS and COX activities were measured by the Griess method and radioimmunoassay respectively. KEY RESULTS: The cholinoceptor agonist carbachol was more effective at stimulating proliferation in iNIH3T3 than in NIH3T3 cells, probably due to the de novo induction of M3 and M5 muscarinic receptors independently of NF-κB activation. iNIH3T3 cells produced higher amounts of NO and PGE2 than NIH3T3 cells, concomitantly with an up-regulation of NOS1 and COX-2, and with the de novo induction of NOS2/3 in inflamed cells. We also found a positive feedback between NOS and COX that could potentiate inflammation. CONCLUSIONS AND IMPLICATIONS: Inflammation induced the expression of muscarinic receptors and, therefore,stimulated carbachol-induced proliferation of fibroblasts. Inflammation also up-regulated the expression of NOS and COX-2, thus potentiating the effect of carbachol on NO and PGE2 production. A positive crosstalk between NOS and COX triggered by carbachol in inflamed cells points to muscarinic receptors as potential therapeutic targets in inflammation.

Mortalidad por trastornos mentales y por causas externas: análisis de una Década en Argentina / Mortality due to mental disorders and external causes: analysis of a decade in Argentina

Objetivo: analizar las tasas de mortalidad de Trastornos Mentales y del Comportamiento (TMyC) y de las Causas Externas (CE) en las Estadísticas Vitales de Argentina, periodo 2000-2009.Metodología: se utilizó las bases de datos de defunciones, Argentina, años 2000 a 2009, de la Dirección de Estadísticas e Información en Salud Ministerial. Se construyeron tasas generales y específicas. Las estimaciones poblacionales, se obtuvieron a partir del aplicativo AGEINT. Según la distribución de la variable, se utilizó análisis de la varianza o test no paramétricos. Resultados: se observa un comportamiento disímil de la tasa de mortalidad por TMyC según sexo, pero con un comportamiento similar por cada año. Los TMyC y las CE, comprometen a la población adulta del país, con tasas mayores en el grupo de varones.Conclusión: tener en cuenta el impacto de los TMyC y CE, permite diseñar políticas públicas en salud adecuadas a las realidades de cada contexto(AU)

Objective: To analyze mortality rates due to mental and behavioral disorders (MBD) and external causes (EC) using Vital Statistics of Argentina, 2000-2009.Methods: Mortality data 2000-2009 were obtained from the Bureau of Statistics and Information, Ministry of Health, Argentina. General and specific rates were set up. Population estimates were obtained from the AGEINT application. According to the distribution of the variable, analysis of variance or nonparametric tests were used.Results: Dissimilar MBD mortality rates according to sex were observed, but with a similar pattern each year. The MBD and EC affect the adult population of the country, with higher rates in the male group.Conclusion: Taking into account the impact of MBD and EC, allows the design of public policies suitable to the realities of each health context(AU)

Mortalidad por trastornos mentales y por causas externas: análisis de una Década en Argentina / Mortality due to mental disorders and external causes: analysis of a decade in Argentina

Objetivo: analizar las tasas de mortalidad de Trastornos Mentales y del Comportamiento (TMyC) y de las Causas Externas (CE) en las Estadísticas Vitales de Argentina, periodo 2000-2009.Metodología: se utilizó las bases de datos de defunciones, Argentina, años 2000 a 2009, de la Dirección de Estadísticas e Información en Salud Ministerial. Se construyeron tasas generales y específicas. Las estimaciones poblacionales, se obtuvieron a partir del aplicativo AGEINT. Según la distribución de la variable, se utilizó análisis de la varianza o test no paramétricos. Resultados: se observa un comportamiento disímil de la tasa de mortalidad por TMyC según sexo, pero con un comportamiento similar por cada año. Los TMyC y las CE, comprometen a la población adulta del país, con tasas mayores en el grupo de varones.Conclusión: tener en cuenta el impacto de los TMyC y CE, permite diseñar políticas públicas en salud adecuadas a las realidades de cada contexto

Objective: To analyze mortality rates due to mental and behavioral disorders (MBD) and external causes (EC) using Vital Statistics of Argentina, 2000-2009.Methods: Mortality data 2000-2009 were obtained from the Bureau of Statistics and Information, Ministry of Health, Argentina. General and specific rates were set up. Population estimates were obtained from the AGEINT application. According to the distribution of the variable, analysis of variance or nonparametric tests were used.Results: Dissimilar MBD mortality rates according to sex were observed, but with a similar pattern each year. The MBD and EC affect the adult population of the country, with higher rates in the male group.Conclusion: Taking into account the impact of MBD and EC, allows the design of public policies suitable to the realities of each health context

Nitric oxide synthase 1 and cyclooxygenase-2 enzymes are targets of muscarinic activation in normal and inflamed NIH3T3 cells.

OBJECTIVE: Fibroblasts are sentinel cells that could serve as intermediaries in the immune reaction in the inflammatory process. In this work, we investigate the action of the muscarinic agonist carbachol (CARB) on the expression and function of nitric oxide synthase (NOS) and cyclooxygenase (COX) in fibroblasts under normal or inflammatory conditions. METHODS: The normal fibroblast cell line, 3T3, from NIH swiss mouse embryo, was used. The inflammatory milieu was mimicked with lipopolysaccharide (LPS) (10 ng/ml) plus interferon gamma (IFNgamma) (0.5 ng/ml). Nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production were measured by Griess reagent and radioimmunoassay, respectively. NOS, COX, and nuclear transcription factor kappa B (NF-kappaB) were studied by Western blot. RESULTS: CARB increased NO synthesis by 57 +/- 5%, while a 150 +/- 10% increase in NO liberation was triggered by LPS plus IFNgamma treatment. CARB added to LPS plus IFNgamma potentiated NO synthesis by 227 +/- 19%. CARB also upregulated NOS1 protein expression via NF-kappaB activation. In addition CARB and LPS plus IFNgamma stimulated PGE(2) synthesis by 72 +/- 9 and 42 +/- 4%, respectively, while CARB added to LPS plus IFNgamma treated cells produced a synergism in PGE(2) liberation (130 +/- 12%) via COX-2. CONCLUSION: Activation of muscarinic acetylcholine receptors can mimic mild inflammatory conditions or can deepen pre-existing inflammation, establishing a fine-tuned set-up on fibroblasts that in turn could be alerting the immune system.

[Bone Paget's disease in the young adult]. / Enfermedad de Paget ósea en el adulto joven.

FOUNDATION: Bone Paget's disease (BPD) is a focal disorder of bone remodeling of unknown etiology that affects mainly patients older than 50 years. BPD is after osteoporosis the most frequent osteopathy of the western world and was described for the first time in 1876 by Sir James Paget who called it osteitis deformans. PATIENTS AND METHODS: We present two patients with BPD younger than 40 years. In this report their clinical, analytical, diagnostic, and therapeutic manifestations are described, with the findings of bone biopsy in one of them. Is noteworthy to us the younger age of the patients, rare for this disease, which means that we have carried out the follow-up of the cases. CONCLUSION: In a young adult with high phosphatase alkaline values we will include BPD in the differential diagnosis.

Enfermedad de Paget ósea en el adulto joven / Bone Paget's disease in the young adult

Fundamento. La enfermedad ósea de Paget es un trastorno focal del remodelado óseo, de etiología desconocida, que afecta principalmente a los mayores de 50 años. Es la osteopatía más frecuente del mundo occidental después de la osteoporosis. Fue descrita por primera vez en 1876 por Sir James Paget con el nombre de "osteítis deformante". Pacientes y métodos. Presentamos dos casos con enfermedad ósea de Paget con edad inferior a los 40 años. Se describen sus características clínicas, analíticas, diagnósticas y terapéuticas con realización de biopsia ósea en uno de ellos. Nos llama la atención la edad de aparición poco habitual de la enfermedad, por lo que hemos realizado un seguimiento de los casos. Conclusión. Ante unas cifras elevadas de la fosfatasa alcalina en un adulto joven, incluiremos en el diagnóstico diferencial la enfermedad ósea de Paget (AU)

Nitric oxide synthase-cyclooxygenase interactions are involved in tumor cell angiogenesis and migration.

Nitric oxide (NO), produced by distinct nitric oxide synthase (NOS) isoforms, and prostaglandins generated by expression of cyclooxygenases are important mediators in tumor progression. Previous studies have shown that NO can influence the formation of prostaglandin E2 (PGE2). We provide evidence that NO, derived from iNOS and eNOS activity in LMM3 murine mammary adenocarcinoma cell line, is involved in tumor angiogenesis and in tumor cell migration. LMM3 cells that also stimulate their neovascularization activity and migration liberate high basal amounts of PGE2. There is large amount of evidence that postulates positive regulatory interactions between NOS and cyclooxygenase (COX) isoforms. We here show that, in the LMM3 cell line, while PGE2 exerts a positive modulation on NOS activity, NO closes the loop with a negative feed back on COX activity. We also provide evidence of a positive regulatory effect of protein tyrosine kinases on NOS as well as on COX enzymatic functions affecting tumor induced angiogenesis and cell migration.

Parasympathetic modulation of amylase secretion by IFN gamma in murine submandibular glands.

IFN gamma is a pleiotropic cytokine that exerts immunologic and non-immunologic functions. We show here that at low doses (10 U/ml), it stimulates amylase secretion in murine submandibular glands (SMG) "via" muscarinic receptor activation, comparable to that produced by the muscarinic agonist carbachol. Both effects are blocked by atropine. NG-monomethyl-L-arginine (L-NMMA) and EGTA inhibited the cytokine effect on amylase secretion, involving the participation of a calcium-dependent isoform of nitric oxide synthase (NOS). We confirm NOS activation because IFN gamma stimulates nitrite production and enzyme activity in SMG. Carbachol (10(-7) M) did not modify basal nitric oxide production. In addition, both IFN gamma and carbachol increase prostaglandin E2 production in SMG, but while indomethacin potentiates IFN gamma effect on amylase secretion, it blunted amylase secretion exerted by carbachol. Thus, IFN gamma and carbachol stimulate IFN gamma secretion on SMG in a dose-dependent manner. Our results are pointing to neuroregulatory functions of IFN gamma in murine SMG, because it regulates its own levels in oral cavity, perhaps to exert a local immuno-surveillance.

Participation of nitric oxide synthase and cyclo-oxygenase in the signal transduction pathway of ileal muscarinic acetylcholine receptors.

Parasympathetic activation of ileal motility is essential for intestinal physiology. We have previously demonstrated that carbachol activates muscarinic acetylcholine receptors (mAChR) of rat intestine and stimulates ileal motility via phospholipase C. This activation induces phosphoinositide turnover and intracellular calcium mobilization. We show here that carbachol stimulation of rat ileal motility is potentiated by the nitric oxide synthase (NOS) inhibitor N(G)-monomethyl arginine. Thus, we confirm that carbachol increases, in a dose-dependent manner, the activity of a NOS isoform that depends on calcium-calmodulin binding. Its product, nitric oxide (NO), activates not only guanylyl cyclase, inducing cGMP synthesis, but also cyclo-oxygenase, producing prostaglandin E(2). The prostanoid probably cooperates with NO to induce ileal smooth muscle relaxation.

Protein kinase C regulates NO-cGMP pathway in muscarinic receptor activation by HIV+-IgA.

In this work we demostrate that IgA purified from HIV infected patients recognizes a band with a molecular weight corresponding to radiolabelled ileal muscarinic acethylcholine receptors (mAChR) by immunoblotting. HIV+-IgA triggers the signals that are the consequence of mAChR stimulation in the intestine, regulating protein kinase C (PKC) and nitric oxide synthase (NOS) activity as well as 3',5'-cyclic guanosine monophosphate (cGMP) formation. On the one hand PKC activation by HIV+-IgA induces NOS inhibition and as a consequence, low amounts of NO that could improve local immunosuppression in the intestine; on the other hand HIV+-IgA stimulates cGMP production which could potentiate ileal motility and loss of water/electrolytes involved in intestinal damage in AIDS.