Acetylcholine polarizes dendritic cells toward a Th2-promoting profile.

BACKGROUND: A growing body of research shows a reciprocal regulation between the neural and immune systems. Acetylcholine (ACh) is the most important parasympathetic neurotransmitter, and increasing evidence indicates that it is able to modulate the immune response. Interestingly, in recent years, it has become clear that immune cells express a non-neuronal cholinergic system, which is stimulated in the course of inflammatory processes. We have previously shown that dendritic cells (DC) express muscarinic receptors, as well as the enzymes responsible for the synthesis and degradation of ACh. Here, we analyzed whether ACh could also modulate the functional profile of DC. METHODS: Dendritic cells were obtained from monocytes cultured for 5 days with GM-CSF+IL-4 or isolated from peripheral blood (CD1c+ DC). The phenotype of DC was evaluated by flow cytometry, the production of cytokines was analyzed by ELISA or intracellular staining and flow cytometry, and the expression of muscarinic and nicotinic receptors was evaluated by flow cytometry or qRT-PCR. RESULTS: Treatment of DC with ACh stimulated the expression of the Th2-promoter OX40L, the production of the Th2-chemokines MDC (macrophage-derived chemokine/CCL22) and TARC (thymus and activation-regulated chemokine/CCL17), and the synthesis of IL-4, IL-5, and IL-13 by T cells, in the course of the mixed lymphocyte reaction (MLR). Moreover, we found that the stimulation of OX40L, HLA-DR, and CD83 expressions in DC induced by the Th2-promoting cytokine TSLP, as well as the production of IL-13, IL-4, and IL-5 by T cells in the course of the MLR, was further enhanced when DC were treated with TSLP plus ACh, instead of TSLP or ACh alone. CONCLUSIONS: Our observations suggest that ACh polarizes DC toward a Th2-promoting profile.

Fucosylated clusterin in semen promotes the uptake of stress-damaged proteins by dendritic cells via DC-SIGN.

STUDY QUESTION: Could seminal plasma clusterin play a role in the uptake of stress-damaged proteins by dendritic cells? SUMMARY ANSWER: Seminal plasma clusterin, but not serum clusterin, promotes the uptake of stress-damaged proteins by dendritic cells via DC-SIGN. WHAT IS KNOWN ALREADY: Clusterin is one of the major extracellular chaperones. It interacts with a variety of stressed proteins to prevent their aggregation, guiding them for receptor-mediated endocytosis and intracellular degradation. The concentration of clusterin in semen is almost 20-fold higher than that found in serum, raising the question about the role of seminal plasma clusterin in reproduction. No previous studies have analyzed whether seminal plasma clusterin has chaperone activity. We have previously shown that seminal plasma clusterin, but not serum clusterin, expresses an extreme abundance of fucosylated glycans. These motifs enable seminal plasma clusterin to bind DC-SIGN with very high affinity. STUDY DESIGN, SIZE, DURATION: In vitro experiments were performed to evaluate the ability of seminal plasma clusterin to inhibit the precipitation of stressed proteins, promoting their uptake by dendritic cells via DC-SIGN (a C-type lectin receptor selectively expressed on dendritic cells (DC)). Moreover, the ability of seminal plasma clusterin to modulate the phenotype and function of DCs was also assessed. PARTICIPANTS/MATERIALS, SETTING, METHODS: Clusterin was purified from human semen and human serum. Catalase, bovine serum albumin, glutathione S-transferase, and normal human serum were stressed and the ability of seminal plasma clusterin to prevent the precipitation of these proteins, guiding them to DC-SIGN expressed by DCs, was evaluated using a fluorescence-activated cell sorter (FACS). Endocytosis of stressed proteins was analyzed by confocal microscopy and the ability of seminal plasma clusterin-treated DCs to stimulate the proliferation of CD25+FOXP3+CD4+ T cells was also evaluated by FACS. MAIN RESULTS AND THE ROLE OF CHANCE: Seminal plasma clusterin interacts with stressed proteins, inhibits their aggregation (P < 0.01) and efficiently targets them to dendritic cells via DC-SIGN (P < 0.01). DCs efficiently endocytosed clusterin-client complexes and sorted them to degradative compartments involved in antigen processing and presentation. Moreover, we also found that the interaction of seminal plasma clusterin with DC-SIGN did not change the phenotype of DCs, but stimulates their ability to induce the expansion of CD25+FOXP3+CD4+ T lymphocytes (P < 0.05 versus control). LIMITATIONS, REASONS FOR CAUTION: All the experiments were performed in vitro; hence the relevance of our observations should be validated in vivo. WIDER IMPLICATIONS OF THE FINDINGS: Our results suggest that by inducing the endocytosis of stress-damaged proteins by DCs via DC-SIGN, seminal plasma clusterin might promote a tolerogenic response to male antigens, thereby contributing to female tolerance to seminal antigens. STUDY FUNDING/COMPETING INTERESTS: The present research was supported by the Consejo Nacional de Investigaciones Científicas y Técnicas, the Buenos Aires University School of Medicine, and the Agencia Nacional de Promoción Científica y Tecnológica (Argentina). The authors have no conflicts of interest to declare.

Evaluation of the efficacy of intramuscular versus intramammary treatment of subclinical Streptococcus agalactiae mastitis in dairy cows in Colombia.

A randomized controlled trial was performed in 17 Colombian dairy herds to determine the cure risk among cows subclinically infected with Streptococcus agalactiae exposed to 2 antibiotic therapies. Composite milk samples were collected before milking at the onset of the trial (pretreatment) and 2 subsequent times over a period of approximately 63 d. The intramammary application (IMM) of ampicillin-cloxacillin was compared with the intramuscular application (IM) of penethamate hydriodide, and cure risks after an initial and retreatment application were assessed. Cure risk after the initial treatment was higher (82.4%) for the IMM treatment than for IM therapy (65.8%). However, no difference was observed in the cure risk of refractory cases after retreatment (IMM=52.6% vs. IM=51.2%). The cumulative cure risk (both initial and retreatment) was 90.4 and 82.9% for the IMM and IM products, respectively. A 2-level random effects logistic model that controlled for pretreatment cow-level somatic cell count, indicated that IM treatment (odds ratio=0.37) had a lower cure risk than IMM and a tendency for a lower cure risk with increasing baseline somatic cell count. Our findings suggest that both products and administration routes can reduce the prevalence of S. agalactiae in affected herds, but the IMM product had a better efficacy in curing the infection. In addition to the treatment protocol, the cow somatic cell count should be considered when making management decisions for cows infected with S. agalactiae.

[Open surgery, laparoscopic Palomo varicocelectomy and embolization in children with varicocele]. / Cirugía abierta, Palomo laparoscópico y embolización en niños con varicocele.

OBJECTIVES: Our aim was to prove the outcomes in varicocele treatment during last 10 years in our institution regarding to the recurrence rate and reactive hydrocele in children and adolescents treated with open technique, laparoscopic approach or embolization. PATIENTS AND METHODS: Medical charts of patients with varicocele younger than 17 years old were reviewed. Age, weight, surgery indications, treatment (open surgery, laparoscopic Palomo varicocelectomy or embolization), location, varicocele grade, hospital stays, recurrence, postoperative hydrocele, genitofemoral nerve damage, infection, bleeding, postoperative incisional hernia and re-do varicocelectomy were collected. RESULTS: From 2000 to 2010, 98 boys with varicocele diagnosis were treated in our institution. Mean age of patients was 12 years. The varicocele location in all cases was on the left side. Grade III varicocele was found in 94 boys and grade II in 4 patients. Indications for surgery were high grade in 81, chronic pain in 16 and testicular hypotrophy in 1. Treatment approach was as follows: 12 patients underwent open surgery (Palomo or Ivanissevich technique), 32 underwent embolization and laparoscopic Palomo varicocelectomy was performed in 54. We found a global recurrence rate of 14.3% and an overall postoperative hydrocele of 24.5% Recurrence rate was higher in the embolization group than the open surgery and laparoscopic group. Three patients presented intraoperative bleeding in the laparoscopic group and there was one conversion to open surgery. CONCLUSIONS: Our retrospective review proves that laparoscopic Palomo varicocelectomy is a safe and efficient approach to treat varicocele in pediatric population, because of its low recurrence rate without any major adverse outcome. Due to our high secondary hydrocele formation, lymphatic sparing laparoscopic procedure should be taken into account in order to decrease this complication.

Extracellular acidosis enhances Zika virus infection both in human cells and ex-vivo tissue cultures from female reproductive tract.

Zika virus (ZIKV) is a flavivirus transmitted by mosquitoes of the genus Aedes, but unlike other flaviviruses, ZIKV can be sexually transmitted by vaginal intercourse. The healthy vaginal pH ranges from 4.0 to 6.0, reaching values of 6.0-7.0 after semen deposition. Here, we report that low extracellular pH values (range 6.2-6.6) dramatically increase ZIKV infection on cell lines of different origin including some derived from the female genital tract and monocyte-derived macrophages. Furthermore, low pH significantly increased ZIKV infection of human ectocervix and endocervix cultured ex-vivo. Enhancement of infection by low pH was also observed using different ZIKV strains and distinct methods to evaluate viral infection, i.e. plaque assays, RT-PCR, flow cytometry, and fluorescence microscopy. Analysis of the mechanisms involved revealed that the enhancement of ZIKV infection induced by low pH was associated with increased binding of the viral particles to the heparan sulphate expressed on the target cell surface. Acidosis represents a critical but generally overlooked feature of the female genital tract, with major implications for sexual transmission diseases. Our results suggest that low vaginal pH might promote male-to-female transmission of ZIKV infection.

Exposure to bisphenol A differentially impacts neurodevelopment and behavior in Drosophila melanogaster from distinct genetic backgrounds.

Bisphenol A (BPA) is a ubiquitous environmental chemical that has been linked to behavioral differences in children and shown to impact critical neurodevelopmental processes in animal models. Though data is emerging, we still have an incomplete picture of how BPA disrupts neurodevelopment; in particular, how its impacts may vary across different genetic backgrounds. Given the genetic tractability of Drosophila melanogaster, they present a valuable model to address this question. Fruit flies are increasingly being used for assessment of neurotoxicants because of their relatively simple brain structure and variety of measurable behaviors. Here we investigated the neurodevelopmental impacts of BPA across two genetic strains of Drosophila-w1118 (control) and the Fragile X Syndrome (FXS) model-by examining both behavioral and neuronal phenotypes. We show that BPA induces hyperactivity in larvae, increases repetitive grooming behavior in adults, reduces courtship behavior, impairs axon guidance in the mushroom body, and disrupts neural stem cell development in the w1118 genetic strain. Remarkably, for every behavioral and neuronal phenotype examined, the impact of BPA in FXS flies was either insignificant or contrasted with the phenotypes observed in the w1118 strain. This data indicates that the neurodevelopmental impacts of BPA can vary widely depending on genetic background and suggests BPA may elicit a gene-environment interaction with Drosophila fragile X mental retardation 1 (dFmr1)-the ortholog of human FMR1, which causes Fragile X Syndrome and is associated with autism spectrum disorder.

Barium selenate supplementation and its effect on intramammary infection in pasture-based dairy cows.

A significant proportion of cattle receive inadequate dietary Se because of its low content in soils and pastures of various regions of the world. Several economically important diseases in dairy cows, such as mastitis, have been associated with Se deficiency. The objective of this study was to evaluate the effect of a single injection of a long-acting form of Se at drying off on the risk and incidence rate of new intramammary infections and on milk somatic cell count in the subsequent lactation in pasture-based dairy cows. Forty-nine Chilean Holstein-Friesian cows were fed a diet containing <0.05 mg of Se/kg of ration dry matter. During the dry period, cows were allocated to 1 of 2 groups, a supplemented (n=24) group treated with a single subcutaneous injection of barium selenate 2 mo before calving and a control group (n=25) that remained unsupplemented. Duplicate foremilk samples were aseptically collected within 6 d after calving and every 2 wk until drying-off for bacteriological culture. Milk samples were also collected monthly for somatic cell count evaluation. Blood samples were collected before treatment and at 30, 90, 180, and 270 d after treatment for analysis of blood glutathione peroxidase (GPx) activity. The activity of glutathione peroxidase was higher in supplemented cows 30 d after the injection until the end of the study. The risk and incidence rate of new intramammary infections was not affected by supplementation. A progressive increase in somatic cell count was observed throughout lactation, but there was no effect of supplementation. In conclusion, a one-time injection of barium selenate 2 mo before calving in these pasture-based dairy cows did not affect udder health in the subsequent lactation, indicating that Se basal intake was adequate for preventing subclinical mastitis in pasture-based cows in southern Chile.

[Structural alterations of the smooth muscle and of the EGFR expression and C-kit in congenital pyeloureteral stenosis. Relationship with its pathogenesis]. / Alteraciones estructurales del músculo liso y de la expresión de EGFR y C-kit en la estenosis pieloureteral congénita. Relación con su patogénesis.

PURPOSE: To assess the role that the muscular dysplasia, epidermal growth factor (EGFR) and interstitial cells of Cajal (ICC) C-kit +, may have in the pathophysiology of pyeloureteral stenosis (EPU). MATERIALS AND METHODS: 30 samples were studied UPJ (ureteropelvic junction), with 25 UPJ obstruction and 5 controls. Performed with Masson's trichrome staining and immunohistochemical techniques for smooth muscle actin, EGFR (epidermal growth factor) and CD117 (C-kit) (Dako). We compared the results statistically. RESULTS: The control group was diffuse positivity of EGFR in the muscle layer in samples of EPU was positive in 4%, weak in 16% and negative in 80%. The controls are C-kit + ICC between the muscle cells showed a decreased density in the samples of obstruction. Masson's trichrome highlighted the increase of inter-and intramuscular collagen and attenuated muscle fibers, thinner and individualized, in the inner muscular layer of the cases of EPU also evident with the actin. Differences between groups were statistically significant (p < 0.001). CONCLUSIONS: Our results suggest that dysplastic changes in the muscle layer, the low expression of EGFR and the decrease or absence of C-kit + ICC, may participate in the pathophysiology of UPJ obstruction.

Meta-analysis of the effect of oral selenium supplementation on milk selenium concentration in cattle.

Soils in many regions of the world have a low Se content. Consequently, forages and crops grown on these soils may provide inadequate dietary Se for humans and grazing animals. Selenium supplementation has been used to enhance Se status and milk Se concentration, but results conflict. Milk Se concentration appears to be a useful indicator of animal and herd Se status, and reflects the responsiveness to supplementation. A systematic review and meta-analysis were carried out to summarize all available scientific evidence for the effect of oral Se supplementation on milk Se concentration in cattle. The literature search was based on electronic and nonelectronic databases. Fixed- and random-effects models of meta-analysis were used, and a meta-regression was carried out to evaluate heterogeneity among studies. Random-effects meta-analysis was performed on 42 studies published between 1977 and 2007. Oral Se supplementation resulted in an average increase in milk Se content of 0.16 (95% confidence interval: 0.117, 0.207) micromol/L, with a significant heterogeneity among studies. Weak publication bias was evident, but it did not change the average effect. The continent where the study was performed, Se source, Se dose, and the interaction between source and dose explained 71% of the between-study variance. On average, American cows supplemented with Se yeast (e.g., 6 mg/h per day) had greater milk Se concentrations (approximately 0.37 micromol/L) 75 d after the beginning of supplementation when compared with those supplemented with inorganic forms of Se. This information provides a basis for tailoring daily animal requirements and for enhancing the Se intake of consumers of dairy products.

A pilot study of a stepped-care brief intervention to help psychologically-distressed women displaced by conflict in Bogotá, Colombia.

BACKGROUND: Colombia's 6.5 million internally displaced persons (IDPs) have been exposed to trauma, loss, and hardships. Common mental disorders (CMDs) are prevalent in this group, yet there are few evidence-based psychosocial interventions for this population. We assessed the feasibility and acceptability of a stepped-care intervention for women IDPs in Bogota, Colombia. METHODS: Feasibility to recruit participants for an intervention trial, to screen for CMDs and displacement-related traumas, to refer high-risk cases to professional consultation, to implement evidence-based interpersonal counseling (IPC) for women with diagnosed CMDs, to retain participants in the intervention, and to conduct follow-up assessments was assessed. Assessment instruments were validated. The intervention was delivered by trained outreach personnel. Intervention acceptability was assessed by monitoring session attendance, dropout rates, and satisfaction. Potential efficacy was evaluated with pre- and post-intervention measures of CMDs. RESULTS: We recruited 279 women IDPs into the intervention. On screening, 177 (63.4%) had symptom levels suggesting a CMD. Participants endorsed a wide range of displacement-related exposures. Most participants receiving IPC decreased their symptom levels at follow-up. Many participants did not complete the recommended number of IPC sessions; loss to follow-up was 30%. The performance of the outreach personnel improved after the initial intervention team was replaced with community members trained to deliver the intervention. The Bogotá health system was unable to reliably accommodate emergency psychiatric referrals. CONCLUSIONS: The IPC intervention shows promise, but significant challenges remain for improving reach, adherence, and participant retention. We identified strategies and partnerships to redress some of the main study limitations.

Psychosocial interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood.

BACKGROUND: Between 4% and 25% of school-age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority of such children, no organic cause for their pain can be found on physical examination or investigation. Although most children are managed by reassurance and simple measures, a large range of psychosocial interventions including cognitive and behavioural treatments and family therapy have been recommended. OBJECTIVES: To determine the effectiveness of psychosocial interventions for recurrent abdominal pain or IBS in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL) 2006 (Issue 4), MEDLINE (1966 to Dec 2006), EMBASE (1980 to Dec 2006), CINAHL (1982 to Dec 2006), ERIC (1966 to Dec 2006), PsycINFO (1872 to Dec 2006), LILACS (1982 to Dec 2006), SIGLE (1980 to March 2005), and JICST (1985 to 06/2000) were searched with appropriate filters. SELECTION CRITERIA: Any study in which the majority of participants were school-age children fulfilling standard criteria for RAP (Apley or the Rome II criteria for functional gastrointestinal diseases) , randomly allocated to any psychosocial treatment compared to standard care or waiting list, were selected. DATA COLLECTION AND ANALYSIS: References identified by the searches were independently screened against the inclusion criteria by two reviewers. Data were extracted and analysed using RevMan 4.2.10. MAIN RESULTS: Six randomised trials (including a total of 167 participants) of cognitive behavioural interventions were identified, with data reported in ten papers. Five studies reported statistically significant improvements in pain, measured in a variety of ways, in children randomised to receive interventions based on cognitive behavioural therapy compared to children on wait lists or receiving standard medical care (Duarte 2006; Humphreys 1998; Robins 2005; Sanders 1989; Sanders 1994). The remaining trial (Hicks 2003) included a wider group of children with recurrent pain and too few with only RAP to provide interpretable data. AUTHORS' CONCLUSIONS: The included trials were small, with methodological weaknesses and a number failed to give appropriate detail regarding numbers of children assessed. In spite of these methodological weaknesses and the clinical heterogeneity, the consistency and magnitude of the effects reported provides some evidence that cognitive behavioural therapy may be a useful intervention for children with recurrent abdominal pain although most children, particularly in primary care, will improve with reassurance and time.

Dietary interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood.

BACKGROUND: Between 4% and 25% of school-age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. It is unclear whether the diagnosis includes children with different aetiologies for their pain. For the majority no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions have been recommended. OBJECTIVES: To determine the effectiveness of dietary interventions for recurrent abdominal pain in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL) 2006 (Issue 4), MEDLINE (1966 to Dec 2006), EMBASE (1980 to Dec 2006), CINAHL (1982 to Dec 2007), ERIC (1966 to Dec 2006), PsycINFO (1872 to Dec 2006), LILACS (1982 to Dec 2006), SIGLE (1980 to March 2005), and JICST (1985 to 06/2000) were searched . Where appropriate, search filters were employed. In addition, researchers working in this area were asked to identify relevant studies. SELECTION CRITERIA: Randomised or quasi-randomised studies of any dietary treatment versus placebo or no treatment in school-age children with a diagnosis of RAP or functional gastrointestinal disorder based on the Rome II criteria. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion, assessed quality and extracted data. Where appropriate studies were pooled using a random effects meta-analysis. MAIN RESULTS: Seven trials were included in this review. Two trials, including 83 participants, compared fibre supplements with placebo (Christensen 1982, Feldman 1985), with data from one study reported in two papers (Christensen 1982, Christensen 1986). The pooled odds ratio for improvement in the frequency of abdominal pain was 1.16 (95% CI 0.45-2.87). Two trials, including 90 participants (Lebenthal 1981, Dearlove 1983) compared lactose-containing with lactose-free diets. Neither reported data in a form which could be used in the meta-analysis and the former trial had a loss to follow-up of 45%. We were not able to obtain further data for either trial. Three trials (Bausserman 2005, Gavronska 2007, Young 1997) comparing supplementation with Lactobacillus with placebo met the inclusion criteria but only two (Bausserman 2005, Gavronska 2007), including a total of 168 children, provided analysable data. The pooled odds ratio for improvement of symptoms was 1.17 (95% CI 0.62, 2.21). AUTHORS' CONCLUSIONS: There is a lack of high quality evidence on the effectiveness of dietary interventions. This review provides no evidence that fibre supplements, lactose free diets or lactobacillus supplementation are effective in the management of children with RAP.

Pharmacological interventions for recurrent abdominal pain (RAP) and irritable bowel syndrome (IBS) in childhood.

BACKGROUND: Between 4% and 25% of school-age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority no organic cause for their pain can be found on physical examination or investigation and although most children are likely managed by reassurance and simple measures, a large range of interventions have been recommended. OBJECTIVES: To determine the effectiveness of medication for recurrent abdominal pain in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL) 2006 (Issue 4), MEDLINE (1966 to Dec 2006), EMBASE (1980 to Dec 2006), CINAHL (1982 to Dec 2007), ERIC (1966 to Dec 2006), PsycINFO (1872 to Dec 2006), LILACS (1982 to Dec 2006), SIGLE (1980 to March 2005), and JICST (1985 to 06/2000) were searched with appropriate filters SELECTION CRITERIA: Studies on school age children with RAP (Apley or the Rome II criteria for gastrointestinal diseases) allocated by random or quasi-random methods to a drug treatment vs. placebo/ no treatment were included. DATA COLLECTION AND ANALYSIS: References identified by the searches were screened against the inclusion criteria by two independent reviewers. Data was extracted and analysed using RevMan 4.2.10. MAIN RESULTS: Three trials met the inclusion criteria. Symon et al report a cross-over trial comparing pizotifen and placebo in 16 children with "abdominal migraine". Data before cross-over was not available. Results for 14 children showed Mean fewer days in pain of 8.21 (95% CI 2.93, 13.48) while taking the active drug. Kline et al compared peppermint oil capsules with placebo in a randomised trial in 50 children with RAP and IBS. 42 children completed the study. OR for improvement was 3.33 (95% CI 0.93-12.1)See et al compared famotidine with placebo in a randomised cross-over trial in 25 children with RAP and dyspepsia. OR for improvement before cross-over was 11 (95%CI 1.6, 75.5). AUTHORS' CONCLUSIONS: This review provides weak evidence of benefit on medication in children with RAP. The lack of clear evidence of effectiveness for any of the recommended drugs suggests that there is little reason for their use outside of clinical trials. Clinicians may choose to prescribe drugs in children with severe symptoms that have not responded to simple management. However, if using drugs as a "therapeutic trial", clinicians should be aware that, RAP is a fluctuating condition and any "response" may reflect the natural history of the condition or a placebo effect rather than drug efficacy.

Seminal vesicle fluid increases the efficacy of intravaginal HSV-2 vaccination.

Once considered merely as a vehicle for spermatozoa, it is now clear that seminal plasma (SP) induces a variety of biological actions on the female reproductive tissues able to modulate the immune response against paternal antigens. To our knowledge, the influence of SP on the immune response against sexually transmitted pathogens has not been yet evaluated. We here analyzed whether the seminal vesicle fluid (SVF), which contributes almost 60% of the SP volume in mice, could modulate the immune response against herpes simplex virus type 2 (HSV-2). We found that SVF does not modify the course of primary infection, but markedly improved protection conferred by vaginal vaccination with inactivated HSV-2 against a lethal challenge. This protective effect was shown to be associated to a robust memory immune response mediated by CD4+ and CD8+ T cells in both the lymph nodes draining the vagina and the vaginal mucosa, the site of viral replication. In contrast with the widespread notion that SP acts as an immunosuppressive agent, our results suggest that SVF might improve the female immune response against sexually transmitted pathogens.

Control of hypertension in patients at high risk of cardiovascular disease.

BACKGROUND: Hypertension is a major cardiovascular risk factor, but knowledge about the real magnitude of the problem and its determinants is lacking. AIM: To assess control of hypertension and evaluate medical resource use, in patients at high risk of cardiovascular disease. DESIGN: Multicentric cross-sectional study. METHODS: We collected data for 2205 adult patients from 36 centres, representative of all regions of Spain. Patients had attended out-patient clinics from July 2002 to August 2003, had an absolute cardiovascular risk > or =20% at 10 years (according to the Framingham guidelines), and had a diagnosis of hypertension. Pregnant and terminally ill patients were excluded. RESULTS: Hypertension was inadequately controlled in 1384 patients (62.8%). LDL cholesterol was higher in patients with uncontrolled hypertension (median 130.2 vs. 120.0 mg/dl, p < 0.001). Haemoglobin A(1c) in diabetic patients was also greater in those with uncontrolled hypertension (median 7.10% vs. 6.90%, p = 0.010). Uncontrolled hypertension was associated with the following variables, in descending strength of association: higher LDL cholesterol, taking antihypertensive medication, living in non-metropolitan areas, and higher body mass index. DISCUSSION: Hypertension is poorly controlled in most patients with a high risk of cardiovascular disease. Uncontrolled hypertension is frequently associated with poor control of other risk factors.

The effect of D-003 (10 mg/day) on biochemical parameters of bone remodelling in postmenopausal women: a randomized, double-blind study.

Biphosphonates, which are antiresorptive agents used to treat osteoporosis, inhibit the mevalonate pathway, preventing protein prenylation and inhibiting osteoclast activity. Statins decrease cholesterol biosynthesis by blocking the mevalonate pathway and have been reported to have beneficial effects on bone. D-003 is a mixture of high molecular weight acids purified from sugarcane wax that inhibits cholesterol biosynthesis before mevalonate production. D-003 prevents bone loss and resorption in rats with osteoporosis induced with ovariectomy or corticoids. Biochemical markers of bone turnover are used to monitor the short-term efficacy of antiosteoporotic therapy. This randomized, double-blind, placebo-controlled study was undertaken to investigate the short-term effects of D-003 (10 mg/day) on biochemical markers of bone turnover in postmenopausal women with low bone mineral density (BMD). After 4 weeks on a low-fat diet, 34 women were randomized to D-003 (10 mg/day) or placebo for 6 months. Pre- and post-treatment samples were analyzed for urinary excretion of deoxypyridinoline (DPD)/creatinine (Cr), a marker of bone resorption, and serum bone specific alkaline phosphatase (BSAP), a marker of bone formation. The effects on lipid profile and safety indicators, as well as adverse events (AE), were investigated. D-003 (10 mg/day) lowered urinary excretion of tDPD/Cr versus baseline (20.6%) (p < 0.001) and placebo (33.7%) (p < 0.01), but did not modify serum BSAP. D-003 decreased low-density lipoprotein-cholesterol (LDL-C) (32.8%), total cholesterol (TC) (16.4%) and the TC/high-density lipoprotein-cholesterol (HDL-C) ratio (34.7%), increased HDL-C (30.3%) (p < 0.001) and did not modify triglycerides. The effects on these variables were significant as early as 3 months after treatment initiation. D-003 was well tolerated. Three patients (one in the placebo group and two in the D-003 group) withdrew from the study. Two of these withdrawals were due to AE: abdominal pain (placebo) and heartburn (D-003). Five patients (four in the placebo group [22.2%] and one in the D-003 group [6.3%]) reported mild AE. In conclusion, D-003 (10 mg/day) reduced urinary excretion of tDPD/Cr, a bone resorption marker and did not change serum BSAP, a bone formation marker, while it lowered cholesterol in study patients. These preliminary results suggest that D-003 could be useful in treating postmenopausal women with low BMD. However, the potential value of D-003 in treating or preventing osteoporosis deserves further clinical investigation.

Influence of formulation and process variables on in vitro release of theophylline from directly-compressed Eudragit matrix tablets.

Extended-release theophylline (TP) matrix tablets were prepared by direct compression of drug and different pH-dependent (Eudragit L100, S100 and L100-55) and pH-independent (Eudragit RLPO and RSPO) polymer combinations. The influence of varying the polymer/polymer (w/w) ratio and the drug incorporation method (simple blend or solid dispersion) was also evaluated. Drug release, monitored using the Through Flow Cell system, markedly depended on both the kind of Eudragit polymer combinations used and their relative content in the matrix. Maintaining a constant 1:1 (w/w) drug/polymers ratio, the selection of appropriate mixtures of pH-dependent and pH-independent polymers enabled achievement of a suitable control of TP release. In particular, matrices with a 0.7:0.3 w/w mixture of Eudragit L100-Eudragit RLPO showed highly reproducible drug release profiles, with an almost zero-order kinetic, and allowed 100% released drug after 360 min. As for the effect of the drug incorporation method, simple blending was better than the solid dispersion technique, which not only did not improve the release data reproducibility, but also caused, unexpectedly, a marked slowing down in drug release rate.

Spinal cord stimulation: a possible therapeutic alternative for chronic mesenteric ischaemia.

A 78-year-old male patient had chronic, unrelieved abdominal pain due to mesenteric ischaemia. Unsuccessful pharmacological approaches included oral morphine plus coadjuvants as well as a sympathetic celiac plexus block which gave pain relief that lasted for 72 h. In order to obtain long-lasting relief, a trial epidural stimulating electrode was implanted after obtaining informed consent and Ethical Committee approval. Complete analgesia was achieved during a trial period of 2 weeks. Thereafter, a spinal cord stimulator was implanted. At the time of writing, 11 months after implantation, the degree of analgesia is complete. We believe that spinal cord stimulation may represent an alternative approach in controlling pain due to mesenteric ischaemia.

Pharmacological interventions for recurrent abdominal pain (RAP) in childhood.

BACKGROUND: Between 4% and 25% of school age children complain of recurrent abdominal pain (RAP) of sufficient severity to interfere with daily activities. For the majority of such children no organic cause for their pain can be found on physical examination or investigation. Although most children are likely managed by reassurance and simple measures, a large range of interventions has been recommended. OBJECTIVES: To determine the effectiveness of medication for recurrent abdominal pain in school-age children. SEARCH STRATEGY: The Cochrane Library (CENTRAL), MEDLINE, EMBASE, CINAHL, ERIC, PsycLIT, LILACS and JICST were searched using a strategy combining (Recurrent OR synonyms) AND (Abdomen OR synonyms) AND (Pain OR synonyms). Where appropriate search filters were employed. In addition, researchers working in this area were asked to identify relevant studies. SELECTION CRITERIA: Any study in which the majority of participants were school age children fulfilling standard criteria for RAP, and who were allocated by random or quasi-random methods to any drug treatment compared with a placebo or no treatment. DATA COLLECTION AND ANALYSIS: References identified by the searches were screened against the inclusion criteria by two independent reviewers. MAIN RESULTS: Only one trial met the inclusion criteria. This cross-over trial in 14 children who met suggested criteria for "abdominal migraine" compared pizotifen and placebo, each given for one month with no washout period. Participants reported a mean of 8.21 (95% CI 2.93, 13.48) fewer days of pain while taking the active drug. They also reported that the mean difference on an "Index of Severity" was -16.21 (95% CI -26.51, -5.90) and on an "Index of Misery" was -56.07 (95% CI -94.07, -18.07). REVIEWER'S CONCLUSIONS: There is little evidence to suggest that recommended drugs are effective in the management of RAP. At present there seems little justification for the use of these drugs other than in clinical trials. There is an urgent need for trials of all suggested pharmacologic interventions in children with RAP.