Usefulness of Delayed Introduction of Tacrolimus in Kidney Transplants Using Type-III Donors After Circulatory Death.

INTRODUCTION: Our study compares 2 immunosuppressive strategies to reduce tacrolimus nephrotoxicity and its risk of acute tubular necrosis: delayed introduction of tacrolimus plus thymoglobulin vs initial tacrolimus plus basiliximab on the results of kidney transplant (KT) using type-III donation after circulatory death (III-DCD). MATERIAL AND METHODS: We analyzed all the transplants performed using type-III DCD in our hospital (42 cases). They were distributed in a first stage with delayed tacrolimus (3°-4° day) + thymoglobulin and a second one with initial tacrolimus + basiliximab, with a follow-up of 6 months. The rate of delayed graft function, the evolution of renal function, and the incidence of rejection were compared. RESULTS: 28 patients received thymoglobulin with delayed tacrolimus, and 13 patients received basiliximab and tacrolimus from day 0 (1 excluded). There were no significant differences in delayed graft function (27% group 1 and 23% group 2) or in rejection (10.7% and 15.4%), respectively. Serum creatinine at day 3, 7, 14, 30, and 180 showed no statistically significant differences. The levels of tacrolimus measured at 10, 30, 90, and 180 days after transplantation were similar, except for the first month: 10.10 ± 2.3 in group 1 and 12 ± 1.7 ng/mL in group 2 (P = .007). CONCLUSIONS: Delayed introduction of tacrolimus does not seem to suppose a benefit in KT using type-III DCD; therefore, the use of thymoglobulin, with its higher profile of adverse effects, seems unjustified in patients with normal immunological risk.

Clinical and microbiological evaluation of the effect of Lactobacillus reuteri in the treatment of mucositis and peri-implantitis: A triple-blind randomized clinical trial.

BACKGROUND AND OBJECTIVE: Oral probiotics appear to improve the treatment of periodontal diseases but there is limited evidence on their efficacy in the treatment of peri-implant diseases. The objective of the present study was to evaluate, clinically and microbiologically, the effect of the oral probiotic, Lactobacillus reuteri Prodentis, as adjuvant to non-surgical mechanical therapy in implants with mucositis or peri-implantitis, placed in patients with a history of periodontal disease. MATERIAL AND METHODS: A randomized, controlled, parallel-design, triple-blind prospective clinical study was designed. Patients included in the study were partially edentulous and had implants with mucositis or peri-implantitis. Implants with radiographic bone loss of ≥5 mm and/or ≥50% of the implant length were excluded, and only one implant per patient was included. After non-surgical mechanical therapy, subjects were randomly assigned to take either 1 probiotic lozenge or 1 placebo lozenge every day for 30 days. Clinical measurements were taken in the whole mouth (general plaque index and general bleeding on probing) and at the implant site (probing pocket depth, plaque index and bleeding on probing) at baseline and 30 and 90 days Microbiological examination (to identify Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, Treponema denticola, Prevotella intermedia, Peptostreptococcus micros, Fusobacterium nucleatum, Campylobacter rectus and Eikenella corrodens) was performed at the same study time points that clinical measurements were made. RESULTS: A total of 44 patients - 22 with mucositis and 22 with peri-implantitis - randomly received treatment with either probiotic or placebo. The probiotic L. reuteri, together with mechanical therapy, produced an additional improvement over treatment with mechanical therapy alone, both in the general clinical parameters of patients with mucositis (bleeding on probing) and at the level of implants with mucositis (probing pocket depth) or peri-implantitis (bleeding on probing and probing pocket depth). However, L. reuteri had a very limited effect on the peri-implant microbiota because the only parameter in which a significant decrease was found was the bacterial load of P. gingivalis in implants with mucositis (P = .031). CONCLUSION: The administration of a daily lozenge of L. reuteri for 30 days, together with mechanical debridement of the whole mouth, improved the clinical parameters of implants with mucositis or peri-implantitis over a period of at least 90 days, but the microbiological effect was much more limited. Probiotics provide an alternative therapeutic approach to consider in the prevention and treatment of peri-implant diseases, but further long-term prospective studies with standardized variables are needed.

Randomised clinical trial: the analgesic properties of dietary supplementation with palmitoylethanolamide and polydatin in irritable bowel syndrome.

BACKGROUND: Intestinal immune activation is involved in irritable bowel syndrome (IBS) pathophysiology. While most dietary approaches in IBS involve food avoidance, there are fewer indications on food supplementation. Palmithoylethanolamide, structurally related to the endocannabinoid anandamide, and polydatin are dietary compounds which act synergistically to reduce mast cell activation. AIM: To assess the effect on mast cell count and the efficacy of palmithoylethanolamide/polydatin in patients with IBS. METHODS: We conducted a pilot, 12-week, randomised, double-blind, placebo-controlled, multicentre study assessing the effect of palmithoylethanolamide/polydatin 200 mg/20 mg or placebo b.d. on low-grade immune activation, endocannabinoid system and symptoms in IBS patients. Biopsy samples, obtained at screening visit and at the end of the study, were analysed by immunohistochemistry, enzyme-linked immunoassay, liquid chromatography and Western blot. RESULTS: A total of 54 patients with IBS and 12 healthy controls were enrolled from five European centres. Compared with controls, IBS patients showed higher mucosal mast cell counts (3.2 ± 1.3 vs. 5.3 ± 2.7%, P = 0.013), reduced fatty acid amide oleoylethanolamide (12.7 ± 9.8 vs. 45.8 ± 55.6 pmol/mg, P = 0.002) and increased expression of cannabinoid receptor 2 (0.7 ± 0.1 vs. 1.0 ± 0.8, P = 0.012). The treatment did not significantly modify IBS biological profile, including mast cell count. Compared with placebo, palmithoylethanolamide/polydatin markedly improved abdominal pain severity (P < 0.05). CONCLUSIONS: The marked effect of the dietary supplement palmithoylethanolamide/polydatin on abdominal pain in patients with IBS suggests that this is a promising natural approach for pain management in this condition. Further studies are now required to elucidate the mechanism of action of palmithoylethanolamide/polydatin in IBS. ClinicalTrials.gov number, NCT01370720.

Mechanisms of Stress-Induced Visceral Pain: Implications in Irritable Bowel Syndrome.

Visceral pain is a term describing pain originating from the internal organs of the body and is a common feature of many disorders, including irritable bowel syndrome (IBS). Stress is implicated in the development and exacerbation of many visceral pain disorders. Recent evidence suggests that stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviours. The Young Investigator Forum at the International Society of Psychoneuroendocrinology (ISPNE) annual meeting reported experimental evidence suggesting the gut microbiota can affect the stress response to affect visceral pain. Building upon human imaging data showing abnormalities in the central processing of visceral stimuli in patients with IBS and knowledge that the amygdala plays a pivotal role in facilitating the stress axis, the latest experimental evidence supporting amygdala-mediated mechanisms in stress-induced visceral pain was reviewed. The final part of the session at ISPNE reviewed experimental evidence suggesting that visceral pain in IBS may be a result, at least in part, of afferent nerve sensitisation following increases in epithelial permeability and mucosal immune activation.

Dietary treatment modulates mast cell phenotype, density, and activity in adult eosinophilic oesophagitis.

BACKGROUND: Mast cells (MCs) are abundant in the inflammatory infiltrate in eosinophilic oesophagitis (EoE), but decrease with disease remission. However, their phenotype, role in the pathophysiology of the disease, and modulation after effective dietary therapy are still unclear. OBJECTIVE: To define the phenotype of oesophageal MCs, their modulation through dietary therapy, and their association with clinical manifestations of EoE. METHODS: Oesophageal mucosal samples from 10 adult patients with EoE obtained before and after effective six-food elimination diet (SFED) therapy, as well as from 10 control subjects were analysed. Eosinophil and MC density were quantified. Gene expression of chemoattractants for eosinophils (CCL11, CCL24, and CCL26), MCs (SCF), and their receptors (CCR3 and SCFR, respectively) were assessed by means of qPCR. Gene and protein expression of specific MC proteases (CPA3, CMA, and TPSB2) were evaluated with qPCR and immunofluorescence. Clinical manifestations and atopic background were recorded. RESULTS: MC density was significantly increased in EoE compared with controls, decreasing after dietary treatment (18.6 to 1.44 cells/hpf, respectively; P < 0.001). The MCTC subtype predominated in the oesophageal mucosa (90%) in both patients with EoE and controls. Gene expression of MC-related proteases, eotaxins, and SCF were up-regulated in patients with EoE, but significantly decreased after therapy, regardless of atopic background. Epithelial peaks of MCs and eosinophils were significantly associated (ρ = 0.80) in EoE and correlated with the symptom score (ρ = 0.78). Gene expression of MC proteases and eotaxins also correlated with the symptom score (P < 0.05). CONCLUSIONS AND CLINICAL RELEVANCE: MC and its proteases seem to play a relevant role in the pathophysiology and symptoms of EoE, which can be reversed after effective dietary treatment.

The joint power of sex and stress to modulate brain-gut-microbiota axis and intestinal barrier homeostasis: implications for irritable bowel syndrome.

BACKGROUND: Intestinal homeostasis is a dynamic process that takes place at the interface between the lumen and the mucosa of the gastrointestinal tract, where a constant scrutiny for antigens and toxins derived from food and microorganisms is carried out by the vast gut-associated immune system. Intestinal homeostasis is preserved by the ability of the mucus layer and the mucosal barrier to keep the passage of small-sized and antigenic molecules across the epithelium highly selective. When combined and preserved, immune surveillance and barrier's selective permeability, the host capacity of preventing the development of intestinal inflammation is optimized, and viceversa. In addition, the brain-gut-microbiome axis, a multidirectional communication system that integrates distant and local regulatory networks through neural, immunological, metabolic, and hormonal signaling pathways, also regulates intestinal function. Dysfunction of the brain-gut-microbiome axis may induce the loss of gut mucosal homeostasis, leading to uncontrolled permeation of toxins and immunogenic particles, increasing the risk of appearance of intestinal inflammation, mucosal damage, and gut disorders. Irritable bowel syndrome is prevalent stress-sensitive gastrointestinal disorder that shows a female predominance. Interestingly, the role of stress, sex and gonadal hormones in the regulation of intestinal mucosal and the brain-gut-microbiome axis functioning is being increasingly recognized. PURPOSE: We aim to critically review the evidence linking sex, and stress to intestinal barrier and brain-gut-microbiome axis dysfunction and the implications for irritable bowel syndrome.

[Consensus document on the clinical use of melatonin in children and adolescents with sleep-onset insomnia]. / Consenso sobre el uso de melatonina en niños y adolescentes con dificultades para iniciar el sueño.

Sleep problems are highly prevalent among our children and adolescents. Its treatment is mainly based on cognitive behavioural therapies and habit modification procedures. However, the use of sleep promoting drugs and substances is widespread without being supported by clinical guidelines. Exogenous melatonin is a neurohormone marketed as a nutritional supplement that is being increasingly used in the management of sleep problems, and with no control over its use. The consensus document is presented on the use of melatonin in sleep-onset insomnia prepared by representatives of the Spanish Paediatric Association, the Spanish Society of Sleep, the Spanish Society of Paediatric Outpatients and Primary Care, the Spanish Society for Adolescent Medicine, the Spanish Society of Child Psychiatry, and the Spanish Society of Paediatric Neurology.

Expert recommendation: contributions to clinical practice of the new prodrug lisdexamfetamine dimesylate (LDX) in the treatment of attention deficit hyperactivity disorder (ADHD).

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobiological disorders in childhood, and is characterized by inappropriate levels of inattention, hyperactivity and/or impulsiveness, with an estimated prevalence of 5.29%. ADHD can have a negative impact upon all areas of the life of the patient. The main clinical guides accept multimodal treatment, involving both pharmacological and psychological measures, as the best management approach in ADHD (psychoeducational, behavioural and academic). Lisdexamfetamine dimesylate (LDX) is a new drug for the treatment of ADHD. A multidiscipline expert document has been developed, compiling the scientific evidence referred to this new molecule. The study also addresses the existing shortcomings in current drug therapy for ADHD and the contributions of LDX to routine clinical practice, in an attempt to help and guide physicians in the use of this new treatment. This document is endorsed by the ADHD and Psychoeducational Development task Group of the Spanish Society of Primary Care Pediatrics (Grupo de TDAH y Desarrollo Psicoeducativo de la Asociación Española de Pediatría de Atención Primaria, AEPap), the Spanish Society of Pediatric Neurology (Sociedad Española de Neurología Pediátrica, SENEP) and the Spanish Society of Out-hospital Pediatrics and Primary Care (Sociedad Española de Pediatría Extrahospitalaria y Atención Primaria, SEPEAP).

Recomendación de expertos: aportaciones a la práctica clínica del nuevo profármaco lisdexanfetamina dimesilato (LDX) en el tratamiento del trastorno por déficit de atención con hiperactividad (TDAH) / Expert Recommendation: contributions to clinical practice of the new prodrug lisdexamfetamine dimesylate (LDX) in the treatment of attention deficit hyperactivity disorder (ADHD)

El Trastorno por Déficit de Atención con Hiperactividad (TDAH) es uno de los trastornos neurobiológicos más frecuentes en la infancia, caracterizado por la existencia de unos niveles inapropiados de inatención, hiperactividad y/o impulsividad con una prevalencia estimada del 5,29%. El trastorno puede afectar negativamente a todas las áreas de la vida del individuo. Las principales guías clínicas aceptan el tratamiento multimodal como el más recomendable en el TDAH, lo que engloba la aproximación farmacológica y psicológica (psicoeducativa, conductual y académica). El dimesilato de lisdexanfetamina (LDX) es un nuevo tratamiento farmacológico para el TDAH. A fin de recopilar las evidencias científicas sobre esta nueva molécula se ha realizado un documento de expertos multidisciplinar. Este trabajo estudia además las carencias existentes en el tratamiento farmacológico actual en el TDAH y las aportaciones que presenta LDX en la práctica clínica diaria, intentando ayudar y guiar a los médicos en el uso de esta novedad terapéutica. Este documento está respaldado con los avales de las siguientes sociedades científicas: Grupo de TDAH y Desarrollo Psicoeducativo de la Asociación Española de Pediatría de Atención Primaria (AEPap), Sociedad Española de Neurología Pediátrica (SENEP) y Sociedad Española de Pediatría Extrahospitalaria y Atención Primaria (SEPEAP)

Attention deficit hyperactivity disorder (ADHD) is one of the most common neurobiological disorders in childhood, and is characterized by inappropriate levels of inattention, hyperactivity and/or impulsiveness, with an estimated prevalence of 5.29%. ADHD can have a negative impact upon all areas of the life of the patient. The main clinical guides accept multimodal treatment, involving both pharmacological and psychological measures, as the best management approach in ADHD (psychoeducational, behavioural and academic). Lisdexamfetamine dimesylate (LDX) is a new drug for the treatment of ADHD. A multidiscipline expert document has been developed, compiling the scientific evidence referred to this new molecule. The study also addresses the existing shortcomings in current drug therapy for ADHD and the contributions of LDX to routine clinical practice, in an attempt to help and guide physicians in the use of this new treatment. This document is endorsed by the ADHD and Psychoeducational Development task Group of the Spanish Society of Primary Care Pediatrics (Grupo de TDAH y Desarrollo Psicoeducativo de la Asociación Española de Pediatría de Atención Primaria, AEPap), the Spanish Society of Pediatric Neurology (Sociedad Española de Neurología Pediátrica, SENEP) and the Spanish Society of Out-hospital Pediatrics and Primary Care (Sociedad Española de Pediatría Extrahospitalaria y Atención Primaria, SEPEAP

Episodios de urgencia hospitalaria relacionados con el consumo de alcohol en personas de entre 10 y 30 años de edad en Castilla y León durante el período 2003-2010 / Hospital emergency events related with alcohol consumption in young. Castile and Leon, Spain

Fundamentos: El consumo excesivo de alcohol en adolescentes (regular o episódico "binge drinking") produce alteraciones psicológicas y físicas. El objetivo es conocer la magnitud, distribución temporal, perfil, y principales categorías diagnósticas de las urgencias hospitalarias relacionadas con el consumo de alcohol en jóvenes en Castilla León. Métodos: Estudio observacional de las urgencias relacionadas con el consumo de alcohol en sujetos de 10 a 30 años, en hospitales de Castilla y León entre 2003 y 2010. Se utilizó la χ2 para la comparación de proporciones (significación p<0,05). Resultados: Se analizaron 4.429 urgencias relacionadas con el consumo de alcohol. Los episodios en varones supusieron el 59,5% y en el grupo de 18-30 años el 68,1% (p=0,000). Se registraron 3.424 casos en fin de semana y 1.005 entre semana, manteniéndose la distribución en ambos sexos (p<0,05). El fin de semana aumentaron más los casos en los <18 años (85,3%) que en los de 18-30 años (73,6%) (p=0,000). Las intoxicaciones agudas fueron más frecuentes en <18 años (94,2%) que en 18-30 años (84,8%) (p=0,000), aunque entre 18-30 años se detectó consumo más perjudicial (10,7%) y mayor dependencia (3,5%) (p=0,000). El alta médica fue más frecuente en mujeres (89,9%) (p=0,000) y <18 años (94,7%) (p=0,000). Conclusiones: El mayor número de casos se detectó en chicos de 18-30 años, siendo además más graves que en menores de esa edad. En éstos se observa un aumento de las urgencias en el sexo femenino respecto a los varones. El diagnóstico más frecuente son las intoxicaciones etílicas y la mayoría no precisan de ingreso hospitalario(AU)

Background: Excessive alcohol consumption (regular or binge drinking) in adolescents produces physical and psychological alterations. The objective is to know its size, timing, distribution, profile and main category diagnostic of emergency department related to the consumption of alcohol in youngster people. Methods: It's an observational analytic study of hospital emergency related to alcohol consumption in young (10-30 years), in Castile and León hospitals, between 2003 and 2010. It is used the χ2 for comparison of proportions (significance p<0.05). Results: 4.429 emergency hospital episodes related with consumption of alcohol have been analyced. The 59.5% of episodes have been registered in men and the 68.1% in the group of 18-30 years (p=0.000). There are 3.424 episodes at the weekend, and 1.005 during the week, no differences by sexes (p<0.05). The weekend raises more cases in youngster under 18 years (85,3%) than in 18-30 years (73,6%) (p=0.000). Acute alcohol intoxication is more common in <18 years (94,2%) than in 18-30 years (84,8%) (p=0.000), although between 18-30 years more harmful use (10,7%) and dependence (3,5%) is detected (p=0.000). The medical discharge is more common in women (89,9%) (p=0.000) and <18 years (p=0.000). Conclusions: The largest number of cases is detected in men of 1830 years; besides, it is more severe than in under eighteen people. An increase in women emergency is detected with respect to men in under eighteen people. The most important diagnostic is acute alcohol intoxication, and more of them don't need admission(AU)

Acute experimental stress evokes a differential gender-determined increase in human intestinal macromolecular permeability.

BACKGROUND: Intestinal epithelial dysfunction is a common pathophysiologic feature in irritable bowel syndrome (IBS) patients and might be the link to its clinical manifestations. We previously showed that chronic psychosocial stress induces jejunal epithelial barrier dysfunction; however, whether this epithelial response is gender-specific and might thus explain the enhanced female susceptibility to IBS remains unknown. METHODS: Intestinal responses to acute stress were compared in age-matched groups of healthy women and men (n = 10 each) experiencing low background stress. A 20-cm jejunal segment, was perfused with an isosmotic solution, and intestinal effluents were collected under basal conditions, for 15 min during cold pain stress and for a 45-min recovery period. Epithelial function (net water flux and albumin output), changes in stress hormones, and cardiovascular and psychologic responses to cold stress were measured. KEY RESULTS: Heart rate and blood pressure significantly increased during cold pain stress with no differences between men and women. Adrenocorticotropic hormone and cortisol levels during cold pain stress were significantly higher in men. Basal net water flux and epithelial permeability were similar in men and women. Cold pain stress increased water flux in both groups (72 ± 23 and 107 ± 18 µL min(-1) cm(-1) , respectively; F(5, 90) = 5.5; P = 0.003 for Time) and, interestingly, this was associated with a marked increase of albumin permeability in women but not in men (0.8 ± 0.2 vs.-0.7 ± 0.2 mg/15 min; P < 0.0001). CONCLUSIONS & INFERENCES: Intestinal macromolecular permeability in response to acute experimental stress is increased in healthy women, a mechanism that may contribute to female oversusceptibility to IBS.

New experimental Oximes in the management of organophosphorus pesticides poisoning.

Organophosphorus compounds (OPCs) are widely used in agriculture as pesticides and occasionally in industrial settings. They have also been developed as warfare nerve agents. OPCs poisoning from intentional, accidental, and occupational exposure is a major public health problem, especially across the rural developing world. The main toxic mechanism of OPCs is the inhibition of the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), resulting in accumulation of acetylcholine (ACh) at the synapse with cholinergic crisis and possible death. Exposure to even small amounts of an OPC can be fatal and death is usually caused by respiratory failure. Standard treatment involves the administration of intravenous atropine and an oxime to counteract acetylcholinesterase inhibition at the synapse, but the usefulness of oximes is still debated. During more than five decades, pyridinium oximes have been developed as therapeutic agents used in the medical treatment of poisoning with OPCs. They act by reactivation of AChE inhibited by OPCs. However, their activity in poisonings with pesticides and warfare nerve agents is different, and there is still no universal oxime sufficiently effective against all known OPCs. The aim of this article was to review the most recent findings in this field and compare the protection conferred by the new K-oximes and sugar oximes with the effect of the four recommended pyridinium oximes (pralidoxime, obidoxime, trimedoxime, and HI-6), in the search for a broad-spectrum AChE reactivator.

Evolución del consumo de drogas por inmigrantes entre los años 2004 y 2008 / Trends in drug consumption among immigrants between 2004 and 2008

ObjetivoConocer el perfil de los inmigrantes drogodependientes atendidos en Castilla y León.MétodoEstudio descriptivo retrospectivo. Descripción y comparación sociodemográfica y del consumo de drogas mediante ji al cuadrado de Pearson.Resultados80,8% varones; edad media de 33,8 años (DE: 9,0), 72,3% de América Latina, Portugal y Europa del Este; 51,6% han residido en España 5 años o menos; droga principal, heroína (43,8%); vía de consumo, fumada (43,5%); iniciaron el consumo en su país de origen (64,3%). Respecto a 2004, se encontraron diferencias significativas (p<0,05) en los hombres: edad media (33,8 frente a 30,9 años), consumo de droga principal durante ≥21 años (19,2% frente a 8,3%); y en las mujeres: droga principal heroína+cocaína (25,6% frente a 3,6%), consumo durante 16 a 20 años (27,9% frente a 4,0%).ConclusionesEl patrón de consumo difiere según la procedencia. La droga más consumida es la heroína, siendo relevante el consumo inyectado. Se plantea la necesidad de reforzar actuaciones de reducción de daños en este colectivo, vigilar la situación y adaptar los servicios(AU)

ObjectiveTo determine the sociodemographic and drug use profile of immigrants attended in Castile-Leon (Spain).MethodsWe performed a retrospective descriptive study comparing sociodemographic profiles and drug use variables through Pearson's chi-square test.ResultsA total of 80.8% of drug users were men, with a mean age 33.8 years (SD: 9.0); 72.3% were from Latin America, Portugal and eastern Europe and 51.6% had lived for 5 years or less in Spain. The main drug used was heroine (43.8%), via smoking (43.5%); most drug users started using in the country of origin (64.3%). Comparisons between 2008 and 2004 showed the following significant differences: for men: mean age (33.8 vs 30.9); length of main drug use:≥21 years (19.2% vs 8.3%); for women: main drug use: heroin plus cocaine (25.6% vs 3.6%); length of main drug use: 16-20 years (27.9% vs 4.0%).ConclusionsThe pattern of drug use differed by country of origin. The most commonly used drug was heroin, and injection was a frequent route of administration. We identified a need to strengthen harm-reduction interventions in this collective, enhance surveillance and adapt health services(AU)

Local B cells and IgE production in the oesophageal mucosa in eosinophilic oesophagitis.

BACKGROUND: Eosinophilic oesophagitis (EO) is an emerging yet increasingly prevalent disorder characterised by a dense and selective eosinophilic infiltration of the oesophageal wall. While EO is considered an atopic disease primarily triggered by food antigens, disparities between standard allergen testing and clinical responses to exclusion diets suggest the participation of distinct antigen-specific immunoglobulin E (IgE) in the pathophysiology of EO. AIM: To find evidence for a local IgE response. METHODS: Endoscopic biopsies of the distal oesophagus of atopic and non-atopic EO and control individuals (CTL) were processed for immunohistochemistry and immunofluorescence to assess the presence of B cells, mast cells, and IgE-bearing cells. Oesophageal RNA was analysed for the expression of genes involved in B cell activation, class switch recombination to IgE and IgE production, including germline transcripts (GLTs), activation-induced cytidine deaminase (AID), IgE heavy chain (Cepsilon) and mature IgE mRNA using polymerase chain reaction and microarray analysis. RESULTS: Regardless of atopy, EO showed increased density of B cells (p<0.05) and of IgE-bounded mast cells compared to CTL. Both EO and CTL expressed muGLT, epsilonGLT, gamma4GLT, AID, Cepsilon and IgE mRNA. However, the frequency of expression of total GLTs (p = 0.002), epsilonGLT (p = 0.024), and Cepsilon (p = 0.0003) was significantly higher in EO than in CTL, independent of the atopic status. CONCLUSION: These results support the heretofore unproven occurrence of both local immunoglobulin class switching to IgE and IgE production in the oesophageal mucosa of EO patients. Sensitisation and activation of mast cells involving local IgE may therefore critically contribute to disease pathogenesis.

Cardiovascular haemodynamics and cardiac autonomic control in patients with subclinical and overt hyperthyroidism.

OBJECTIVE: To characterize cardiac structure and function and cardiac autonomic control in patients with subclinical and overt hyperthyroidism. DESIGN: Thirty patients with subclinical hyperthyroidism and 30 with overt disease were selected from patients never previously treated for endocrinological disease in the outpatient clinic of our institution. Twenty normal individuals were studied as control group. METHODS: Left ventricular structure and function and cardiac autonomic control were evaluated, respectively, by two-dimensional Doppler echocardiography and by 24-h Holter recording with heart rate variability analysis. RESULTS: Patients with overt hyperthyroidism showed greater values of left ventricular end-diastolic volume (P<0.05) and left ventricular mass (P<0.05) than patients with subclinical disease. In addition, the mean velocity of left ventricular fibre shortening (P<0.05) and left ventricular ejection fraction (P<0.05) were greater in patients with overt hyperthyroidism than in patients with subclinical disease. No difference in any of these parameters was detectable between normal subjects and patients with subclinical disease. The isovolumic relaxation period was shorter in patients with subclinical hyperthyroidism than in control individuals (P<0.05) and in patients with overt hyperthyroidism (P<0.05). As regards cardiac autonomic control, all time and frequency domain measures decreased progressively from control individuals to patients with subclinical hyperthyroidism and those with overt disease (P<0.001). CONCLUSIONS: Thyrotoxic patients show changes in left ventricular structure and increased echocardiographic indexes of myocardial contractility, whereas the only echocardiographic feature detectable in patients with subclinical hyperthyroidism is an increased velocity of left ventricular relaxation. Cardiac parasympathetic withdrawal is evident in patients with overt hyperthyroidism and in patients with subclinical disease.

Circulating levels of cytokines and their site of production in patients with mild to severe chronic heart failure.

BACKGROUND: Patients with chronic heart failure have elevated levels of proinflammatory cytokines; however, the mechanism for their increased expression and the site of their production are unknown. METHODS: Twenty-two patients with heart failure, New York Heart Association functional class II to IV, underwent hemodynamic evaluation and echocardiographic study. Blood samples for cytokine evaluation were performed in the ascending aorta, coronary sinus, inferior vena cava, and hepatic vein. Levels of tumor necrosis factor-alpha (TNF-alpha), its soluble receptors sTNF-RI and sTNF-RII, interleukin-6 (IL-6), IL-6 soluble receptor, soluble gp130, interleukin-2 soluble receptor, and soluble Fas were measured with enzyme-linked immunosorbent assay kits. RESULTS: IL-6 concentrations were higher in class IV patients than in class III patients, which in turn were higher than those in class II. TNF-alpha, sTNF-RI, and sTNF-RII were higher in class IV patients than in class III and II patients. Significant correlations were found between IL-6 concentrations and left ventricular end-systolic volume (r = 0.64; P <.001), pulmonary wedge pressure (r = 0.56; P <.01), and left ventricular ejection fraction (r = -0.56; P <.01). No correlation was found between TNF-alpha and its soluble receptors and left ventricular volumes or hemodynamic measures. Finally, no difference in cytokine concentrations was found among the different sample sites. CONCLUSIONS: Among inflammatory cytokines, IL-6 concentrations better reflect the hemodynamic derangement in patients with heart failure. No cardiac or gut production of cytokines occurs in patients with mild to severe heart failure.

Effects of losartan treatment on cardiac autonomic control during volume loading in patients with DCM.

This study evaluated the effect of angiotensin II receptor blockade on cardiac autonomic control adaptation and urine output in response to acute isotonic volume load in patients with idiopathic dilated cardiomyopathy (DCM) and asymptomatic to mildly symptomatic heart failure. Left ventricular volumes and heart rate variability measurements were assessed at baseline and during intravenous saline load in 14 patients before and after 2 mo of losartan treatment. After losartan treatment, blood pressure values were lower, whereas left ventricular ejection fraction was higher (F = 79, P < 0.001), than before treatment. During saline load, ejection fraction decreased before losartan treatment (F = 5.6, P < 0.05) but did not change after treatment. Urinary volume, unchanged during saline load in untreated patients, increased after losartan (F = 9.38, P < 0. 001). Time-domain measurements that represent vagal modulation of heart rate (root-mean-square successive differences and percentage of differences between successive R-R intervals >50 ms) decreased during saline load in untreated patients (F = 3.1, P < 0.05 and F = 6.5, P < 0.01, respectively), but not after losartan. Similarly, a decrease in very low frequency (F = 3.2, P < 0.05), low-frequency (F = 2.9, P < 0.05), and high-frequency power (F = 6.1, P < 0.01) after saline load was observed only in untreated patients. In patients with DCM, losartan treatment improves the cardiac autonomic adaptation and increases urine output in response to volume overload.

Independent and incremental prognostic value of heart rate variability in patients with chronic heart failure.

BACKGROUND: Decreased heart rate variability (HRV), indicating derangement in cardiac autonomic control, has been reported in patients with chronic heart failure. However, the independent and incremental prognostic value of HRV over clinical data and measures of left ventricular dysfunction has been less thoroughly investigated. This study was designed to evaluate the predictive value of HRV and Poincaré plots as assessed by 24-hour Holter recording in patients with chronic heart failure. METHODS: Ninety-seven patients, mean age 55 +/- 13 years, with radionuclide left ventricular ejection fraction 50 ms (hazard ratio 0.93), and age (hazard ratio 1.06). Furthermore, HRV analysis improved (P <. 001) the prognostic power of a model including clinical and echocardiographic data, left ventricular ejection fraction, and ventricular arrhythmias at Holter recording, whereas the inclusion of Poincaré plots did not add further predictive value. CONCLUSIONS: Our investigation demonstrated that HRV has independent and incremental prognostic value in patients with chronic heart failure and seems useful to stratify patients at high risk of cardiac death.

Wavelet transform analysis of heart rate variability during dipyridamole-induced myocardial ischemia: relation to angiographic severity and echocardiographic dyssynergy.

BACKGROUND: Analysis of heart rate variability (HRV) is a valuable noninvasive method for quantifying autonomic cardiac control in humans and has been utilized during dipyridamole echocardiographic test to differentiate positive from negative test results. HYPOTHESIS: We aimed to evaluate, by means of HRV analysis, the influence of the angiographic severity of coronary artery disease on cardiac autonomic control during dipyridamole-induced myocardial ischemia. METHODS: We analyzed RR interval variability changes during dipyridamole-induced myocardial ischemia in 31 selected patients (mean age 54 +/- 9 years) with available coronary angiography and positive dipyridamole echocardiographic test. Spectral components of HRV were assessed by means of wavelet transform analysis for the last 5 min before the beginning of the test (baseline) and for 5 min after the onset of ischemia-related events (peak dipyridamole effect). RESULTS: Patients were divided into three groups according to the number of coronary diseased vessels (Group A, single-vessel disease; Group B, double-vessel disease; Group C, triple-vessel disease). No difference was detectable at baseline among the three groups. After dipyridamole, low-frequency power, a measure of sympathetic modulation of heart rate, increased and echocardiographic wall motion score index worsened in all groups (p < 0.001). The increase in low-frequency power was more evident in Group C patients than in the other two groups (p < 0.005). Furthermore, after dipyridamole, a direct correlation was found between low-frequency power and wall motion score index (r = 0.59; p < 0.001). CONCLUSIONS: These data suggest that HRV analysis performed during dipyridamole echocardiographic test provides useful information to assess the severity of coronary artery disease.

Prognostic value of coronary angiography in patients with chronic ischemic left ventricular dysfunction and evidence of viable myocardium on thallium reinjection imaging.

BACKGROUND: We evaluated the independent and incremental prognostic value of cardiac catheterization and coronary angiographic data over thallium reinjection after stress redistribution imaging in patients with myocardial infarction and left ventricular dysfunction. METHODS AND RESULTS: Sixty-nine patients with a first myocardial infarction (> 8 weeks) and left ventricular ejection fraction < or = 40% underwent thallium-201 reinjection after stress redistribution tomographic imaging and cardiac catheterization. During follow-up (mean 26 months) 11 cardiac events (8 cardiac deaths and 3 nonfatal myocardial infarctions) occurred. On Cox regression analysis independent predictors of cardiac events were the sum of reversible and moderately irreversible defects at thallium reinjection (chi 2, 16.4, p < 0.005) and the number of reversible defects at stress redistribution (chi 2, 5.1, p < 0.05). Moreover, thallium reinjection imaging improved the prognostic power of clinical, exercise, and stress redistribution data (p < 0.01). The inclusion of left ventricular ejection fraction produced a borderline improvement (p = 0.06), whereas the number of vessels with coronary disease did not. In contrast, in patients at high risk such as those with at least 25% of viable myocardium at reinjection, the number of diseased vessels provided additional prognostic information (p < 0.05). CONCLUSIONS: In patients with chronic ischemic left ventricular dysfunction, left ventricular ejection fraction, but not the number of diseased vessels, provides additional prognostic information to thallium imaging. Therefore coronary angiography seems unnecessary in these patients, unless a significative amount of viable myocardium is detectable.