Enfermedad pulmonar intersticial en Esclerosis Sistémica: diferencia en la presentación clínica y evolución clínica y evolución entre pacientes con anticuerpos Scl-70 frente PM-Scl

La esclerosis sistémica (ES) es una enfermedad autoinmune multisistémica que afecta de forma variable a diferentes órganos. En el pulmón produce la enfermedad pulmonar intersticial difusa (EPID), cuyo pronóstico difiere según el autoanticuerpo asociado. Se estudiaron las características clínicas y espirométricas de 63 pacientes diagnosticados de ES y EPID, con positividad para anti-Scl-70 o anti-PM-Scl. En el grupo anti-Scl-70 se documentó mayor prevalencia de úlceras digitales y afección gastrointestinal, con mayor pérdida de capacidad vital forzada (CVF) al final del seguimiento y mayor proporción de patrón restrictivo grave. El grupo anti-PM-Scl presentó mayor miopatía inflamatoria y mejor evolución espirométrica.

Extramediastinal surgical problems in heart transplant recipients.

BACKGROUND: As heart transplantation has gained wide acceptance, a growing number of recipients are at risk of experiencing extramediastinal surgical problems. STUDY DESIGN: We retrospectively reviewed our experience in the diagnosis and management of surgical problems occurring in 94 consecutive patients having heart transplantation. During the period of the study, we progressively adopted a policy of low-level immunosuppression, aiming toward monotherapy with cyclosporine. RESULTS: Seventy-four extramediastinal surgical problems developed in 44 of 94 patients (47%). The type of problems were gastrointestinal in 17 of 74 (23%), vascular in 13 of 74 (17.5%), urogenital in 8 of 74 (11%), and neurologic in 4 of 74 (5.5%). There were also 9 of 74 cases of trauma (12%), 9 of 74 skin tumors (12%), and 14 of 74 miscellaneous diseases (19%). Sixty-two surgical diseases occurring in 40 patients required 75 surgical interventions, 11 of them (15%) on an emergency basis. Operations were performed for 12 of 74 neoplasms (16%) and 12 of 74 infectious or potentially infectious diseases (16%). Surgical diseases occurred most commonly within the first 6 months after transplantation (20 of 74; 27%). Complications occurred in 8 of 75 surgical interventions (9%). A high proportion of surgical disease was potentially related to immunosuppressive therapy (37 of 74; 50%) or to transplantation itself (7 of 74; 9%). CONCLUSIONS: Extramediastinal diseases after heart transplantation involve most surgical specialties. Most of them are potentially linked with either the immunosuppressive therapy or the transplantation procedure, supporting our low-level immunosuppression policy. Expectant management is not justified in this population, who withstands operations well both early and late after transplantation.

Prise en charge nutritionnelle préopératoire. [Preoperative nutritional support.]

Undernutrition is an independent factor of postoperative morbidity and mortality The aim of a preoperative nutritional support is to enhance immune muscular and cognitive functions, and to support wound healing This nutritional support (e g dietary management enteral or parenteral nutrition) should be limited to high risk situations with a beneficial effect of nutrition for the patient undernutrition major surgery and elderly Preoperative nutritional support should be scheduled for atleast 7 to 10 days before the surgery During the preoperative period the type and route of an eventual postoperative nutritional assistance should be anticipated In the case of emergency surgery nutritional assessment of the patient should be done as soon as possible before surgery or in the 48 h postoperative period Finally, in elective surgery, preoperative fasting should be limited to 2-3 hours for clear liquids and 6 hours for solids (C) 2010 Published by Elsevier Masson SAS

Imatinib plasma concentrations variability in oncologic patients

Imatinib (Glivec®) has transformed the treatment and short-term prognosis of chronic myeloid leukemia (CML) and gastrointestinal stromal tumor (GIST). However, the treatment must be taken indefinitely, it is not devoid of inconvenience and toxicity. Moreover, resistance or escape from disease control occurs in a significant number of patients. Imatinib is a substrate of the cytochromes P450 CYP3A4/5 and of the multidrug transporter P-glycoprotein (product of the MDR1 gene). Considering the large inter-individual differences in the expression and function of those systems, the disposition and clinical activity of imatinib can be expected to vary widely among patients, calling for dosage individualization. The aim of this exploratory study was to determine the average pharmacokinetic parameters characterizing the disposition of imatinib in the target population, to assess their inter-individual variability, and to identify influential factors affecting them. A total of 321 plasma concentrations, taken at various sampling times after the latest dose, were measured in 59 patients receiving Glivec at diverse regimens, using a validated HPLC-UV method developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A one-compartment model with first-order absorption appeared appropriate to describe the data, with an average apparent clearance of 12.4 l/h, a distribution volume of 268 l and an absorption constant of 0.47 h-1. The clearance was affected by body weight, age and sex. No influences of interacting drugs were found. DNA samples were used for pharmacogenetic explorations. At present, only the MDR1 polymorphism has been assessed and seems to affect the pharmacokinetic parameters of imatinib. Large inter-individual variability remained unexplained by the demographic covariates considered, both on clearance (40 %) and distribution volume (71 %). Together with intra-patient variability (34 %), this translates into an 8-fold width of the 90 %-prediction interval of plasma concentrations expected under a fixed dosing regimen. This is a strong argument to further investigate the possible usefulness of a therapeutic drug monitoring program for imatinib. It may help to individualize the dosing regimen before overt disease progression or observation of treatment toxicity, thus improving both the long-term therapeutic effectiveness and tolerability of this drug.

Combined laparoscopic-endoscopic method using an omental plug for therapy of gastroduodenal ulcer perforation.

BACKGROUND: Laparoscopic techniques have been proposed as an alternative to open surgery for therapy of peptic ulcer perforation. They provide better postoperative comfort and absence of parietal complications, but leakage occurs in 5% of cases. We describe a new method combining laparoscopy and endoluminal endoscopy, designed to ensure complete closure of the perforation. METHODS: Six patients with anterior ulcer perforations (4 duodenal, 2 gastric) underwent a concomitant laparoscopy and endoluminal endoscopy with closure of the orifice by an omental plug attracted into the digestive tract. RESULTS: All perforations were sealed. The mean operating time was 72 minutes. The mean hospital stay was 5.5 days. There was no morbidity and no mortality. At the 30-day evaluation all ulcers but one (due to Helicobacter pylori persistence) were healed. CONCLUSIONS: This method is safe and effective. Its advantages compared with open surgery or laparoscopic patching as well as its cost-effectiveness should be studied in prospective randomized trials.

Relationship of imatinib-free plasma levels and target genotype with efficacy and tolerability

Imatinib has revolutionised the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GIST). Using a nonlinear mixed effects population model, individual estimates of pharmacokinetic parameters were derived and used to estimate imatinib exposure (area under the curve, AUC) in 58 patients. Plasma-free concentration was deduced from a model incorporating plasma levels of alpha(1)-acid glycoprotein. Associations between AUC (or clearance) and response or incidence of side effects were explored by logistic regression analysis. Influence of KIT genotype was also assessed in GIST patients. Both total (in GIST) and free drug exposure (in CML and GIST) correlated with the occurrence and number of side effects (e.g. odds ratio 2.7+/-0.6 for a two-fold free AUC increase in GIST; P<0.001). Higher free AUC also predicted a higher probability of therapeutic response in GIST (odds ratio 2.6+/-1.1; P=0.026) when taking into account tumour KIT genotype (strongest association in patients harbouring exon 9 mutation or wild-type KIT, known to decrease tumour sensitivity towards imatinib). In CML, no straightforward concentration-response relationships were obtained. Our findings represent additional arguments to further evaluate the usefulness of individualizing imatinib prescription based on a therapeutic drug monitoring programme, possibly associated with target genotype profiling of patients.

Imatinib plasma concentrations variability in oncologic patients

The anticancer drug imatinib has transformed the treatment and prognosis of chronic myeloid leukemia and gastrointestinal stromal tumor. However, the treatment must be taken indefinitely and is not devoid of inconveniences and toxicity. Moreover, resistance or escape from disease control are occurring. Considering the large interindividual differences in the function of the enzymatic and transport systems involved in imatinib disposition, exposure to this drug can be expected to vary widely among patients. This book describes an observational clinical trial aiming at exploring the influence of these covariates on imatinib pharmacokinetics and assessing the interindividual variability of the pharmacokinetic parameters of the drug. A large interindividual variability was observed, together with some preliminary concentration-effect relationships. These elements are arguments to further investigate the potential benefit of a therapeutic drug monitoring program to optimize the use of imatinib in patients. Such results should be especially useful to clinical oncologists or scientists involved in clinical oncology research.

Mecanismos fisiopatológicos en la rumiación

La fisiopatología del síndrome de rumiación es mal conocida. Por ello, el objetivo del estudio es determinar las características clínicas, fisiológicas y psicopatológicas de los pacientes con rumiación respecto a un grupo de dispepsia funcional. Se estudiaron ambos grupos de forma prospectiva durante dos años, realizándose manometría gastrointestinal y esofágica, vaciamiento gástrico, barostato gástrico y valoración psipatológica. Concluimos que el síndrome de rumiación se presenta en pacientes con características funcionales de dispepsia funcional, sin evidenciarse diferencias en la patología psiquiátrica pero con una mejor percepción de la enfermedad respecto al grupo de dispépticos.

Troubles gastro-intestinaux et activités sportives [Lower intestinal distress during sports activities].

This article reviews the literature regarding gastrointestinal disturbances in particular in runners. The lower intestinal problems of motility and blood loss are discussed. These problems are directly related to running. These symptoms, especially diarrhea are common and can impact adversely both performance and the health of the athlete. Most cases are relatively benign. The sport medicine clinician should be familiar with the management of these problems in order to optimize the treatment and facilitate return to sport.

Congenital diaphragmatic hernia : a European population-based study of epidemiology, prenatal diagnosis and mortality

Aim: To study the epidemiology and the impact of prenatal diagnosis on mortality and morbidity in infants with isolated congenital diaphragmatic hernia (CDH). Methods: Cases were identified in eight population-based registries of congenital malformations (Eurocat) in Europe. Results: A total of 183 live births were included in the study. Sixty per cent died and 67% of all deaths were during the first day of life. CDH was diagnosed prenatally in 39% of cases. Both mortality and morbidity were significantly higher for infants diagnosed prenatally compared to those diagnosed postnatally. The Apgar score was a very sensitive indicator for survival. Gestational age at birth was significantly lower for infants diagnosed prenatally compared to those diagnosed postnatally (37.6 weeks vs. 38.8 weeks, p < 0.01). At the end of follow-up, half of the survivors were leading a normal life. The most frequently reported health problems were respiratory and gastrointestinal symptoms. Conclusions: In this population-based study, mortality for infants with CDH was high (60%) and early prenatal diagnosis was a risk factor for survival. Intervention at the time of birth seems too late for the majority of newborn infants with CDH.

Haemorrhage into the pancreatic duct (Hemosuccus pancreaticus): recognition and management.

OBJECTIVE: To highlight the clinical presentation, investigation and treatment of haemorrhage into the pancreatic duct. DESIGN: Retrospective study and review of publications. SETTING: University hospital, Switzerland. SUBJECTS: All 4 cases from 1972 to 1993. INTERVENTIONS: 2 Whipple procedures, 1 resection of the pancreatic head, 1 exploratory laparotomy. Radiological embolisation in one case. MAIN OUTCOME MEASURES: Cessation of haemorrhage and survival. RESULTS: The diagnosis was made preoperatively in three cases by gastroduodenoscopy and arteriography. Operation was the primary treatment in all patients and was effective with low morbidity and no mortality in three of them. Embolisation stopped the haemorrhage in the fourth patient, who was alcoholic and died of progressive liver insufficiency and variceal haemorrhage. CONCLUSIONS: There is no specific indication for haemorrhage into the pancreatic duct. The diagnosis is suggested by endoscopy (absence of a more common cause, or blood in the second part of the duodenum). Arteriography is essential to confirm the site of the bleeding and to attempt embolization. Operation is usually the definitive treatment.

Haben selektive COX-2-Hemmer unerwünschte renale und kardiovaskuläre Wirkungen [Do selective COX-2 inhibitors have adverse renal and cardiovascular effects?].

Selective cyclooxygenase-2-inhibitors (COX-2) were developed as an alternative to the non-steroidal anti-inflammatory drugs (NSAID) in order to reduce their known gastrointestinal and renal toxicity. Several recent studies have shown the complex mechanism of the cyclooxygenase-2. The inhibition of the COX-2 has effects on renal hemodynamics, renal salt and water retention and may increase the thromboembolic and therefore the cardiovascular risk. The renal toxicity of the COX-2 inhibitors is similar to that of traditional NSAID. Regarding these data, COX-2 inhibitors should be prescribed with much caution to high risk patients, that is, patients with renal failure and/or cardiovascular diseases.

Review article: Intestinal epithelia and barrier functions.

The mucosal epithelia of the digestive tract acts as a selective barrier, permeable to ions, small molecules and macromolecules. These epithelial cells aid the digestion of food and absorption of nutrients. They contribute to the protection against pathogens and undergo continuous cell renewal which facilitates the elimination of damaged cells. Both innate and adaptive defence mechanisms protect the gastrointestinal-mucosal surfaces against pathogens. Interaction of microorganisms with epithelial cells triggers a host response by activating specific transcription factors which control the expression of chemokines and cytokines. This host response is characterized by the recruitment of macrophages and neutrophils at the site of infection. Disruption of epithelial signalling pathways that recruit migratory immune cells results in a chronic inflammatory response. The adaptive defence mechanism relies on the collaboration of epithelial cells (resident sampling system) with antigen-presenting and lymphoid cells (migratory sampling system); in order to obtain samples of foreign antigen, these samples must be transported across the barriers without affecting the integrity of the barrier. These sampling systems are regulated by both environmental and host factors. Fates of the antigen may differ depending on the way in which they cross the epithelial barrier, i.e. via interaction with motile dendritic cells or epithelial M cells in the follicle-associated epithelium.

Single-dose oral amoxicillin or linezolid for prophylaxis of experimental endocarditis due to vancomycin-susceptible and vancomycin-resistant Enterococcus faecalis.

Endocarditis prophylaxis following genitourinary or gastrointestinal procedures targets Enterococcus faecalis. Prophylaxis recommendations advocate oral amoxicillin (2 g in the United States and 3 g in the United Kingdom) in moderate-risk patients and intravenous amoxicillin (2 g) or vancomycin (1 g) plus gentamicin in high-risk patients. While ampicillin-resistant (or amoxicillin-resistant) E. faecalis is still rare, there is a concern that these regimens might fail against vancomycin-resistant and/or aminoglycoside-resistant isolates. The present study tested oral linezolid as an alternative. Rats with catheter-induced aortic vegetations were given prophylaxis simulating human pharmacokinetics of oral amoxicillin (2- to 3-g single dose), oral linezolid (600 mg, single or multiple oral doses every 12 h), or intravenous vancomycin (1-g single dose). Rats were then inoculated with the minimum inoculum infecting 90% of the animals (90% infective dose [ID(90)]) or with 10 times the ID(90) of the vancomycin-susceptible E. faecalis strain JH2-2 or the vancomycin-resistant (VanA phenotype) E. faecalis strain UCN41. Amoxicillin was also tested with two additional vancomycin-susceptible E. faecalis strains, 309 and 1209. Animals were sacrificed 3 days later. All the tested bacteria were susceptible to amoxicillin and gentamicin. Single-dose amoxicillin provided 100% protection against all four isolates at both the ID(90) and 10 times the ID(90). In contrast, linezolid required up to four consecutive doses to provide full protection against the vancomycin-resistant isolate. Vancomycin protected only against the vancomycin-susceptible strain. The high efficacy of single-dose oral amoxicillin suggests that this regimen could be used for prophylaxis in both moderate-risk and high-risk patients without additional aminoglycosides. Linezolid appears to be less reliable, at least against the vancomycin-resistant strain.