Subtherapeutic triazole concentrations as result of a drug-drug interaction with lumacaftor/ivacaftor.

Lumacaftor/ivacaftor (Orkambi®, LUM/IVA) is indicated for the treatment of cystic fibrosis (CF) patients aged ≥ 2 years with homozygous F580del mutation in the CFTR gene. Triazole fungal agents are used to treat fungal disease in CF. The use of triazoles is limited by pharmacokinetic challenges, such as drug-drug interactions. The most notable drug-drug interaction between triazoles and LUM/IVA is due to strong induction of CYP3A4 and UGT by LUM. In this real-world retrospective observational study, we described the effect of LUM/IVA on the trough concentration of triazoles. Concomitant use of LUM/IVA with itraconazole, posaconazole or voriconazole resulted in subtherapeutic triazole levels in 76% of the plasma samples. In comparison, in patients with triazole agents without LUM/IVA only 30.6% of the plasma samples resulted in subtherapeutic concentrations. Subtherapeutic plasma concentrations of triazoles should be considered in CF patients on LUM/IVA and further research is warranted for other dosing strategies and alternative antifungal therapy.

Radiation damage by extensive local water ionization from two-step electron-transfer-mediated decay of solvated ions.

Biomolecular radiation damage is largely mediated by radicals and low-energy electrons formed by water ionization rather than by direct ionization of biomolecules. It was speculated that such an extensive, localized water ionization can be caused by ultrafast processes following excitation by core-level ionization of hydrated metal ions. In this model, ions relax via a cascade of local Auger-Meitner and, importantly, non-local charge- and energy-transfer processes involving the water environment. Here, we experimentally and theoretically show that, for solvated paradigmatic intermediate-mass Al3+ ions, electronic relaxation involves two sequential solute-solvent electron transfer-mediated decay processes. The electron transfer-mediated decay steps correspond to sequential relaxation from Al5+ to Al3+ accompanied by formation of four ionized water molecules and two low-energy electrons. Such charge multiplication and the generated highly reactive species are expected to initiate cascades of radical reactions.

Lung imaging in bronchopulmonary dysplasia: a systematic review.

BACKGROUND: Bronchopulmonary dysplasia (BPD) remains a common complication of preterm birth. Both historically and in current practice, radiologic evaluation of the lungs has an important role in assessing disease severity and complications. AIM: To provide an overview of imaging techniques for detecting lung abnormalities in patients with BPD in all age ranges. METHODS: A systematic literature search was conducted in PubMed, Web of Science and the Cochrane Library. Records were screened by title and abstract and then by full text. A total of 37 records were selected and included in this qualitative literature overview. RESULTS: Computed tomography (CT) was the most commonly used imaging modality, followed by chest radiography and magnetic resonance imaging (MRI). Several qualitative and quantitative scoring systems were presented and most showed good correlation with BPD severity. The association with functional and clinical outcomes was only rarely reported, showing varying correlation with spirometry results and respiratory exacerbations. MRI is an upcoming imaging technique for BPD that is technically feasible, showing clear differences in the lung parenchyma of patients with BPD. CONCLUSION: Several imaging and scoring methods indicate that lung imaging continues to play a role in BPD care. Standardization and correlation with functional and clinical outcomes will become increasingly important for further research.

Population pharmacokinetic modelling of intravenous paracetamol in fit older people displays extensive unexplained variability.

AIMS: Paracetamol is the analgesic most used by older people. The physiological changes occurring with ageing influence the pharmacokinetics (PK) of paracetamol and its variability. We performed a population PK-analysis to describe the PK of intravenous (IV) paracetamol in fit older people. Simulations were performed to illustrate target attainment and variability of paracetamol exposure following current dosing regimens (1000 mg every 6 h, every 8 h) using steady-state concentration (Css-mean ) of 10 mg l-1 as target for effective analgesia. METHODS: A population PK-analysis, using NONMEM 7.2, was performed based on 601 concentrations of paracetamol from 30 fit older people (median age 77.3 years, range [61.8-88.5], body weight 79 kg [60-107]). All had received an IV paracetamol dose of 1000 mg (over 15 min) after elective knee surgery. RESULTS: A two-compartment PK-model best described the data. Volume of distribution of paracetamol increased exponentially with body weight. Clearance was not influenced by any covariate. Simulations of the standardized dosing regimens resulted in a Css of 9.2 mg l-1 and 7.2 mg l-1 , for every 6 h and every 8 h respectively. Variability in paracetamol PK resulted in Css above 5.4 and 4.1 mg l-1 , respectively, in 90% of the population and above 15.5 and 11.7, respectively, in 10% at these dosing regimens. CONCLUSIONS: The target concentration was achieved in the average patient with 1000 mg every 6 h, while every 8 h resulted in underdosing for the majority of the population. Furthermore, due to a large (unexplained) interindividual variability in paracetamol PK a relevant proportion of the fit older people remained either under- or over exposed.

[Radium-223 dichloride in patients with castration-refractory prostate cancer]. / Alpharadin-Therapie bei Patienten mit metastasiertem kastrationsrefraktärem Prostatakarzinom.

Since November 2013, the alpha emitter radium-223 dichloride (Alpharadin/Xofigo®) has been approved for the treatment of men with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases and no known visceral metastatic disease. In the ASYMPCA clinical trial, radium-223 was shown to improve overall survival and to reduce the time to the first symptomatic skeletal event. The use of radium-223 was associated with a reduction of pain and an improvement of health-related quality of life compared to the placebo arm. The efficacy of radium-223 dichloride was not inhibited by the use of chemotherapy with docetaxel. Studies have demonstrated a longer overall survival (OS) in patients with a combined treatment of abiraterone or enzalutamide; however, until this data is validated in larger clinical trials, the combination of radium-223 and abiraterone/enzalutamide cannot be recommended. Patients who have received concomitant medication with denosumab appeared to have a longer OS compared to patients who did not. A second treatment cycle of radium-223 was not associated with any adverse events when compared to the outcomes reported in the ASLYMPCA trial. Here the median radiographic progression-free survival was 9 months.

Population pharmacokinetics of haloperidol in terminally ill adult patients.

PURPOSE: Over 80% of the terminally ill patients experience delirium in their final days. In the treatment of delirium, haloperidol is the drug of choice. Very little is known about the pharmacokinetics of haloperidol in this patient population. We therefore designed a population pharmacokinetic study to gain more insight into the pharmacokinetics of haloperidol in terminally ill patients and to find clinically relevant covariates that may be used in developing an individualised dosing regimen. METHODS: Using non-linear mixed effects modelling (NONMEM 7.2), a population pharmacokinetic analysis was conducted with 87 samples from 28 terminally ill patients who received haloperidol either orally or subcutaneously. The covariates analysed were patient and disease characteristics as well as co-medication. RESULTS: The data were accurately described by a one-compartment model. The population mean estimates for oral bioavailability, clearance and volume of distribution for an average patient were 0.86 (IIV 55%), 29.3 L/h (IIV 43%) and 1260 L (IIV 70%), respectively. This resulted in an average terminal half-life of haloperidol of around 30 h. CONCLUSION: Our study showed that the pharmacokinetics of haloperidol could be adequately described by a one-compartment model. The pharmacokinetics in terminally ill patients was comparable to other patients. We were not able to explain the wide variability using covariates.

Phenotypic and functional characterization of in vitro cultured human mast cells.

BACKGROUND: Mast cell progenitor cells, derived from CD34+ hematopoietic stem cells, enter the circulation and subsequently mucosal or connective tissues where they mature to mast cells. Upon activation, mast cells increase the expression of activation markers, e.g. CD63, and release histamine amongst other mediators. Traditionally, release of these mediators is quantified using assays measuring their extracellular concentration in the supernatant of stimulated cells. METHODS: Human mast cells (HuMC) were cultured from peripheral blood, phenotypically characterized, passively sensitized with allogenic IgE antibodies and finally stimulated by anti-IgE that crosslinks IgE/FcεRI complexes. Alterations in the number of cells positive for CD63 and release of histamine were quantified simultaneously by flow cytometry. RESULTS: In culture, two distinct CD45+ cell populations were identified: CD117+ CD203c+hi and CD117- CD203c+low cells. Both populations showed positivity for FcεRI, tryptase and chymase, and contained histamine. Activation resulted in a significant increase of cells positive for CD63+ up to 21% (range: 11-39) for CD117+ CD203c+hi cells (P = 0.005), and 27% (18-55) CD63+ for CD117- CD203c+low cells (P = 0.02). Baseline histamine content was higher for CD117+ CD203c+hi cells than for CD117- CD203c+low cells, respectively 994 (695-6815) Molecules of Equivalent Specific Fluorochrome V500 per cell (MESF-V500/cell) and 797 (629-4978) MESF-V500/cell (P = 0.02). After activation, CD117+ CD203c+hi cells showed significant histamine release of 578 (366-1521) MESF-V500/cell, whilst CD117- CD203c+low cells resulted in 310 (217-366) MESF-V500/cell histamine release. CONCLUSION: This study discloses that culturing HuMC from CD34+ progenitors yields 2 phenotypically distinct cell populations that display a greatly similar response upon cross-linking of IgE/FcεRI complexes. © 2016 International Clinical Cytometry Society.

Pharmacokinetic considerations and recommendations in palliative care, with focus on morphine, midazolam and haloperidol.

INTRODUCTION: A variety of medications are used for symptom control in palliative care, such as morphine, midazolam and haloperidol. The pharmacokinetics of these drugs may be altered in these patients as a result of physiological changes that occur at the end stage of life. AREAS COVERED: This review gives an overview of how the pharmacokinetics in terminally ill patients may differ from the average population and discusses the effect of terminal illness on each of the four pharmacokinetic processes absorption, distribution, metabolism, and elimination. Specific considerations are also given for three commonly prescribed drugs in palliative care: morphine, midazolam and haloperidol). EXPERT OPINION: The pharmacokinetics of drugs in terminally ill patients can be complex and limited evidence exists on guided drug use in this population. To improve the quality of life of these patients, more knowledge and more pharmacokinetic/pharmacodynamics studies in terminally ill patients are needed to develop individualised dosing guidelines. Until then knowledge of pharmacokinetics and the physiological changes that occur in the final days of life can provide a base for dosing adjustments that will improve the quality of life of terminally ill patients. As the interaction of drugs with the physiology of dying is complex, pharmacological treatment is probably best assessed in a multi-disciplinary setting and the advice of a pharmacist, or clinical pharmacologist, is highly recommended.

Mechanisms contributing to visceral hypersensitivity: focus on splanchnic afferent nerve signaling.

BACKGROUND: Visceral hypersensitivity is a main characteristic of functional bowel disorders and is mediated by both peripheral and central factors. We investigated whether enhanced splanchnic afferent signaling in vitro is associated with visceral hypersensitivity in vivo in an acute and postinflammatory rat model of colitis. METHODS: Trinitrobenzene sulfonic acid (TNBS)-colitis was monitored individually by colonoscopy to confirm colitis and follow convalescence and endoscopic healing in each rat. Experiments were performed in controls, rats with acute colitis and in postcolitis rats. Colonic afferent mechanosensitivity was assessed in vivo by quantifying visceromotor responses (VMRs), and by making extracellular afferent recordings from splanchnic nerve bundles in vitro. Multiunit afferent activity was classified into single units identified as low threshold (LT), wide dynamic range (WDR), high threshold (HT), and mechanically insensitive afferents (MIA). KEY RESULTS: During acute TNBS-colitis, VMRs were significantly increased and splanchnic nerve recordings showed proportionally less MIA and increased WDR and HT afferents. Acute colitis gave rise to an enhanced spontaneous activity of both LT and MIA and augmented afferent mechanosensitivity in LT, WDR and HT afferents. Postcolitis, VMRs remained significantly increased, whereas splanchnic nerve recordings showed that the proportion of LT, WDR, HT and MIA had normalized to control values. However, LT and MIA continued to show increased spontaneous activity and WDR and HT remained sensitized to colorectal distension. CONCLUSIONS & INFERENCES: Visceral hypersensitivity in vivo is associated with sensitized splanchnic afferent responses both during acute colitis and in the postinflammatory phase. However, splanchnic afferent subpopulations are affected differentially at both time points.

Effect of schistosomiasis on CX3CR1-expressing mononuclear phagocytes in the ileum and mesenteric lymph nodes of the mouse.

BACKGROUND: Intestinal dendritic cells (DCs) maintain immune homeostasis, only initiating an active immune response against invading pathogens. However, little information is available on the reaction of mononuclear phagocytes (MNP) to intestinal trematode infection, a reaction equally important in helminth-based therapies. The CD11c(+)  CX3CR1(+)  F4/80(-) DCs in the ileal lamina propria (LP) of the mouse were proven to migrate to the mesenteric lymph nodes (MLNs). We analyzed all MNP subsets present in the mouse LP and MLNs, under steady-state conditions and during acute Schistosoma mansoni-induced inflammation. Furthermore, we studied the uptake of schistosomal antigens by MNP in vivo in the LP and MLNs. METHODS: Using a combination of immunohistochemistry and multiparametric flow cytometry, we investigated distributional changes of the MNP during acute intestinal schistosomiasis. Next, S. mansoni-derived products, i.e., S. mansoni soluble worm proteins (SmSWP) and S. mansoni soluble egg antigens (SmSEA) were intraperitoneally injected into CX3CR1(+/) (GFP) C57BL/6 mice and antigen uptake was analyzed using confocal microscopy. KEY RESULTS: The CD11c(+)  CX3CR1(+)  F4/80(-) DCs significantly increased during intestinal schistosomiasis in the LP and MLNs. Only CX3CR1-expressing DC and MФ subsets, but not other LP DCs, are involved in both SmSWP and SmSEA antigen uptake and processing. CONCLUSIONS & INFERENCES: The significant upregulation of CD11c(+)  CX3CR1(+)  F4/80(-) DCs during intestinal schistosomiasis and the restriction of phagocytosis of parasitic antigens to CX3CR1-expresssing MNP indicate a crucial role for this immune cell niche in response to trematodiasis. These findings add insight into the functional specialization of LP immune cells and add to the understanding of cellular mechanisms behind helminth-based therapies.

Histamine H4 receptors in the gastrointestinal tract.

Histamine is a well-established mediator involved in a variety of physiological and pathophysiological mechanisms and exerts its effect through activation of four histamine receptors (H1-H4). The histamine H4 receptor is the newest member of this histamine receptor family, and is expressed throughout the gastrointestinal tract as well as in the liver, pancreas and bile ducts. Functional studies using a combination of selective and non-selective H4 receptor ligands have rapidly increased our knowledge of H4 receptor involvement in gastrointestinal processes both under physiological conditions and in models of disease. Strong evidence points towards a role for H4 receptors in the modulation of immune-mediated responses in gut inflammation such as in colitis, ischaemia/reperfusion injury, radiation-induced enteropathy and allergic gut reactions. In addition, data have emerged implicating H4 receptors in gastrointestinal cancerogenesis, sensory signalling, and visceral pain as well as in gastric ulceration. These studies highlight the potential of H4 receptor targeted therapy in the treatment of various gastrointestinal disorders such as inflammatory bowel disease, irritable bowel syndrome and cancer.

Apoptosis and necrosis: two different outcomes of cigarette smoke condensate-induced endothelial cell death.

Cigarette smoking is one of the most important and preventable risk factors for atherosclerosis. However, because of the complex composition of cigarette smoke, the detailed pathophysiological mechanisms are not fully understood. Based on controversial reports on the pro-atherogenic activity of cigarette smoke condensate, also called tar fraction (CSC), we decided to analyse the effects of CSC on the viability of endothelial cells in vitro. The results of this study show that low concentrations of the hydrophobic tar fraction induces DNA damage resulting in a P53-dependent and BCL-XL-inhibitable death cascade. Western blot analyses showed that this cascade is caspase-independent and immunofluorescence analysis have shown that the apoptotic death signalling is mediated by the release of apoptosis-inducing factor. Higher CSC concentrations also induce apoptotic-like signalling but the signalling cascade is then redirected to necrosis. Despite the fact that CSC induces a profound increase in cellular reactive oxygen species production, antioxidants exhibit only a minimal cell death protective effect. Our data indicates that not only hydrophilic constituents of cigarette smoke extract, but also CSC is harmful to endothelial cells. The mode and the outcome of CSC-induced cell death signalling are highly concentration dependent: lower concentrations induce caspase-independent apoptosis-like cell death, whereas incubation with higher concentrations interrupts apoptotic signalling and induces necrosis.

The use of colonoscopy to follow the inflammatory time course of TNBS colitis in rats.

BACKGROUND AND STUDY AIMS: Animal models of colitis are widely used to study the pathogenesis of inflammatory bowel diseases (IBD) and irritable bowel syndrome (IBS). However techniques allowing sequential assessment of colonic inflammation over time, without the need to sacrifice the animal, are required. This study evaluated in vive colonoscopy to follow the evolution of colitis in rats in comparison with the more commonly used post-mortem macroscopic, microscopic and biochemical assays of inflammation. METHODS: Colitis was induced in rats by a single intrarectal instillation of trinitrobenzene sulphonic acid (TNBS). Using a baby upper gastrointestinal endoscope, the severity of colitis was monitored at days 3, 10, 28 and 56 after the induction of colitis. Inflammation was scored by colonoscopy based on the degree of ulceration, extent of inflammation, mucosal bleeding, oedema and stenosis. During follow-up, rats were randomly selected for postmortem macroscopic and microscopic histology and myeloperoxidase (MPO) assessment of the colon. RESULTS: Colonoscopy showed signs of severe mucosal inflammation in the distal colon 3 days after induction of TNBS colitis. Subsequently, colitis subsided at days 10 and 28 with complete endoscopic remission at day 56. During the acute phase of inflammation, endoscopic findings were consistent with the post-mortem inflammatory parameters (macroscopic and microscopic histopathology, MPO colonic activity). A strong correlation between endoscopy and macroscopy remained even during the chronic phase of inflammation. CONCLUSIONS: Our findings suggest that routine endoscopy is a reliable method for monitoring the development and follow-up of the degree of TNBS colitis in rats.

Physical activity and memory functions: are neurotrophins and cerebral gray matter volume the missing link?

Epidemiological studies reveal better cognitive function in physically active individuals. Possible mediators for this effect are neurotrophins, which are up-regulated through physical exercise and induce neuronal growth and synaptogenesis in the animal model. Here we cross-sectionally assessed 75 healthy older individuals for levels of physical activity, aerobic fitness, and memory encoding, as well as neurotrophin levels and cerebral gray matter volume. We found that physical activity, but not cardiovascular fitness, was associated with better memory encoding after controlling for age, sex, education, depression, alcohol consumption, and smoking. Higher levels of physical activity were associated with higher levels of the neurotrophin granulocyte colony stimulating factor (G-CSF) and increased cerebral gray matter volume in prefrontal and cingulate cortex as assessed by magnetic resonance voxel-based morphometry. While mediating factors will need to be further elucidated, these findings indicate that even low-level physical activity exerts beneficial effects on memory functions in older individuals.

[Use of a gelatine-thrombin matrix for closure of the access tract without a nephrostomy tube in minimally invasive percutaneous nephrolitholapaxy]. / Die Verwendung von Gelatine-Thrombin-Matrix zum Verschluss des Arbeitskanals bei der nephrostomielosen minimal-invasiven perkutanen Nephrolitholapaxie.

BACKGROUND: The spectrum of percutaneous stone treatment was significantly widened following the introduction of the miniaturized percutaneous nephrolitholapaxy. At the end of the procedure usually a nephrostomy tube was placed to avoid urine paravasation and prolonged bleeding. In this work the tube-less mini-PCNL with direct closure of the access tract was compared to traditional mini-PCNL with placement of the nephrostomy tube. PATIENTS AND METHODS: Twenty consecutive patients undergoing mini-PCNL with placement of a nephrostomy tube at the end of the procedure were compared to 20 consecutive patients with direct closure of the access tracts following percutaneous stone removal. Clinical data like decrease in Hb, complications, need for analgesics and duration of hospital stay were compared. RESULTS: Both groups underwent the procedure without complications. There was no need for blood transfusions. The difference in total analgetic dose was not statistically significant; however, patients in the nephrostomy group needed analgetics for a longer period of time. There was no difference in duration of hospital stay (3.2 days in the tube-less group versus 3.4 days in the nephrostomy group). The primary stone-free rate was higher in the group with direct closure of the access tract (95 versus 85%). CONCLUSIONS: Closure of the percutaneous access following mini-PCNL with a gelatine-thrombin-haemostatic sealant is a safe alternative to the commonly used nephrostomy tube and can help to reduce postoperative pain and patient discomfort.

Acute distal colitis impairs gastric emptying in rats via an extrinsic neuronal reflex pathway involving the pelvic nerve.

BACKGROUND AND AIMS: Patients with inflammatory bowel disease often present with abnormal gut motility away from the inflammatory site. We studied remote motility disturbances and their pathophysiology in a rat model of colitis. METHODS: Colitis was induced 72 h prior to experiments using trinitrobenzene sulphate (TNBS) instillation. Inflammation was verified using histology and myeloperoxidase (MPO) measurements. To assess gut motility, we determined gastric emptying, distal front and geometric centre (GC) of intestinal transit 30 min after intragastric administration of a semiliquid Evans blue solution. The effects of hexamethonium (20 mg/kg), capsaicin (125 mg/kg) and pelvic nerve section on colitis induced motility changes were evaluated. c-Fos expression was studied in the pelvic nerve dorsal root ganglion (DRG) S1. RESULTS: Colitis reduced gastric emptying from 38.4 (3.6)% in controls to 22.7 (4.4)% in TNBS treated rats in the absence of local gastric inflammation. Colitis had no effect on the distal front or on the geometric centre of small intestinal transit. Hexamethonium reduced gastric emptying in controls to 26.3 (4.1)% but restored it to 35.8 (4.4)% in TNBS treated rats. Capsaicin significantly impaired gastric emptying in controls from 33.1 (5.2)% to 9.5 (3.3)% while this effect was less pronounced in TNBS treated rats (from 19.2 (2.3)% to 11.5 (3.8)%; NS). In TNBS treated rats, pelvic nerve section completely restored gastric emptying from 19.8 (5.3)% to 52.5 (6.3)% without any effect on gastric emptying in control rats. TNBS colitis induced de novo c-Fos expression in the DRG S1. CONCLUSIONS: Experimental colitis in rats delays gastric emptying via a neuronal pathway involving pelvic afferent nerve hyperactivity.

[EGFR-expression in pulmonary neuroendocrine cell hyperplasia]. / EGFR-Expression in pulmonalen neuroendokrinen Zellhyperplasien.

15 cases of pulmonary neuroendocrine cell hyperplasia (carcinoid-tumorlets, diffuse idiopathic pulmonary neuroendocrine cell hyperplasia/DIPNECH) and 20 neuroendocrine pulmonary tumors (10 carcinoid tumors, 5 large cell neuroendocrine, and 5 small cell neuroendocrine lung carcinomas) were immunohistochemically analyzed for the expression of epidermal growth factor receptor (EGFR, = HER-1). All cases of neuroendocrine cell hyperplasia exhibited a maximum EGFR expression (score 3 in 100% of cells) showing predominantly membranous, partly cytoplasmic staining. 4 ot the 10 carcinoid tumors were strongly positive for EGFR, whereas the other 6 were EGFR-negative. A total of 90% of large cell neuroendocrine and small cell neuroendocrine carcinomas were negative for EGFR. Overexpression of EGFR in pulmonary neuroendocrine cell hyperplasia might be significant for the pathogenesis of these lesions. As DIPNECH is characterized by clinical signs and symptoms including mild cough and obstructive functional impairment, a specific antagonistic therapeutic trial could aim at blocking EGFR/HER-1 or its subsequent signal transduction pathway.

Leukocytosis and blood eosinophilia in a polyparasitised population in north-eastern Brazil.

It has long been known that leukocytosis and blood eosinophilia are common in the tropical environment, but data derived from population-based studies are scarce. A study was undertaken in a fishing village in north-east Brazil where both intestinal helminthiases and parasitic skin diseases are common. Of 409 individuals studied, 128 (31.3%) were infected with one intestinal helminth or ectoparasite species, 93 (22.7%) with two, 61 (14.9%) with three, 25 (6.1%) with four and 11 (2.7%) with more than four species; no parasites were found in 91 (22.2%) individuals. Leukocyte counts ranged between 3,300 cells/microl and 16,100 cells/microl (median, 7,200 cells/microl) and eosinophil counts between 40 cells/microl and 5,460 cells/microl (median, 455 cells/microl). Eosinophilia (>500/microl) was detected in 44.7% of the individuals, and hypereosinophilia (>1,000/microl) in 12.9%. Thirty-six (8.8%) individuals showed leukocytosis. While 75% of individuals with normal eosinophil counts were considered parasite-free, only 14% with eosinophilia and 11% with hypereosinophilia did not have enteroparasites or ectoparasites. Multivariate regression showed that the probability of eosinophilia and hypereosinophilia, but not of leukocytosis, increased with the number of parasite species present. The data show that eosinophilia occurs in almost one-half of the individuals from a resource-poor setting and that it is significantly associated with the presence of intestinal helminths, but not with the presence of ectoparasites.

Role of oxidative stress in the pathogenesis of septic ileus in mice.

We investigated the role of oxidative stress in the pathogenesis of septic ileus. Sepsis was induced by intraperitoneal (i.p.) injection of lipopolysaccharides (LPS, 20 mg kg(-1)) in mice. The effect of two i.p. injections of superoxide dismutase [polyethylene glycol (PEG)-SOD, 4000 U kg(-1)] and catalase (PEG-CAT, 15,000 U kg(-1)) was investigated on gastric emptying, intestinal transit and total nitrite plasma concentrations. We also performed immunohistochemical experiments on gastric and ileal tissue. LPS significantly delayed gastric emptying and intestinal transit while plasma nitrite levels increased. Polyethylene glycol (PEG)-SOD reversed the endotoxin-induced delay in gastric emptying and improved the delay in intestinal transit without effect on plasma nitrite levels. PEG-CAT slightly improved the delay in gastric emptying without effect on intestinal transit. Immunohistochemistry showed the presence of nitrotyrosine (NT) and 4-hydroxy-2-nonenal (HNE) in the gastric and ileal mucosa of LPS-treated mice. Treatment with PEG-SOD or PEG-CAT of LPS mice diminished the presence of NT or HNE in both tissues. In addition, LPS induced a significant increase in inducible nitric oxide synthase (iNOS)-positive residential macrophages in the external musculature of stomach and ileum, which significantly decreased after PEG-SOD or PEG-CAT treatment. The present results support a role for oxidative and nitrosative stress in the pathogenesis of septic ileus in mice.