Probiotic prophylaxis in patients with predicted severe acute pancreatitis (PROPATRIA): design and rationale of a double-blind, placebo-controlled randomised multicenter trial [ISRCTN38327949]

BACKGROUND: Infectious complications are the major cause of death in acute pancreatitis. Small bowel bacterial overgrowth and subsequent bacterial translocation are held responsible for the vast majority of these infections. Goal of this study is to determine whether selected probiotics are capable of preventing infectious complications without the disadvantages of antibiotic prophylaxis; antibiotic resistance and fungal overgrowth. METHODS/DESIGN: PROPATRIA is a double-blind, placebo-controlled randomised multicenter trial in which 200 patients will be randomly allocated to a multispecies probiotic preparation (Ecologic 641) or placebo. The study is performed in all 8 Dutch University Hospitals and 7 non-University hospitals. The study-product is administered twice daily through a nasojejunal tube for 28 days or until discharge. Patients eligible for randomisation are adult patients with a first onset of predicted severe acute pancreatitis: Imrie criteria 3 or more, CRP 150 mg/L or more, APACHE II score 8 or more. Exclusion criteria are post-ERCP pancreatitis, malignancy, infection/sepsis caused by a second disease, intra-operative diagnosis of pancreatitis and use of probiotics during the study. Administration of the study product is started within 72 hours after onset of abdominal pain. The primary endpoint is the total number of infectious complications. Secondary endpoints are mortality, necrosectomy, antibiotic resistance, hospital stay and adverse events. To demonstrate that probiotic prophylaxis reduces the proportion of patients with infectious complications from 50% to 30%, with alpha 0,05 and power 80%, a total sample size of 200 patients was calculated. CONCLUSION: The PROPATRIA study is aimed to show a reduction in infectious complications due to early enteral use of multispecies probiotics in severe acute pancreatitis

Differences in tidal breathing between infants with chronic lung diseases and healthy controls

BACKGROUND: The diagnostic value of tidal breathing (TB) measurements in infants is controversially discussed. The aim of this study was to investigate to what extent the breathing pattern of sleeping infants with chronic lung diseases (CLD) differ from healthy controls with the same postconceptional age and to assess the predictive value of TB parameters. METHODS: In the age of 36–42 postconceptional weeks TB measurements were performed in 48 healthy newborns (median age and weight 7d, 3100 g) and 48 infants with CLD (80d, 2465 g)) using the deadspace-free flow-through technique. Once the infants had adapted to the mask and were sleeping quietly and breathing regularly, 20–60 breathing cycles were evaluated. Beside the shape of the tidal breathing flow-volume loop (TBFVL) 18 TB parameters were analyzed using ANOVA with Bonferroni correction. Receiver-operator characteristic (ROC) curves were calculated to investigate the discriminative ability of TB parameters. RESULTS: The incidence of concave expiratory limbs in CLD infants was 31% and significantly higher compared to controls (2%) (p < 0.001). Significant differences between CLD infants and controls were found in 11/18 TB parameters. The largest differences were seen in the mean (SD) inspiratory time 0.45(0.11)s vs. 0.65(0.14)s (p < 0.0001) and respiratory rate (RR) 55.4(14.2)/min vs. 39.2(8.6)/min (p < 0.0001) without statistically significant difference in the discriminative power between both time parameters. Most flow parameters were strongly correlated with RR so that there is no additional diagnostic value. No significant differences were found in the tidal volume and commonly used TB parameters describing the expiratory flow profile. CONCLUSION: The breathing pattern of CLD infants differs significantly from that of healthy controls. Concave TBFVL and an increased RR measured during quiet sleep and under standardized conditions may indicate diminished respiratory functions in CLD infants whereas most of the commonly used TB parameters are poorly predictive

Randomized controlled trial using bosentan to enhance the impact of exercise training in subjects with type 2 diabetes mellitus

In type 2 diabetes patients, endothelin (ET) receptor blockade may enhance blood flow responses to exercise training. The combination of exercise training and ET receptor blockade may represent a more potent stimulus than training alone to improve vascular function, physical fitness and glucose homeostasis. We assessed the effect of an 8 week exercise training programme combined with either ET blockade or placebo on vasculature, fitness and glucose homeostasis in people with type 2 diabetes. In a double-blind randomized controlled trial, brachial endothelium-dependent and -independent dilatation (using flow-mediated dilatation and glyceryl trinitrate, respectively), glucose homeostasis (using Homeostasis Model Assessment for Insulin Resistance (HOMA-IR)) and physical fitness (maximal cycling test) were assessed in 18 men with type 2 diabetes (60 ± 6 years old). Subjects underwent an 8 week exercise training programme, with half of the subjects receiving ET receptor blockade (bosentan) and the other half a placebo, followed by reassessment of the tests above. Exercise training improved physical fitness to a similar extent in both groups, but we did not detect changes in vascular function in either group. This study suggests that there is no adaptation in brachial and femoral artery endothelial function after 8 weeks of training in type 2 diabetes patients. Endothelin receptor blockade combined with exercise training does not additionally alter conduit artery endothelial function or physical fitness in type 2 diabetes

Pancreatitis after percutaneous ethanol injection into HCC: a minireview of the literature

Deaths after percutaneous ethanol injection (PEI) into hepatocellular carcinoma (HCC) may occur within a few hours to a few days following the procedure because of hemoperitoneum and haemorrhage from oesophageal varices or hepatic insufficiency. Pancreatitis has been recently reported as a rare lethal complication of intra-arterial PEI, another modality for treating HCCs. In this minireview, we analyze the literature concerning the development of acute pancreatitis after PEI. Pathogenesis of pancreatitis from opioids and ethanol is also addressed. Treatment with opioids to reduce the patient's abdominal pain after PEI in combination with the PEI itself may lead to direct toxic effects, thus favouring the development of pancreatitis

Deciphering the Chemical Basis of Nestmate Recognition

Social insects maintain colony cohesion by recognizing and, if necessary, discriminating against conspecifics that are not part of the colony. This recognition ability is encoded by a complex mixture of cuticular hydrocarbons (CHCs), although it is largely unclear how social insects interpret such a multifaceted signal. CHC profiles often contain several series of homologous hydrocarbons, possessing the same methyl branch position but differing in chain length (e.g., 15-methyl-pentatriacontane, 15-methyl-heptatriacontane, 15-methyl-nonatriacontane). Recent studies have revealed that within species these homologs can occur in correlated concentrations. In such cases, single compounds may convey the same information as the homologs. In this study, we used behavioral bioassays to explore how social insects perceive and interpret different hydrocarbons. We tested the aggressive response of Argentine ants, Linepithema humile, toward nest-mate CHC profiles that were augmented with one of eight synthetic hydrocarbons that differed in branch position, chain length, or both. We found that Argentine ants showed similar levels of aggression toward nest-mate CHC profiles augmented with compounds that had the same branch position but differed in chain length. Conversely, Argentine ants displayed different levels of aggression toward nest-mate CHC profiles augmented with compounds that had different branch positions but the same chain length. While this was true in almost all cases, one CHC we tested elicited a greater aggressive response than its homologs. Interestingly, this was the only compound that did not occur naturally in correlated concentrations with its homologs in CHC profiles. Combined, these data suggest that CHCs of a homologous series elicit the same aggressive response because they convey the same information, rather than Argentine ants being unable to discriminate between different homologs. This study contributes to our understanding of the chemical basis of nestmate recognition by showing that, similar to spoken language, the chemical language of social insects contains “synonyms,” chemicals that differ in structure, but not meaning

Palmitoylation Regulates Epidermal Homeostasis and Hair Follicle Differentiation

Palmitoylation is a key post-translational modification mediated by a family of DHHC-containing palmitoyl acyl-transferases (PATs). Unlike other lipid modifications, palmitoylation is reversible and thus often regulates dynamic protein interactions. We find that the mouse hair loss mutant, depilated, (dep) is due to a single amino acid deletion in the PAT, Zdhhc21, resulting in protein mislocalization and loss of palmitoylation activity. We examined expression of Zdhhc21 protein in skin and find it restricted to specific hair lineages. Loss of Zdhhc21 function results in delayed hair shaft differentiation, at the site of expression of the gene, but also leads to hyperplasia of the interfollicular epidermis (IFE) and sebaceous glands, distant from the expression site. The specific delay in follicle differentiation is associated with attenuated anagen propagation and is reflected by decreased levels of Lef1, nuclear β-catenin, and Foxn1 in hair shaft progenitors. In the thickened basal compartment of mutant IFE, phospho-ERK and cell proliferation are increased, suggesting increased signaling through EGFR or integrin-related receptors, with a parallel reduction in expression of the key differentiation factor Gata3. We show that the Src-family kinase, Fyn, involved in keratinocyte differentiation, is a direct palmitoylation target of Zdhhc21 and is mislocalized in mutant follicles. This study is the first to demonstrate a key role for palmitoylation in regulating developmental signals in mammalian tissue homeostasis

Prolactin receptor is a negative prognostic factor in patients with squamous cell carcinoma of the head and neck

Background: The influence of human prolactin (hPRL) on the development of breast and other types of cancer is well established. Little information, however, exists on the effects of hPRL on squamous cell carcinomas of the head and neck (SCCHNs). Methods: In this study, we evaluated prolactin receptor (PRLR) expression in SCCHN cell lines and assessed by immunohistochemistry the expression in 89 patients with SCCHNs. The PRLR expression was correlated with clinicopathological characteristics as well as clinical outcome. The effect of hPRL treatment on tumour cell growth was evaluated in vitro. Results: Immunoreactivity for PRLR was observed in 85 out of 89 (95%) tumours. Multivariate COX regression analysis confirmed high levels of PRLR expression (>25% of tumour cells) to be an independent prognostic factor with respect to overall survival (HR=3.70, 95% CI: 1.14–12.01; P=0.029) and disease-free survival (P=0.017). Growth of PRLR-positive cancer cells increased in response to hPRL treatment. Conclusion: Our data indicate that hPRL is an important growth factor for SCCHN. Because of PRLR expression in a vast majority of tumour specimens and its negative impact on overall survival, the receptor represents a novel prognosticator and a promising drug target for patients with SCCHNs

Spermidine Promotes Human Hair Growth and Is a Novel Modulator of Human Epithelial Stem Cell Functions

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Concurrent chemoradiation with capecitabine and weekly irinotecan as preoperative treatment for rectal cancer: results from a phase I/II study

The aim of this study was to investigate the efficacy and safety of chemoradiation using capecitabine and irinotecan as neoadjuvant therapy for patients with rectal cancer. Conventional radiation was given at daily fractions of 1.8 Gy on 5 days a week for a total dose of 55.8 (50.4+5.4) Gy. Concurrently, irinotecan 40 mg m−2 once weekly and capecitabine continuously at dose levels of 500, 650, 750 and 825 mg m−2 twice daily were administered. Surgery was performed 4–6 weeks following completion of chemoradiation. A total of 28 patients (3 UICC II, 25 UICC III) were enrolled and all received treatment. Dose-limiting toxicity was diarrhoea grade IV and hand–foot syndrome at the 825 mg m−2 dose level. The maximum tolerated dose of capecitabine was 750 mg m−2. Diarrhoea was the most common toxicity: grade III in nine patients. Two patients died, one due to pneumonia and one due to sudden cardiac death. A complete response and only microfocal residual tumour disease was achieved in four and three patients (27%). In all, 25 of 28 patients undergoing surgery, 24 (96%) had R0 resection. Preoperative chemoradiation based on continuous daily capecitabine and weekly irinotecan appears to tolerated and effective in patients with rectal cancer

Intensified concurrent chemoradiotherapy with 5-fluorouracil and irinotecan as neoadjuvant treatment in patients with locally advanced rectal cancer

This study aimed to evaluate the feasibility and efficacy of neoadjuvant chemoradiotherapy intensified with irinotecan in patients with locally advanced rectal cancer. Eligible patients had nonmetastatic disease at a locally advanced stage that made R0 resection and sphincter preservation uncertain. They received preoperative radiation over 6 weeks to 45 Gy and boost of 5.4 Gy and concurrent continuous infusion 5-fluorouracil 250 mg m−2 day−1 and weekly irinotecan 40 mg m−2. In all, 37 patients entered the study. T stage at baseline as determined by ultrasound was T2/T3/T4 in 2/19/16 patients; 31 patients had lymph node involvement. The predominant toxicity was diarrhoea (grade 3/4 in 10/2 patients). Haematologic toxicity and surgical complications were moderate. Among 36 patients undergoing surgery, 32 (89%) had R0 resection and 23 (64%) sphincter preservation. Pathologic complete response (pCR) was achieved in eight (22%) of 36 patients, and 10 patients (28%) had only microscopic residual disease. At 4 years, overall survival was 66%, disease-free survival 73%, local relapse rate 7%, and distant failure rate 24%. Extent of resection and postoperative nodal status were significant predictors of overall and disease-free survival. Intensified neoadjuvant chemoradiotherapy with irinotecan can be safely administered and results in a high pCR rate