Angiotensin converting enzyme inhibitor therapy in children with Alport syndrome: effect on urinary albumin, TGF-β, and nitrite excretion

BACKGROUND: Angiotensin converting enzyme inhibitors are routinely prescribed to patients with chronic kidney disease because of their known renoprotective effects. We evaluated the effect of short-term therapy with the angiotensin converting enzyme inhibitor, enalapril, in early Alport syndrome, defined as disease duration less than 10 years and a normal glomerular filtration rate. METHODS: 11 children with early Alport syndrome were investigated. Two consecutive early morning urine specimens were collected at the start of the study for measurement of urinary creatinine, total protein, albumin, TGF-β, and nitrite excretion. Patients were treated with enalapril, ≅ 0.2 mg/kg/day, once a day for 14 days. Two early morning urine specimens were collected on days 13 and 14 of enalapril treatment and two weeks later for measurement of urinary creatinine, total protein, albumin, TGF-β, and nitrite excretion. RESULTS: Prior to treatment, urinary excretion of transforming growth factor-β and nitrite, the major metabolite of nitric oxide, was within normal limits in all patients. Administration of enalapril for 2 weeks did not alter urinary albumin, transforming growth factor-β, or nitrite excretion. CONCLUSION: These findings suggest that early Alport syndrome represents a disease involving exclusively intrinsic glomerular barrier dysfunction. At this stage of the illness, there is no evidence of angiotensin II-mediated proteinuria or increased production of transforming growth factor-β and, therefore, routine treatment with an angiotensin converting enzyme inhibitor may not be warranted

The propensity to bargain while on a vacation

This article assesses how tourists' bargaining motivations and attitudes moderate their willingness to return to Italy, where bargaining is perceived as one of the best ways to deal with sellers. A non-probability quota sampling technique was used to survey domestic tourists in Italy through an online questionnaire which encompassed 26 bargaining values and one item to measure the likelihood that the tourists would bargain at the same destination in the future. The data comprised a total of 812 observations. An order probit model and marginal effects were estimated to measure the tourists' propensity to return to Italy for bargaining purposes. The study findings indicate that tourists' propensity to return for bargaining purposes is taken with the awareness that they will not obtain what they expected; as a matter of fact, they are unlikely to care about the final result but instead engage in this behaviour to have fun.FCT - National Funding Agency for Science, Research and Technology [UID/ECO/04007/2013 CEFAGE

Postglacial expansion of the arctic keystone copepod calanus glacialis

Calanus glacialis, a major contributor to zooplankton biomass in the Arctic shelf seas, is a key link between primary production and higher trophic levels that may be sensitive to climate warming. The aim of this study was to explore genetic variation in contemporary populations of this species to infer possible changes during the Quaternary period, and to assess its population structure in both space and time. Calanus glacialis was sampled in the fjords of Spitsbergen (Hornsund and Kongsfjorden) in 2003, 2004, 2006, 2009 and 2012. The sequence of a mitochondrial marker, belonging to the ND5 gene, selected for the study was 1249 base pairs long and distinguished 75 unique haplotypes among 140 individuals that formed three main clades. There was no detectable pattern in the distribution of haplotypes by geographic distance or over time. Interestingly, a Bayesian skyline plot suggested that a 1000-fold increase in population size occurred approximately 10,000 years before present, suggesting a species expansion after the Last Glacial Maximum.GAME from the National Science Centre, the Polish Ministry of Science and Higher Education Iuventus Plus [IP2014 050573]; FCT-PT [CCMAR/Multi/04326/2013]; [2011/03/B/NZ8/02876

Sensitivity of the Quantiferon-Gold In-Tube Assay in Sputum Smear Positive TB Cases in Indonesia

BACKGROUND: As part of a formal evaluation of the Quantiferon-Gold in-tube assay (QFT-IT) for latent TB infection we compared its sensitivity to the tuberculin skin test (TST) in confirmed adult TB cases in Indonesia. Smear-positive TB disease was used as a proxy gold standard for latent TB infection. METHODS AND FINDINGS: We compared the sensitivity of QFT-IT and TST in 98 sputum smear and chest x-ray positive TB cases and investigated risk factors for negative and discordant results in both tests. Both tests showed high sensitivity; (QFT-IT; 88.7%: TST; 94.9%), not significantly different from each other (p value 0.11). Very high sensitivity was seen when tests were combined (98.9%). There were no variables significantly associated with discordant results or with a negative TST. For QFT-IT which particular staff member collected blood was significantly associated with test positivity (p value 0.01). Study limitations include small sample size and lack of culture confirmation or HIV test results. CONCLUSIONS: The QFT-IT has similar sensitivity in Indonesian TB cases as in other locations. However, QFT-IT, like the TST cannot distinguish active TB disease from LTBI. In countries such as Indonesia, with high background rates of LTBI, test specificity for TB disease will likely be low. While our study was not designed to evaluate the QFT-IT in the diagnosis of active TB disease in TB suspects, the data suggest that a combination of TST and QFT-IT may prove useful for ruling out TB disease. Further research is required to explore the clinical role of QFT-IT in combination with other TB diagnostic tests

Search for sterile neutrino mixing in the MINOS long-baseline experiment

A search for depletion of the combined flux of active neutrino species over a 735 km baseline is reported using neutral-current interaction data recorded by the MINOS detectors in the NuMI neutrino beam. Such a depletion is not expected according to conventional interpretations of neutrino oscillation data involving the three known neutrino flavors. A depletion would be a signature of oscillations or decay to postulated noninteracting sterile neutrinos, scenarios not ruled out by existing data. From an exposure of 3.18×1020 protons on target in which neutrinos of energies between ~500¿¿MeV and 120 GeV are produced predominantly as ¿µ, the visible energy spectrum of candidate neutral-current reactions in the MINOS far detector is reconstructed. Comparison of this spectrum to that inferred from a similarly selected near-detector sample shows that of the portion of the ¿µ flux observed to disappear in charged-current interaction data, the fraction that could be converting to a sterile state is less than 52% at 90% confidence level (C.L.). The hypothesis that active neutrinos mix with a single sterile neutrino via oscillations is tested by fitting the data to various models. In the particular four-neutrino models considered, the mixing angles ¿24 and ¿34 are constrained to be less than 11° and 56° at 90% C.L., respectively. The possibility that active neutrinos may decay to sterile neutrinos is also investigated. Pure neutrino decay without oscillations is ruled out at 5.4 standard deviations. For the scenario in which active neutrinos decay into sterile states concurrently with neutrino oscillations, a lower limit is established for the neutrino decay lifetime t3/m3>2.1×10-12¿¿s/eV at 90% C.L

Optical Coherence Tomography and Fibrous Cap Characterization

The pathophysiology of acute coronary syndromes has long been associated with atherosclerotic plaque rupture. Inflammation, thinning, and disruption of the fibrous cap have been implicated with the final processes leading to plaque rupture, but confirmation of these mechanisms of coronary thrombosis in humans has been hampered by the lack of imaging methods with sufficient resolution to resolve fibrous cap characterization and thickness in vivo. Intravascular optical coherence tomography (OCT) provides images with micron-level axial and lateral resolution, enabling detailed visualization of micro-structural changes of the arterial wall. The present article provides an overview of the potential role of OCT in identifying and characterizing fibrous cap morphology, thickness, and inflammation in human coronary plaques

A phase I/II study of irinotecan when added to 5-fluorouracil and leucovorin and pelvic radiation in locally advanced rectal cancer: a Colorectal Clinical Oncology Group Study

The objective of this study was to evaluate the maximum tolerated dose (MTD) and recommended dose of irinotecan administered as a 5-day schedule synchronously with 5-fluorouracil (5FU), leucovorin (LV) and preoperative pelvic radiation (45 Gy) for primary borderline/unresectable, locally advanced rectal cancer. The study used escalating doses of intravenous irinotecan (6, 8, 10, 12, 14, 16, 18, and 20 mg m−2) administered on days 1–5 and 29–33 followed by low dose LV (20 mg m−2) and 5FU (350 mg m−2 over 1 h) in sequential cohorts. Preoperative pelvic radiotherapy using a three- or four-field technique and megavoltage photons comprised 45 Gy given in 25 fractions, 1.8 Gy per fraction. Surgery in the form of mesorectal excision was performed 6–10 weeks later. Histopathological examination of the resected specimen was performed according to techniques of Quirke, and compared with clinical staging. A distance of 1 mm or less between the peripheral extent of the tumour and the radial resection margin defined an involved circumferential resection margin (CRM). The MTD was determined as the dose causing more than a third of patients to have a dose-limiting toxicity (DLT) defined as specific grade 3 or 4 toxicities. Once the MTD was reached, a further 14 patients were treated at the dose level below the MTD. In total, 57 patients received irinotecan at the eight dose levels. The final cohort reached DLT after only four patients had been enrolled. The median age was 62 years (range 26–75), 37 male and 20 female subjects. The MTD of irinotecan in this schedule was 20 mg m−2 when three out of four patients experienced DLT. Dose limiting grade 3 or 4 diarrhoea was reported in seven out of 57 patients, three at the 20 mg m−2 dose level. Serious haematological toxicity (grade 3) was minimal and reported in only three patients; one grade 3 neutropaenia, one grade 4 neutropaenia and one grade 3 febrile neutropaenia and anaemia. Compliance was good with 93 and 89% of patients completing radiotherapy and chemotherapy, respectively. The remaining patients had only minor deviations from protocol therapy. Eight patients did not proceed to surgery, in six cases because they remained unresectable or had developed metastatic disease, one patient was unfit for surgery and one died as a result of complications from radiotherapy. Forty-nine patients underwent a potentially curative surgical resection. Histopathological examination of the resected specimen demonstrated pCR 12 out of 49 (24%) and 12 out of 57 (21%) overall. A histologically confirmed clear circumferential resection margin (CRM) was achieved in 39 out of 49 (80%) of those resected, and 39 out of 57 (68%) overall. In conclusion, MTD with this scheduled regimen of irinotecan is 20 mg m−2 (days 1–5 and 29–33). The acceptable toxicity and compliance at 18 mg m−2 recommend testing this dose in future phase III studies. The tumour downstaging and complete resection rates (negative CRM) are encouragingly high for this very locally advanced group

Expression, localization and polymorphisms of the nuclear receptor PXR in Barrett's esophagus and esophageal adenocarcinoma

Background: The continuous exposure of esophageal epithelium to refluxate may induce ectopic expression of bile-responsive genes and contribute to the development of Barrett's esophagus (BE) and esophageal adenocarcinoma. In normal physiology of the gut and liver, the nuclear receptor Pregnane × Receptor (PXR) is an important factor in the detoxification of xenobiotics and bile acid homeostasis. This study aimed to investigate the expression and genetic variation of PXR in reflux esophagitis (RE), Barrett's esophagus (BE) and esophageal adenocarcinoma.Methods: PXR mRNA levels and protein expression were determined in biopsies from patients with adenocarcinoma, BE, or RE, and healthy controls. Esophageal cell lines were stimulated with lithocholic acid and rifampicin. PXR polymorphisms 25385C/T, 7635A/G, and 8055C/T were genotyped in 249 BE patients, 233 RE patients, and 201 controls matched for age and gender.Results: PXR mRNA levels were significantly higher in adenocarcinoma tissue and columnar Barrett's epithelium, compared to squamous epithelium of these BE patients (P < 0.001), and RE patients (P = 0.003). Immunohistochemical staining of PXR showed predominantly cytoplasmic expression in BE tissue, whereas nuclear expression was found in adenocarcinoma tissue. In cell lines, stimulation with lithocholic acid did not increase PXR mRNA levels, but did induce nuclear translocation of PXR protein. Genotyping of the PXR 7635A/G polymorphism revealed that the G allele was significantly more prevalent in BE than in RE or controls (P = 0.037).Conclusions: PXR expresses in BE and adenocarcinoma tissue, and showed nuclear localization in adenocarcinoma tissue. Upon stimulation with lithocholic acid, PXR translocates to the nuclei of OE19 adenocarcinoma cells. Together with the observed association of a PXR polymorphism and BE, this data implies that PXR may have a function in prediction and treatment of esophageal disease

Quantification of longitudinal tissue pO2 gradients in window chamber tumours: impact on tumour hypoxia

We previously reported that the arteriolar input in window chamber tumours is limited in number and is constrained to enter the tumour from one surface, and that the pO2 of tumour arterioles is lower than in comparable arterioles of normal tissues. On average, the vascular pO2 in vessels of the upper surface of these tumours is lower than the pO2 of vessels on the fascial side, suggesting that there may be steep vascular longitudinal gradients (defined as the decline in vascular pO2 along the afferent path of blood flow) that contribute to vascular hypoxia on the upper surface of the tumours. However, we have not previously measured tissue pO2 on both surfaces of these chambers in the same tumour. In this report, we investigated the hypothesis that the anatomical constraint of arteriolar supply from one side of the tumour results in longitudinal gradients in pO2 sufficient in magnitude to create vascular hypoxia in tumours grown in dorsal flap window chambers. Fischer-344 rats had dorsal flap window chambers implanted in the skin fold with simultaneous transplantation of the R3230AC tumour. Tumours were studied at 9–11 days after transplantation, at a diameter of 3–4 mm; the tissue thickness was 200 μm. For magnetic resonance microscopic imaging, gadolinium DTPA bovine serum albumin (BSA-DTPA-Gd) complex was injected i.v., followed by fixation in 10% formalin and removal from the animal. The sample was imaged at 9.4 T, yielding voxel sizes of 40 μm. Intravital microscopy was used to visualize the position and number of arterioles entering window chamber tumour preparations. Phosphorescence life time imaging (PLI) was used to measure vascular pO2. Blue and green light excitations of the upper and lower surfaces of window chambers were made (penetration depth of light ~50 vs >200 μm respectively). Arteriolar input into window chamber tumours was limited to 1 or 2 vessels, and appeared to be constrained to the fascial surface upon which the tumour grows. PLI of the tumour surface indicated greater hypoxia with blue compared with green light excitation (P < 0.03 for 10th and 25th percentiles and for per cent pixels < 10 mmHg). In contrast, illumination of the fascial surface with blue light indicated less hypoxia compared with illumination of the tumour surface (P < 0.05 for 10th and 25th percentiles and for per cent pixels < 10 mmHg). There was no significant difference in pO2 distributions for blue and green light excitation from the fascial surface nor for green light excitation when viewed from either surface. The PLI data demonstrates that the upper surface of the tumour is more hypoxic because blue light excitation yields lower pO2 values than green light excitation. This is further verified in the subset of chambers in which blue light excitation of the fascial surface showed higher pO2 distributions compared with the tumour surface. These results suggest that there are steep longitudinal gradients in vascular pO2 in this tumour model that are created by the limited number and orientation of the arterioles. This contributes to tumour hypoxia. Arteriolar supply is often limited in other tumours as well, suggesting that this may represent another cause for tumour hypoxia. This report is the first direct demonstration that longitudinal oxygen gradients actually lead to hypoxia in tumours. © 1999 Cancer Research Campaig

Higher Rates of Hemolysis Are Not Associated with Albuminuria in Jamaicans with Sickle Cell Disease

BACKGROUND: Albuminuria is a marker of glomerular damage in Sickle Cell Disease (SCD). In this study, we sought to determine the possible predictors of albuminuria in the two more prevalent genotypes of SCD among the Jamaica Sickle Cell Cohort Study participants. METHODS: An age-matched cohort of 122 patients with HbSS or HbSC genotypes had measurements of their morning urine albumin concentration, blood pressure, body mass index, haematology and certain biochemistry parameters done. Associations of albuminuria with possible predictors including hematological parameters, reticulocyte counts, aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) levels were examined using multiple regression models. RESULTS: A total of 122 participants were recruited (mean age 28.6 years ±2.5 years; 85 HbSS, 37 HbSC). 25.9% with HbSS and 10.8% with HbSC disease had microalbuminuria (urine albumin/creatinine ratio  =  30-300 mg/g of creatinine) whereas 16.5% of HbSS and 2.7% of HbSC disease had macroalbuminuria (urine albumin/creatinine ratio>300 mg/g of creatinine). Mean arterial pressure, hemoglobin levels, serum creatinine, reticulocyte counts and white blood cell counts were statistically significant predictors of albuminuria in HbSS, whereas white blood cell counts and serum creatinine predicted albuminuria in HbSC disease. Both markers of chronic hemolysis, i.e. AST and LDH levels, showed no associations with albuminuria in either genotype. CONCLUSIONS: Renal disease, as evidenced by excretion of increased amounts of albumin in urine due to a glomerulopathy, is a common end-organ complication in SCD. It is shown to be more severe in those with HbSS disease than in HbSC disease. Rising blood pressure, lower hemoglobin levels and higher white blood cell counts are hints to the clinician of impending renal disease, whereas higher rates of hemolysis do not appear to play a role in this complication of SCD