Short bowel mucosal morphology,proliferation and inflammation at first and repeat STEP procedures

Background

Although serial transverse enteroplasty (STEP) improves function of dilated short bowel, a significant proportion of patients require repeat surgery. To address underlying reasons for unsuccessful STEP, we compared small intestinal mucosal characteristics between initial and repeat STEP procedures in children with short bowel syndrome (SBS).

Prevalence of shift work disorder among hospital personnel: A cross‐sectional study using objective working hour data

The prevalence of shift work disorder (SWD) has been studied using self‐reported data and the International Classification of Sleep Disorders, Second Edition (ICSD‐2) criteria. We examined the prevalence in relation to ICSD‐2 and ICSD‐3 criteria, work schedules and the number of non‐day shifts (work outside 06:00–18:00 hours) using objective working‐hours data. Secondly, we explored a minimum cut‐off for the occurrence of SWD symptoms. Hospital shift workers without (n = 1,813) and with night shifts (n = 2,917) and permanent night workers (n = 84) answered a survey (response rate 69%) on SWD and fatigue on days off. The prevalence of SWD was calculated for groups with ≥1, ≥3, ≥5 and ≥7 monthly non‐day shifts utilizing the working hours registry. ICSD‐3‐based SWD prevalence was 2.5%–3.7% (shift workers without nights), 2.6%–9.5% (shift workers with nights) and 6.0% (permanent night workers), depending on the cut‐off of non‐day shifts (≥7–1/month, respectively). The ICSD‐2‐based prevalence was higher: 7.1%–9.2%, 5.6%–33.5% and 16.7%, respectively. The prevalence was significantly higher among shift workers with than those without nights (p‐values <.001) when using the cut‐offs of ≥1–3 non‐day shifts. Shift workers with nights who had ≥3 days with ICSD‐3‐based SWD symptoms/month more commonly had fatigue on days off (49.3%) than those below the cut‐off (35.8%, p < .05). The ICSD‐3 criteria provided lower estimates for SWD prevalence than ISCD‐2 criteria, similarly to exclusion of employees with the fewest non‐day shifts. The results suggest that a plausible cut‐off for days with ICSD‐3‐based SWD symptoms is ≥3/month, resulting in 3%–6% prevalence of SWD.     

Short-term consumption of probiotic-containing cheese and its effect on dental caries risk factors

Cheese is known to contain compounds that reduce the risk of dental caries. The long-term consumption of milk containing Lactobacillus rhamnosus GG, ATCC 53103 (LGG), has been shown to reduce caries risk in children. The aim of the present study was to examine whether short-term consumption of cheese containing LGG and Lactobacillus rhamnosus LC 705 would diminish caries-associated salivary microbial counts in young adults. Altogether, 74 18-35 year-old subjects completed this double-blinded, randomised, placebo-controlled study. During the 3 week intervention, the subjects ate 5 x 15 g cheese per day. Oral examinations were made before and after the study. Stimulated salivary secretion rates, buffer capacity and counts of salivary Streptococcus mutans, yeast and lactobacilli were evaluated before and after the intervention and after a 3 week post-treatment period. The results showed no statistically significant difference between the groups in Streptococcus mutans counts after the intervention, but during the post-treatment period there was a significantly greater reduction in these counts in the intervention group compared to the control group (P=0.05). However, Streptococcus mutans counts decreased in 20% (P=0.01) and yeast counts in 27% (P=0.005) of all the subjects, regardless of the intervention group. Results from logistic regression showed a trend indicating that probiotic intervention might reduce the risk of the highest level of Streptococcus mutans (OR=0.37, 95% CI 0.08-1.75, P=0.21) and salivary yeasts (OR=0.40, 0.09-1.71, P=0.22).     

Conventional radiographic and computed tomographic findings in cases of fracture of the mandibular condylar process

A total of 40 patients with 46 fractures of the mandibular condylar process were examined an average of 47 months after the injury. The conventional radiologic examination consisted of panoramic radiography and lateral transcranial view of the fracture in the mouth-open and mouth-closed positions. Sixteen patients with 21 fractures of the condylar process were examined additionally by computed tomography (CT) because of temporomandibular joint problems in the sagittal and coronal projection. Computed tomography revealed bony changes in the fractured mandibular condyle and its position in the mandibular fossa more exactly than conventional radiographic examinations. Furthermore, the results showed that disturbances in the position and function of the articular disc may be more common than was earlier anticipated, suggesting the more frequent use of CT examinations to evaluate temporomandibular joint changes after condylar process fractures.     

Spatial aspects of oncogenic signalling determine the response to combination therapy in slice explants from Kras‐driven lung tumours

A key question in precision medicine is how functional heterogeneity in solid tumours informs therapeutic sensitivity. We demonstrate that spatial characteristics of oncogenic signalling and therapy response can be modelled in precision‐cut slices from Kras‐driven non‐small‐cell lung cancer with varying histopathologies. Unexpectedly, profiling of in situ tumours demonstrated that signalling stratifies mostly according to histopathology, showing enhanced AKT and SRC activity in adenosquamous carcinoma, and mitogen‐activated protein kinase (MAPK) activity in adenocarcinoma. In addition, high intertumour and intratumour variability was detected, particularly of MAPK and mammalian target of rapamycin (mTOR) complex 1 activity. Using short‐term treatment of slice explants, we showed that cytotoxic responses to combination MAPK and phosphoinositide 3‐kinase–mTOR inhibition correlate with the spatially defined activities of both pathways. Thus, whereas genetic drivers determine histopathology spectra, histopathology‐associated and spatially variable signalling activities determine drug sensitivity. Our study is in support of spatial aspects of signalling heterogeneity being considered in clinical diagnostic settings, particularly to guide the selection of drug combinations. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.     

Pharmacokinetics and pharmacodynamics of pravastatin in pediatric and adolescent cardiac transplant recipients on a regimen of triple immunosuppression

BACKGROUND: In adults, pravastatin reduces the development and progression of transplant vasculopathy, the main long-term risk after cardiac transplantation. The pharmacokinetics of pravastatin is not known in children taking calcineurin inhibitors. Our aim was to determine the single-dose pharmacokinetics and short-term safety of pravastatin in children undergoing regular triple-drug immunosuppressive therapy after cardiac transplantation. METHODS: Nineteen pediatric cardiac transplant recipients (aged 4.4 to 18.9 years) receiving triple immunosuppression therapy consisting of methylprednisolone (19 patients), cyclosporine (INN, cyclosporin) (17 patients) or tacrolimus (2 patients), and azathioprine (18 patients) or mycophenolate mofetil (1 patient) ingested a single 10-mg dose of pravastatin, and plasma pravastatin concentrations were measured up to 24 hours. Subsequently, the patients took 10 mg pravastatin orally once daily for 8 weeks. The lipid-lowering effect and the safety of pravastatin therapy were studied. RESULTS: The mean peak plasma concentration (C(max)) of pravastatin was 122.2 +/- 88.2 ng/mL (range, 11.4-305.0 ng/mL), and the area under the plasma concentration-time curve of pravastatin from 0 to 10 hours [AUC(0-10)] was 264.1 +/- 192.4 ng.h/mL (range, 30.8-701.6 ng.h/mL). These C(max) and AUC(0-10) values are nearly 10-fold higher than the corresponding values reported in hypercholesterolemic children in the absence of immunosuppressive therapy. The time of peak concentration (t(max)) of pravastatin was 1.1 +/- 0.4 hours (range, 0.5-2 hours), and the mean elimination half-life (t(1/2)) was 1.2 +/- 0.3 hours (range, 0.7-2.2 hours); these parameters were similar to those in the hypercholesterolemic children. By 8 weeks of treatment, the concentration of serum total cholesterol decreased by 13% (P =.005), low-density lipoprotein cholesterol by 27% (P <.0001), and triglycerides by 6% (not significant, P =.28); the concentration of high-density lipoprotein cholesterol increased by 7% (not significant, P =.30). No clinically significant increases in serum ALT, creatine kinase, or creatinine levels were observed. CONCLUSIONS: The plasma concentrations of pravastatin in pediatric cardiac recipients receiving triple immunosuppressive medication are nearly 10-fold higher than in hypercholesterolemic children after the same pravastatin dose. However, the short-term therapy of pravastatin was well tolerated and effective in lowering serum cholesterol levels in cardiac recipients.     

Histological confirmation and biological significance of cartilage canals demonstrated using high field MRI in swine at predilection sites of osteochondrosis

Cartilage canal vessels in epiphyseal cartilage have a pivotal role in the pathogenesis of osteochondrosis/osteochondritis dissecans. The present study aimed to validate high field magnetic resonance imaging (MRI) methods to visualize these vessels in young pigs. Osteochondral samples from the distal femur and distal humerus (predilection sites of osteochondrosis) of piglets were imaged post‐mortem: (1) using susceptibility‐weighted imaging (SWI) in an MRI scanner, followed by histological evaluation; and (2) after barium perfusion using µCT, followed by clearing techniques. In addition, both stifle joints of a 25‐day‐old piglet were imaged in vivo using SWI and gadolinium enhanced T1‐weighted MRI, after which distal femoral samples were harvested and evaluated using µCT and histology. Histological sections were compared to corresponding MRI slices, and three‐dimensional visualizations of vessels identified using MRI were compared to those obtained using µCT and to the cleared specimens. Vessels contained in cartilage canals were identified using MRI, both ex vivo and in vivo; their locations matched those observed in the histological sections, µCT images, and cleared specimens of barium‐perfused tissues. The ability to visualize cartilage canal blood vessels by MRI, without using a contrast agent, will allow future longitudinal studies to evaluate their role in developmental orthopedic disease. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:2006–2012, 2013     

SLCO1B1 polymorphism and sex affect the pharmacokinetics of pravastatin but not fluvastatin

OBJECTIVE: Pravastatin is a hydrophilic substrate and fluvastatin a lipophilic substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 encoded by SLCO1B1. Our aim was to compare the effects of SLCO1B1 polymorphism on the pharmacokinetics of pravastatin and fluvastatin. METHODS: We recruited 4 healthy volunteers (3 men and 1 woman) with the homozygous SLCO1B1 c.521CC genotype, 12 (7 men and 5 women) with the heterozygous c.521TC genotype, and 16 (8 men and 8 women) with the homozygous c.521TT genotype (control subjects). In a crossover study each subject ingested a single 40-mg dose of fluvastatin and pravastatin with a washout period of at least 1 week. Plasma fluvastatin and pravastatin concentrations were measured for 12 hours. RESULTS: In men with the c.521CC genotype, the mean peak concentration in plasma and area under the plasma concentration-time curve from time 0 to infinity of pravastatin were 274% (95% confidence interval [CI], 92%-456%; P = .001) and 232% (95% CI, 74%-391%; P = .002) greater than those in men with the c.521TT genotype and 120% (95% CI, 11%-230%; P = .026) and 102% (95% CI, 3%-200%; P = .040) greater than those in men with the c.521TC genotype. In addition, women with the c.521TT genotype had a 147% (95% CI, 12%-281%; P = .028) greater peak concentration in plasma and a 142% (95% CI, 7%-242%; P = .034) greater area under the plasma concentration-time curve from time 0 to infinity than men with the c.521TT genotype. The pharmacokinetic variables of pravastatin were approximately similar among women with different SLCO1B1 genotypes. No significant differences were seen in the pharmacokinetics of fluvastatin between subjects with different SLCO1B1 genotypes or between the sexes. CONCLUSIONS: SLCO1B1 polymorphism has a large effect on the pharmacokinetics of pravastatin but not fluvastatin. This suggests that the lipophilic fluvastatin can penetrate the hepatocyte plasma membrane via passive diffusion or that uptake transporters other than organic anion transporting polypeptide 1B1 mainly mediate its hepatic uptake. Moreover, the results suggest that sex may affect the pharmacokinetics of pravastatin and possibly the functional consequences of SLCO1B1 polymorphism.