[Progressive familial intrahepatic cholestasis (Byler disease): current genetics and therapy].
Progressive familial intrahepatic cholestasis (PFIC) is a congenital liver disease. First symptoms can frequently be seen shortly after birth. Quality and expectation of life are substantially reduced due to severe pruritus and the complications of progressive liver cirrhosis. PFIC is diagnosed on the basis of characteristic clinical and laboratory parameters and genetic analysis after exclusion of other liver diseases leading to intrahepatic cholestasis. Medical therapy is only effective in a proportion of children with PFIC. Partial biliary diversion (PBD) is nowadays considered the therapy of choice in patients with therapy-refractive pruritus. If performed in time, damage to the liver can be delayed or arrested, thus orthotopic liver transplantation (OLT) can be postponed or even avoided in at least some patients with PFIC. Besides providing a current overview of PFIC, we report on three patients who were successfully treated surgically. One patient was subjected to a new technique of PBD (cholecysto-appendicostomy), the other two had OLT.


[Proximal femur replacement in revision arthroplasty].
Today, megaendoprostheses--which were originally designed for osseous defect reconstructions in tumour surgery--are being more frequently used for extensive bone defects in revision arthroplasty. The purpose of this study was to assess the complication rate and the functional results associated with megaendoprosthesis reconstruction of the proximal femur in a non-oncological patient group. 28 patients (average age 72; SD 10 years) with a proximal femur replacement were retrospectively (mean follow-up 43 months) evaluated regarding the complication rate. The Harris hip score was used to assess the outcome. The revision surgery was indicated because of large bone defects caused by implant-associated infection (n = 16), periprosthetic fracture (n = 8) or aseptic loosening (n = 4). Overall 8 patients (28.6 %) had to undergo 1 (n = 5) or more (2 n = 2, 4 n = 1) revision surgeries because of dislocation (n = 4), aseptic loosening of the stem (n = 2) and periprosthetic infection (n = 2). A significant pain relief could be achieved from on average 9.0 to 38.7 (according to the Harris hip score). All patients could be mobilised postoperatively, but walking aids were necessary for the majority of patients. A proximal femur replacement in revision arthroplasty should be regarded as a salvage procedure for restoration of extremity function. With this procedure it is possible to achieve a--limited--walking ability for patients who were immobilised preoperatively in most cases. Furthermore, pain relief can be achieved. However, the--mostly multimorbid--patients must be informed preoperatively about restrictions in daily life in order to avoid exorbitant expectations.


The pharmacokinetics of cyclosporine. II. Blood plasma distribution and binding studies.
The pharmacokinetic consequences of alterations in the blood plasma distribution of cyclosporine are examined in this study. A series of solutions of cyclosporine of known concentration were prepared in rabbit blood. The plasma, separated at 37 degrees C, was then assayed for cyclosporine using an HPLC method. A mathematical model relating the blood and plasma concentrations of cyclosporine at equilibrium was derived and used to fit the data. The model assumes that the free fraction of the drug in plasma (fp) is constant but that the free fraction in blood is not. In the rabbit, fp was estimated to equal 0.405. This may be attributed to cyclosporine binding to lipoproteins, and to the lower concentrations of lipoproteins in rabbit serum compared to that in human serum. The capacity factor and the binding affinity constant of the drug for blood cells were estimated to equal 3590 micrograms/liter and 0.00682 liter/microgram in the rabbit. These results and the findings of a previous study suggest that the free fraction of the drug in blood increased, while the free intrinsic clearance did not change, with increases in the steady state blood concentration of the drug. It was concluded that the changes in binding characteristics of cyclosporine in blood at higher concentration and not the changes in the metabolic activity of the liver, as measured by intrinsic clearance, are responsible for the nonlinear pharmacokinetic behavior exhibited by cyclosporine in the rabbit.


Therapeutic implications of down-regulation of cyclophilin D in bipolar disorder.
We previously reported that neuron-specific mutant Polg1 (mitochondrial DNA polymerase) transgenic (Tg) mice exhibited bipolar disorder (BD)-like phenotypes such as periodic activity change and altered circadian rhythm. In this study, we re-evaluated two datasets resulting from DNA microarray analysis to estimate a biological pathway associated with the disorder. The gene lists were derived from the comparison between post-mortem brains of BD patients and control subjects, and from the comparison between the brains of Tg and wild-type mice. Gene ontology analysis showed that 16 categories overlapped in the altered gene expression profiles of BD patients and the mouse model. In the brains of Tg mice, 33 genes showed similar changes in the frontal cortex and hippocampus compared to wild-type mice. Among the 33 genes, SFPQ and PPIF were differentially expressed in post-mortem brains of BD patients compared to control subjects. The only gene consistently down-regulated in both patients and the mouse model was PPIF, which encodes cyclophilin D (CypD), a component of the mitochondrial permeability transition pore. A blood-brain barrier-permeable CypD inhibitor significantly improved the abnormal behaviour of Tg mice at 40 mg/kg.d. These findings collectively suggest that CypD is a promising target for a new drug for BD.


[Taste affection and its causes].
Basic anatomophysiological evidence underlying sense of taste, main causes of taste disorders, guides for practitioners how to detect these disorders and differentiate them with physicians of allied specialities, make prognosis and design policy of the disease treatment are reviewed.


The spectrophotometric sulfo-phospho-vanillin assessment of total lipids in human meibomian gland secretions.
Human meibomian gland secretions (meibum) are the major lipid component of the human preocular tear film. The predominant lipid classes found in meibum include waxes (WE), cholesteryl esters (CE), and varying amounts of cholesterol (Chl). The classical sulfo-phospho-vanillin assay (SPVA), adapted for a microplate reader, was used to quantitate lipids in meibum. To account for varying reactivities of different lipids in SPVA, a model meibomian lipid mixture (MMx) that approximated the WE/CE/Chl composition of meibum was developed and used to quantitate meibomian lipids. The overall SPV responses of MMx and meibum were found to be close, with similar intermediate and final reaction products for both. Saturated WE that had not been expected to be reactive were found to be SPV-positive. A reaction mechanism for these compounds in SPVA which involves the formation of alkenyl ethers is proposed and discussed. Tested proteins were non-reactive in SPVA. Thus, by comparing the results of gravimetric analyses of meibum samples with the results of a properly calibrated SPVA, it was estimated that the SPV-reactive lipid content of dry meibum in tested samples was about 78 % (w/w). The SPV method can also be adopted for analyzing other types of complex lipids secretions, such as sebum, as well as whole lipid extracts from other lipid-enriched organs and tissues, if proper standards are chosen.


Parental behaviour of a precocial species: implications for juvenile survival.
Parents determine habitat selection for precocial young by leading their young to foraging areas until the chicks attain full independence. There are potential benefits and costs to reproductive success associated with changing habitats while caring for young. This study investigated the relationship between different types of habitats and their quality on chick survival and brood movements of a declining upland shorebird, the mountain plover Charadrius montanus.From 2004 to 2006, a total of 153 mountain plover broods were monitored on the primary breeding habitats in eastern Colorado, USA; two shortgrass prairie habitats that were either occupied or unoccupied by black-tailed prairie dogs Cynomys ludovicianus and agricultural lands. Habitat quality hypotheses were tested using newly developed statistical applications to estimate survival of chicks and brood movement patterns.Chick survival and brood movements were influenced by habitat. Chick survival over the 30-day brood-rearing period was substantially higher on nesting habitat of shortgrass occupied by prairie dogs compared with agricultural land and shortgrass unoccupied by prairie dogs. The rate of brood movement away from shortgrass with prairie dogs was lower than shortgrass without prairie dogs, but higher than agricultural lands for each year of the study.This study suggests that complex processes influence how different habitats affect brood-rearing activity of mountain plovers. Even though broods moved off nesting habitat of shortgrass occupied by prairie dogs, this habitat had the highest survival rate and is highly important to mountain plover reproductive success.Synthesis and applications. In order to develop effective conservation strategies, the provision of adequate breeding habitat should include information on patterns of habitat selection for all stages of the breeding cycle, including the nesting and dependent young periods. From a conservation perspective, understanding the habitat use of young birds is critical when population dynamics show great sensitivity to survival of young. Previous studies on mountain plovers have suggested that nest success is similar among shortgrass prairie habitats and agricultural lands. Thus, conservation measures that increase nest success may be ineffective for mountain plovers unless they are accompanied by measures promoting chick survival.


Dioscin improves postmenopausal osteoporosis through inducing bone formation and inhibiting apoptosis in ovariectomized rats.
Postmenopausal osteoporosis (PMO) has become a public health problem worldwide. Hormonal replacement therapy (HRT) is the most popular treatment for PMO at present, but the side effects, including increased risk of endometrial cancer and breast cancer, limit its clinical use. Therefore, finding a new medication with high efficiency and less side-effects is urgently required. Dioscin is the main ingredient of some medicinal plants such as Dioscorea nipponica Makino and Dioscorea zingiberensis Wrigh. It is reported that dioscin has anti-tumoral and anti-atherosclerotic activity as well as an inhibitory effect on hepatic fibrosis. In this study, the effects of dioscin on PMO were examined and the mechanisms were analyzed. The results indicated that the bone mineral density and ultimate load of PMO rats were increased after being treated with dioscin. H&E staining and immunohistochemical staining showed the bone trabeculae formation and bone differentiation of PMO rats were promoted by dioscin. Western blots revealed that dioscin could activate the PI3K/P38/AKT signaling pathway and inhibit the apoptosis signaling pathway in bone tissue cells of PMO rats. In addition, MTT assays showed that MC3T3-E1 cell viability could be improved by dioscin. These results suggest dioscin is a potential therapeutic reagent for osteoporosis and deserves further investigation.


Hippocampal long-term potentiation is disrupted during expression and extinction but is restored after reinstatement of morphine place preference.
Learned associations between environmental cues and morphine use play an important role in the maintenance and/or relapse of opioid addiction. Although previous studies suggest that context-dependent morphine treatment alters glutamatergic transmission and synaptic plasticity in the hippocampus, their role in morphine conditioned place preference (CPP) and reinstatement remains unknown. We investigated changes in synaptic plasticity and NMDAR expression in the hippocampus after the expression, extinction, and reinstatement of morphine CPP. Here we report that morphine CPP is associated with increased basal synaptic transmission, impaired hippocampal long-term potentiation (LTP), and increased synaptic expression of the NR1 and NR2b NMDAR subunits. Changes in synaptic plasticity, synaptic NR1 and NR2b expression, and morphine CPP were absent when morphine was not paired with a specific context. Furthermore, hippocampal LTP was impaired and synaptic NR2b expression was increased after extinction of morphine CPP, indicating that these alterations in plasticity may be involved in the mechanisms underlying the learning of drug-environment associations. After extinction of morphine CPP, a priming dose of morphine was sufficient to reinstate morphine CPP and was associated with LTP that was indistinguishable from saline control groups. In contrast, morphine CPP extinguished mice that received a saline priming dose did not show CPP and had disrupted hippocampal LTP. Finally, we found that reinstatement of morphine CPP was prevented by the selective blockade of the NR2b subunit in the hippocampus. Together, these data suggest that alterations in synaptic plasticity and glutamatergic transmission play an important role in the reinstatement of morphine CPP.


Growing and analyzing static biofilms.
Many bacteria can exist as surface-attached aggregations known as biofilms. Presented in this unit are several approaches for the study of these communities. The focus here is on static biofilm systems, which are particularly useful for examination of the early stages of biofilm formation, including initial adherence to the surface and microcolony formation. Furthermore, most of the techniques presented are easily adapted to the study of biofilms under a variety of conditions and are suitable for either small- or relatively large-scale studies. Unlike assays involving continuous-flow systems, the static biofilm assays described here require very little specialized equipment and are relatively simple to execute. In addition, these static biofilm systems allow analysis of biofilm formation with a variety of readouts, including microscopy of live cells, macroscopic visualization of stained bacteria, and viability counts. Used individually or in combination, these assays provide useful means for the study of biofilms.


Development of a New Patient-Reported Medication Adherence Instrument: Concerns Influencing Medication Adherence.
The purpose of this research was to conceptualize and develop a tool for identifying persons who are, or are likely to be, non-adherent to medications prescribed by their healthcare provider(s) by identifying concerns that patients have regarding their treatments. The target populations were persons diagnosed with atrial fibrillation or osteoarthritis, who were prescribed anticoagulants or over-the-counter or prescription pain medications, respectively. In this two-stage, multi-year, qualitative research study, relevant concepts were explored, confirmed and refined. The focus was on non-adherence due to active (thus potentially modifiable) patient decisions to forego taking medications as prescribed. The most common concerns among participants with atrial fibrillation were medication-related side effects and fear of bleeding. Participants with osteoarthritis were most concerned about short-term stomach problems and long-term kidney and liver side effects. The Concerns Influencing Medication Adherence (CIMA) instrument was developed based on these concerns and those identified in the literature. It is comprised of 16 items: a core set of 11 items potentially applicable to multiple disease states, 3 items specific to atrial fibrillation, and 2 items unique to osteoarthritis. The instrument is intended to be completed electronically, and publicly available for use in direct patient care in the United States or in population health management. To our knowledge, this is the first instrument focused on medication adherence that includes documented details of patient input as recommended by the United States Food and Drug Administration guidance. Patient input is considered a key component of content validity. In this research, for example, the concerns that patients have regarding their treatments can be expected to have affected past medication adherence and can potentially impact future adherence. Although applicability outside atrial fibrillation or osteoarthritis was not assessed, the general items may be useful in assessing adherence in other chronic diseases.


Risk factors for ischaemic heart disease: the prospective phase of the British Regional Heart Study.
Risk factors for major ischaemic heart disease (acute myocardial infarction or sudden death) have been investigated in a prospective study of 7735 men aged 40-59 years drawn from general practices in 24 British towns. After a mean follow-up of 4.2 years, there have been 202 cases of major ischaemic heart disease. Univariate estimates of the risk of ischaemic heart disease show that serum total cholesterol, HDL-cholesterol and triglyceride concentrations, systolic and diastolic blood pressures, cigarette smoking, and body mass index are all associated with increased risk of ischaemic heart disease. Evidence of ischaemic heart disease at initial examination is also strongly associated with increased risk of subsequent ischaemic heart disease. All these factors were then considered simultaneously using multiple logistic models. Definite myocardial infarction on electrocardiogram and recall of a doctor diagnosis of ischaemic heart disease remained predictive of subsequent major ischaemic heart disease, after allowance for all other risk factors. Serum total cholesterol, blood pressure, and cigarette smoking each remained as highly significant independent risk factors whereas overweight, above average levels of HDL-cholesterol and serum triglyceride were not predictive of risk after allowance for the above factors. Men with and without pre-existing ischaemic heart disease were examined separately in the same way (using multiple logistic models). The strength of association between the principal risk factors and subsequent major ischaemic heart disease was reduced in the men with pre-existing ischaemic heart disease, only age and serum total cholesterol remaining highly significant. Overall the levels of the major risk factors commonly encountered in British men have a marked effect on the risk of ischaemic heart disease. Modification of these risk factors in the general population constitutes an important national priority.


Primary color decoding using deep learning on source reconstructed EEG signal responses.
The brain's response to visual stimuli of different colors might be used in a brain-computer interface (BCI) paradigm, for letting a user control their surroundings by looking at specific colors. Allowing the user to control certain elements in its environment, such as lighting and doors, by looking at corresponding signs of different colors could serve as an intuitive interface. This paper presents work on the development of an intra-subject classifier for red, green, and blue (RGB) visual evoked potentials (VEPs) in recordings performed with an electroencephalogram (EEG). Three deep neural networks (DNNs), proposed in earlier papers, were employed and tested for data in source- and electrode space. All the tests performed in electrode space yielded better results than those in source space. The best classifier yielded an accuracy of 77% averaged over all subjects, with the best subject having an accuracy of 96%.Clinical relevance- This paper demonstrates that deep learning can be used to classify between red, green and blue visual evoked potentials in EEG recordings with an average accuracy of 77%.


A bit of salt, a trace of life: Gender norms and the impact of a salt iodization program on human capital formation of school aged children.
This paper evaluates the effect of a national salt iodization program on the cognition of school-aged children in China. We focus on the role of gender preferences. Linking pre-eradication iodine deficiency rates with household survey data, we find a strong positive impact of prenatal exposure to the program on cognition and schooling for girls. For boys, we find no effect. Child preferences play an important role in parental investment decisions and impact program effects. We find that parents invest more in girls with a high initial endowment. For boys, this is different. Parents invest in boys, irrespective of their initial endowment. The nationally implemented program may therefore primarily benefit low endowment girls. We then exploit village-level variation in gender attitudes and find that gender attitudes are related to parental investment behavior and that the program's impact is stronger for girls born to parents with strong preferences for boys.


Highly directional transurethral ultrasound applicators with rotational control for MRI-guided prostatic thermal therapy.
Transurethral ultrasound applicators with highly directional energy deposition and rotational control were investigated for precise treatment of benign prostatic hyperplasia (BPH) and adenocarcinoma of the prostate (CaP). Two types of catheter-based applicators were fabricated, using either 90 degrees sectored tubular (3.5 mm OD x 10 mm) or planar transducers (3.5 mm x 10 mm). They were constructed to be MRI compatible, minimally invasive and allow for manual rotation of the transducer array within a 10 mm cooling balloon. In vivo evaluations of the applicators were performed in canine prostates (n = 3) using MRI guidance (0.5 T interventional magnet). MR temperature imaging (MRTI) utilizing the proton resonance frequency shift method was used to acquire multiple-slice temperature overlays in real time for monitoring and guiding the thermal treatments. Post-treatment T1-weighted contrast-enhanced imaging and triphenyl tetrazolium chloride stained tissue sections were used to define regions of tissue coagulation. Single sonications with the 90 degrees tubular applicator (9-15 W, 12 min, 8 MHz) produced coagulated zones covering an 80 degrees wedge of the prostate extending from 1-2 mm outside the urethra to the outer boundary of the gland (16 mm radial coagulation). Single sonications with the planar applicator (15-20 W, 10 min, approximately 8 MHz) generated thermal lesions of approximately 30 degrees extending to the prostate boundary. Multiple sequential sonications (sweeping) of a planar applicator (12 W with eight rotations of 30 degrees each) demonstrated controllable coagulation of a 270 degrees contiguous section of the prostate extending to the capsule boundary. The feasibility of using highly directional transurethral ultrasound applicators with rotational capabilities to selectively coagulate regions of the prostate while monitoring and controlling the treatments with MRTI was demonstrated in this study.


Human in vitro Model Reveals the Effects of Collagen Cross-linking on Keratoconus Pathogenesis.
Keratoconus (KC) is a corneal thinning disorder that leads to severe vision impairment As opposed to corneal transplantation; corneal collagen crosslinking (CXL) is a relatively non-invasive procedure that leads to an increase in corneal stiffness. In order to evaluate the effect of CXL on human corneal stromal cells in vitro, we developed a 3-D in vitro CXL model, using primary Human corneal fibroblasts (HCFs) from healthy patients and Human Keratoconus fibroblasts (HKCs) from KC patients. Cells were plated on transwell polycarbonate membranes and stimulated by a stable vitamin C. CXL was performed using a mixed riboflavin 0.1% PBS solution followed by UVA irradiation. Our data revealed no significant apoptosis in either HCFs or HKCs following CXL. However, corneal fibrosis markers, Collagen III and α-smooth muscle actin, were significantly downregulated in CXL HKCs. Furthermore, a significant downregulation was seen in SMAD3, SMAD7, and phosphorylated SMADs -2 and -3 expression in CXL HKCs, contrary to a significant upregulation in both SMAD2 and Lysyl oxidase expression, compared to HCFs. Our novel 3-D in vitro model can be utilized to determine the cellular and molecular effects on the human corneal stroma post CXL, and promises to establish optimized treatment modalities in patients with KC.


P16(INK4a) protein expression in endocervical, endometrial and metastatic adenocarcinomas of extra-uterine origin: diagnostic and clinical considerations.
Determining the primary site of uterine adenocarcinoma (ADC) may be problematic, especially with small specimens. This is particularly important in light of the increase of endocervical and endometrial adenocarcinoma and the decrease in incidence of squamous cell carcinoma. P16(INK4a) , a member of the INK4 family of cell cycle regulatory proteins, plays a critical role. It functions as a negative regulator of cell cycle progression and differentiation by controlling the activity of the tumor-suppressor protein retinoblastoma (pRb), which regulates the cell cycle. Its expression is variable according to the tumoral histotype and in metastasis. The aim of this study was to investigate P16(INK4a) expression in endocervical, endometrial, and metastatic ADCs of extra-uterine origin. Fifty gynaecological biopsies (cervix or endometrium) comprised the study for P16(INK4a) determination. Cases were classified as (1) diffuse positive (P), in intense nuclear immunostaining and/or cytoplasmic in > 30% of neoplastic cells; (2) focal positive (FP), in intense immunostaining in 10% to 30% in isolated cells or small groups; and (3) negative (N), in absence of immunostaining or weak, sporadic immunostaining in < 10% of neoplastic cells. Included in the study were the following: 6 endocervical ADCs, 11 endometrioid-type endometrial ADCs, 5 endometrial serous papillary ADCs, 7 ovarian ADCs, 4 large intestine ADCs, 1 breast ADC, 12 not-otherwise-specified (NOS) ADCs, and 4 endocervical biopsy without atypia (as control). Diffuse, strong positivity with P16(INK4a) suggests an endocervical rather than an endometrial or metastatic ADC. In fact, a P16(INK4a) positive immunostaining pattern was prevalent in endocervical (83%) and serous papillary ADCs of endometrial or ovarian origin, whereas endometrioid ADCs such as metastatic non-ovarian lesions generally presented only focal or negative immunostaining. 10/12 cases of ADC-NOS were reclassified using P16(INK4a) immunostaining: 2 as endocervical ADCs (2 P), 4 as endometrioid-type endometrial ADCs (2 FP, 2 N), 3 as endometrial serous papillary ADCs (3 FP), and 1 as ovarian serous papillary ADC (1 FP).


Effect of cholesterol and cholestyramine feeding and of fasting on sterol synthesis in the liver, lleum, and lung of the guinea pig.
The effects of feeding diest containing either cholesterol (0.24% w/w) or cholestyramine (2.5% w/w) and of fasting on sterol synthesis in the liver, ileum, and lung of both male and female guinea pigs have been studied by measuring the incorporation by tissue slices of 14C-labeled acetate into total digitoninpredipitable sterols. Cholesterol feeding significantly decreased (P less than 0.05) sterol synthesis in the liver, ileum, and lung of the males and in the ileum of females. Cholestyramine feeding stimulated the rate of hepatic sterol synthesis 13-fold but did not significantly affect sterologenesis in the ileum. Sterol synthesis in the lung was significantly increased (P less than 0.05) but to a much lesser extent than in the liver. Fatty acid synthesis in the liver, ileum, and lung was not significantly affected by either cholesterol or cholestyramine feeding. In guinea pigs fasted for 24 hr, sterol synthesis was inhibited in all three tissues, the most pronounced effect occurring in the liver. Only in the lung was fatty acid synthesis significantly decreased (P less than 0.001) by fasting. Cholesterol feeding resulted in increased concentrations of cholesterol in the plasma and liver. Cholestyramine feeding reduced plasma cholesterol concentration by 81% in females and by 64% in males. However, it did not significantly change the tissue cholesterol concentrations. Fasting resulted in a significant increase (P less than 0.05) in plasma cholesterol concentration but did not effect the concentration of cholesterol in the tissues. It was concluded that in the normal guinea pig, the feedback inhibition produced by both cholesterol and also possibly by bile acids suppresses sterol synthesis in the liver to very low rates compared to those in the small intestine, where sterologenesis is not only less sensitive to the cholesterol negative feedback system than that in the liver, but also is not subject to regulation by the bile acid negative feedback system.


Driving Pressure During General Anesthesia for Open Abdominal Surgery (DESIGNATION): study protocol of a randomized clinical trial.
Intraoperative driving pressure (ΔP) is associated with development of postoperative pulmonary complications (PPC). When tidal volume (VT) is kept constant, ΔP may change according to positive end-expiratory pressure (PEEP)-induced changes in lung aeration. ΔP may decrease if PEEP leads to a recruitment of collapsed lung tissue but will increase if PEEP mainly causes pulmonary overdistension. This study tests the hypothesis that individualized high PEEP, when compared to fixed low PEEP, protects against PPC in patients undergoing open abdominal surgery. The "Driving prESsure durIng GeNeral AnesThesIa for Open abdomiNal surgery trial" (DESIGNATION) is an international, multicenter, two-group, double-blind randomized clinical superiority trial. A total of 1468 patients will be randomly assigned to one of the two intraoperative ventilation strategies. Investigators screen patients aged ≥ 18 years and with a body mass index ≤ 40 kg/m2, scheduled for open abdominal surgery and at risk for PPC. Patients either receive an intraoperative ventilation strategy with individualized high PEEP with recruitment maneuvers (RM) ("individualized high PEEP") or one in which PEEP of 5 cm H2O without RM is used ("low PEEP"). In the "individualized high PEEP" group, PEEP is set at the level at which ΔP is lowest. In both groups of the trial, VT is kept at 8 mL/kg predicted body weight. The primary endpoint is the occurrence of PPC, recorded as a collapsed composite of adverse pulmonary events. DESIGNATION will be the first randomized clinical trial that is adequately powered to compare the effects of individualized high PEEP with RM versus fixed low PEEP without RM on the occurrence of PPC after open abdominal surgery. The results of DESIGNATION will support anesthesiologists in their decisions regarding PEEP settings during open abdominal surgery. Clinicaltrials.gov, NCT03884543. Registered on 21 March 2019.


Advanced glycation end product (AGE) accumulation on Bruch's membrane: links to age-related RPE dysfunction.
Advanced glycation end products (AGEs) accumulate during aging and have been observed in postmortem eyes within the retinal pigment epithelium (RPE), Bruch's membrane, and subcellular deposits (drusen). AGEs have been associated with age-related dysfunction of the RPE-in particular with development and progression to age-related macular degeneration (AMD). In the present study the impact of AGEs at the RPE-Bruch's membrane interface was evaluated, to establish how these modifications may contribute to age-related disease. AGEs on Bruch's membrane were evaluated using immunohistochemistry. A clinically relevant in vitro model of substrate AGE accumulation was established to mimic Bruch's membrane ageing. Responses of ARPE-19 growing on AGE-modified basement membrane (AGE-BM) for 1 month were investigated by using a microarray approach and validated by quantitative (q)RT-PCR. In addition to identified AGE-related mRNA alterations, lysosomal enzyme activity and lipofuscin accumulation were also studied in ARPE-19 grown on AGE-BM. Autofluorescent and glycolaldehyde-derived AGEs were observed in clinical specimens on Bruch's membrane and choroidal extracellular matrix. In vitro analysis identified a range of dysregulated mRNAs in ARPE-19 exposed to AGE-BM. Altered ARPE-19 degradative enzyme mRNA expression was observed on exposure to AGE-BM. AGE-BM caused a significant reduction in cathepsin-D activity in ARPE-19 (P < 0.05) and an increase in lipofuscin accumulation (P < 0.01). AGEs influence ARPE-19 mRNA expression profiles and may contribute to reduced lysosomal enzyme degradative capacity and enhanced accumulation of lipofuscin. Formation of AGEs on Bruch's membrane may have important consequences for age-related dysfunction of the RPE, perhaps leading to age-related outer retinal disease.


How nurses can participate in the development of an ICNP.
The goals set for an International Classification for Nursing Practice cannot be achieved by technical means alone, nor by the consultants or ICN alone. They require the collaboration and commitment of many people in many organizations and many countries. Developing an ICNP must be a truly participative process. The greater the contribution from nurses in all countries and in all fields of practice, the more confident we can be that an ICNP truly represents nursing practice and that it is a useful tool for its purposes.


Rab27b contributes to radioresistance and exerts a paracrine effect via epiregulin in glioblastoma.
Radiotherapy is the standard treatment for glioblastoma (GBM). However, radioresistance of GBM cells leads to recurrence and poor patient prognosis. Recent studies suggest that secretion factors have important roles in radioresistance of tumor cells. This study aims to determine whether Rab27b, a small GTPase involved in secretory vesicle trafficking, plays a role in radioresistance of GBM. Microarray analysis, cell viability analysis, apoptosis assay, immunostaining, and in vivo experiments were performed to assess the effect of Rab27b on radioresistance of GBM. We further investigated paracrine effects mediated by Rab27b after X-ray irradiation using coculture systems of glioma cell lines. Rab27b was specifically upregulated in irradiated U87MG cells. Furthermore, Rab27b knockdown decreased the proliferation of GBM cells after irradiation. Knockdown of Rab27b in U87MG cells combined with radiation treatment suppressed orthotopic tumor growth in the mouse brain and prolonged the survival of recipient mice. Interestingly, the co-upregulation of Rab27b and epiregulin (EREG), a member of the epidermal growth factor (EGF) family, correlated with radioresistance in glioma cell lines. Additionally, EREG, which was secreted from U87MG cells via Rab27b-mediated mechanism, activated EGF receptor and contributed to H4 cell proliferation in a paracrine manner. Our results show that Rab27b mediates the radioresistance of highly malignant GBM cells. Rab27b promotes the proliferation of adjacent cells through EREG-mediated paracrine signaling after irradiation. Thus, the Rab27b-EREG pathway is a novel potential target to improve the efficacy of radiotherapy in GBM.


The influence of insulin-like Growth Factor-1-Receptor expression and endocrine treatment on clinical outcome of postmenopausal hormone receptor positive breast cancer patients: A Dutch TEAM substudy analysis.
Signaling via the Insulin-like Growth Factor type 1 Receptor (IGF1R) plays a crucial role in cancer development. In breast cancer (BC), IGF1R and estrogen receptor expression are correlated. In this current study we explored the hypothesis that postmenopausal hormone receptor positive (HR+ve) BC patients with high IGF1R tumor expression still have estrogen driven IGF1R stimulated tumor growth when treated with tamoxifen, resulting in detrimental clinical outcome compared to patients treated with exemestane. Additionally, we assessed the added value of metformin as this drug may lower IGF1R stimulation. Of 2,446 Dutch TEAM patients, randomized to either exemestane for 5 years or sequential treatment (tamoxifen for 2-3 years followed by exemestane for another 3-2 years) tumor tissue microarray sections were immunohistochemically stained for IGF1R. Overall Survival (OS), Breast Cancer specific Survival (BCSS) and Relapse-Free Survival (RFS) were assessed in patient subgroups with low and high IGF1R expression, and in patients with or without metformin use. High IGF1R tumor expression was significantly associated with exemestane therapy for RFS (Hazard Ratio (HR) 0.74, 95% Confidence Interval (CI) 0.58-0.95, p = 0.02). In addition, the combination of metformin with exemestane resulted in improved efficacy, yielding a 5-yrs RFS of 95% (HR 0.32, 95% CI 0.10-1.00, p = 0.02, compared to sequential treatment). No relation was observed in tumors with low IGF-1R expression. This study suggests IGF1R as a potential biomarker of improved clinical outcome in HR+ve BC patients treated with exemestane. Adding metformin to exemestane treatment may add to this effect.


Cytotoxic activity of the MK2 inhibitor CMPD1 in glioblastoma cells is independent of MK2.
MAPK-activated protein kinase 2 (MK2) is a checkpoint kinase involved in the DNA damage response. MK2 inhibition enhances the efficacy of chemotherapeutic agents; however, whether MK2 inhibition alone, without concurrent chemotherapy, would attenuate survival of cancer cells has not been investigated. CMPD1 is a widely used non-ATP competitive inhibitor that prevents MK2 phosphorylation. We employed CMPD1 together with MK2 knock-down and ATP-competitive MK2 inhibitor III (MK2i) in a panel of glioblastoma cells to assess whether MK2 inhibition could induce cancer cell death. While CMPD1 was effective at selective killing of cancer cells, MK2i and MK2 knock-down had no effect on viability of glioblastoma cells. CMPD1 treatment induced a significant G2/M arrest but MK2i-treated cells were only minimally arrested at G1 phase. Intriguingly, at doses that were cytotoxic to glioblastoma cells, CMPD1 did not inhibit phosphorylation of MK2 and of its downstream substrate Hsp27. These results suggest that CMPD1 exhibits cytotoxic activity independently of MK2 inhibition. Indeed, we identified tubulin as a primary target of the CMPD1 cytotoxic activity. This study demonstrates how functional and mechanistic studies with appropriate selection of test compounds, combining genetic knock-down and pharmacological inhibition, coordinating timing and dose levels enabled us to uncover the primary target of an MK2 inhibitor commonly used in the research community. Tubulin is emerging as one of the most common non-kinase targets for kinase inhibitors and we propose that potential tubulin-targeting activity should be assessed in preclinical pharmacology studies of all novel kinase inhibitors.


Ultrasound guidance versus anatomical landmarks for subclavian vein catheterization: a prospective study.
Several clinical practice guidelines strongly support the use of ultrasound guidance (USG) for internal jugular vein catheterization. The level of evidence concerning the use of USG for subclavian vein (SCV) cannulation remains low. To compare the effectiveness and safety of USG and anatomical landmarks approaches for cannulation of SCV. This was a prospective randomized study. Patients aged over 18 years old who requiring elective central venous catheterization were included. Non-inclusion criteria were thrombosis of the vein or major coagulopathy. All catheterizations were performed by two anaesthesiology residents. Patients were randomized into two groups: ultrasound guidance group (US group) and anatomical landmarks (LM group). The main outcome was the success rate. The secondary outcomes were the first attempt success rate and the incidence of complications. Seventy patients were included (35 in each group). The success rate was higher in US group compared to LM group without statistical significance (100% vs 85.7%; p=0.054). The first attempt success rate was significantly higher in the US group (82.9% vs. 40%; p <10-3). The incidence of mechanical complications was significantly lower in the US group compared to LM group (5.7% vs. 37.1%; p=0,001). according to our study, US guidance for SCV catheterization seems to be an interesting alternative to anatomical landmarks approaches.


Toward healthy and sustainable diets for the 21st century: Importance of sociocultural and economic considerations.
Four years after the EAT-Lancet landmark report, worldwide movements call for action to reorient food systems to healthy diets that respect planetary boundaries. Since dietary habits are inherently local and personal, any shift toward healthy and sustainable diets going against this identity will have an uphill road. Therefore, research should address the tension between the local and global nature of the biophysical (health, environment) and social dimensions (culture, economy). Advancing the food system transformation to healthy, sustainable diets transcends the personal control of engaging consumers. The challenge for science is to scale-up, to become more interdisciplinary, and to engage with policymakers and food system actors. This will provide the evidential basis to shift from the current narrative of price, convenience, and taste to one of health, sustainability, and equity. The breaches of planetary boundaries and the environmental and health costs of the food system can no longer be considered externalities. However, conflicting interests and traditions frustrate effective changes in the human-made food system. Public and private stakeholders must embrace social inclusiveness and include the role and accountability of all food system actors from the microlevel to the macrolevel. To achieve this food transformation, a new "social contract," led by governments, is needed to redefine the economic and regulatory power balance between consumers and (inter)national food system actors.


Reducing mental illness stigma in healthcare settings: Proof of concept for a social contact intervention to address what matters most for primary care providers.
Initiatives for integration of mental health services into primary care are underway through the World Health Organization's mental health Gap Action Programme (mhGAP) and related endeavors. However, primary healthcare providers' stigma against persons with mental illness is a barrier to success of these programs. Therefore, interventions are needed to reduce stigma among primary healthcare providers. We developed REducing Stigma among HealthcAre ProvidErs (RESHAPE), a theoretically-grounded intervention that draws upon the medical anthropology conceptual framework of "what matters most." RESHAPE addresses three domains of threats to what matters most: survival, social, and professional. In a proof-of-concept study, mental health service users and aspirational healthcare providers (primary healthcare providers actively incorporating mental health services) were trained to co-facilitate the RESHAPE intervention embedded within mhGAP training in Nepal. Two trainings with the RESHAPE anti-stigma component were held with 41 primary healthcare providers in Nepal. Evaluation of the training included four focus groups and 25 key informant interviews. Stigmatizing attitudes and role play-based clinical competency, assessed with the ENhancing Assessment of Common Therapeutic factors tool (ENACT), were evaluated pre-training and followed-up at four and 16 months. The study was conducted from February 2016 through June 2017. In qualitative interviews, primary healthcare providers described changes in perceptions of violence (survival threats) and the ability to treat mental illness effectively (professional threats). Willingness to interact with a person with mental illness increased from 54% pre-training to 81% at 16 months. Observed clinical competency increased from 49% pre-training to 93% at 16-months. This proof-of-concept study supports reducing stigma by addressing what matters most to healthcare providers, predominantly through mitigating survival and professional threats. Additional efforts are needed to address social threats. These findings support further exploration of service user and aspirational figure involvement in mhGAP trainings based on a "what matters most" conceptual framework.


Knot-tying habits, tier handedness, and experience.
Previous research concerning tier handedness, experience and the configuration of simple, habitual knots has been scant and conflicting. Survey data were collected from 21 disparate groups comprising 562 respondents in total. Regardless of experience, respondents tied both Granny and Reef Knots. Dextral tying was dominated by S knots. Left-handers tied Z knots more frequently than right-handers. However, the frequency of S and Z knots relative to tier hand dominance, which is not binary, occurred on a continuum. Averaging all survey tasks, more than 70% of knots tied by dextrals were S, whereas only 56% of those tied by sinistrals were S. These percentages varied somewhat according to specific tying tasks and the number of working ends. Furthermore, tiers' shoelace and parcel knots were not always identical, and a ranked pattern in parcel and shoelace knots was revealed. The examination of habitual knots could benefit criminal investigations.


Sodium arsenite exposure inhibits histone acetyltransferase p300 for attenuating H3K27ac at enhancers in mouse embryonic fibroblast cells.
Both epidemiological investigations and animal studies have linked arsenic-contaminated water to cancers, including skin, liver and lung cancers. Besides genotoxicity, arsenic exposure-related pathogenesis of disease is widely considered through epigenetic mechanisms; however, the underlying mechanism remains to be determined. Herein we explore the initial epigenetic changes via acute sodium arsenite (As) exposures of mouse embryonic fibroblast (MEF) cells and histone H3K79 methyltransferase Dot1L knockout (Dot1L-/-) MEF cells. Our RNA-seq and Western blot data demonstrated that, in both cell lines, acute As exposure abolished histone acetyltransferase p300 at the RNA level and subsequent protein level. Consequently, p300-specific main target histone H3K27ac, a marker separating active from poised enhancers, decreased dramatically as validated by both Western blot and ChIP-qPCR/seq analyses. Concomitantly, H3K4me1 as another well-known marker for enhancers also showed significant decreases, suggesting an underappreciated crosstalk between H3K4me1 and H3K27ac involved in As exposure. Significantly, As exposure-reduced H3K27ac and H3K4me1 inhibited the expression of genes including EP300 itself and Kruppel Like Factor 4(Klf4) that both are tumor suppressor genes. Collectively, our investigations identified p300 as an internal bridging factor within cells to sense external environmental As exposure to alter chromatin, thereby changing gene transcription for disease pathogenesis.


Stereospecificity of multiple receptor sites in a labellar sugar receptor of the fleshfly for amino acids and small peptides.
N-Formylation and N-methylation of the alpha-amino group of L-phenylalanine result in extremely decreased responses of the labellar sugar receptor of the fleshfly, whereas the same structural alteration of L-valine hardly affects the response. Methyl esterification of the alpha-carboxyl group of phenylalanine, on the other hand, maintains the response to some extent, but similar treatment of valine completely diminishes the response. The aromatic structure in phenylalanine is not essential for stimulation. These results suggest a substantial difference in the stereospecificities and functional group specificities of the furnase (F) and aliphatic carboxylate (T) sites in the sugar receptor. The effect of small peptides on the sugar receptor was examined systematically. Their effectiveness depends mainly on the place of the constituent amino acids rather than on their composition, indicating the decisive role that certain aliphatic amino acids in the C-terminal position play in stimulation. Remarkable regularities in the stimulating effectiveness of small peptides exactly correspond to the stereospecificity of each receptor site. We propose two hypothetical models of the F and T sites, which involve three and two subsites, respectively, that are capable of hydrogen bond formation. The F and T sites also have a hydrophobic subsite that discriminates the R groups of the stimulants and a few spatial barriers.


The Feasibility of 18F-FDG PET scans 1 month after completing radiotherapy of squamous cell carcinoma of the head and neck.
Our purpose was to prospectively evaluate the efficacy of PET with (18)F-FDG 1 mo after the completion of radiotherapy in patients with squamous cell carcinoma of the head and neck (SCCHN). Ninety-seven patients underwent (18)F-FDG PET scans before and after radiotherapy for nondisseminated SCCHN. The first scans were obtained no more than 4 wk before the start of radiotherapy, and follow-up scans were obtained 1 mo after the completion of radiotherapy. (18)F-FDG PET images were analyzed using standardized uptake values (SUVs). All patients were followed for at least 6 mo or until death. The median SUVs of preradiotherapy primary sites and nodes were 6.5 (range, 2.3-23.0) and 5.6 (range, 1.2-16.8), respectively. The median SUVs of postradiotherapy primary sites and nodes were 1.8 (range, basal status value to 9.7) and 1.8 (range, basal status value to 8.6), respectively. Evaluation of the postradiotherapy status of tumors in these SCCHN patients showed the sensitivity of (18)F-FDG PET to be 88%, the specificity to be 95%, and the overall diagnostic accuracy to be 94.9%. Our results indicate that (18)F-FDG PET might be a valuable imaging method for evaluating the response to radiotherapy in patients with SCCHN. One month after the completion of radiotherapy is not too early for follow-up (18)F-FDG PET to be performed to evaluate the response to radiotherapy.


Food Addiction Symptoms and Amygdala Response in Fasted and Fed States.
Few studies have investigated the underlying neural substrates of food addiction (FA) in humans using a recognised assessment tool. In addition, no studies have investigated subregions of the amygdala (basolateral (BLA) and central amygdala), which have been linked to reward-seeking behaviours, susceptibility to weight gain, and promoting appetitive behaviours, in the context of FA. This pilot study aimed to explore the association between FA symptoms and activation in the BLA and central amygdala via functional magnetic resonance imaging (fMRI), in response to visual food cues in fasted and fed states. Females (n = 12) aged 18-35 years completed two fMRI scans (fasted and fed) while viewing high-calorie food images and low-calorie food images. Food addiction symptoms were assessed using the Yale Food Addiction Scale. Associations between FA symptoms and activation of the BLA and central amygdala were tested using bilateral masks and small-volume correction procedures in multiple regression models, controlling for BMI. Participants were 24.1 ± 2.6 years, with mean BMI of 27.4 ± 5.0 kg/m2 and FA symptom score of 4.1 ± 2.2. A significant positive association was identified between FA symptoms and higher activation of the left BLA to high-calorie versus low-calorie foods in the fasted session, but not the fed session. There were no significant associations with the central amygdala in either session. This exploratory study provides pilot data to inform future studies investigating the neural mechanisms underlying FA.


[Do health personnel talk about passive smoking with parents of small children?].
Almost seven out of ten parents who smoke state that they have never received information on passive smoking from health personnel when they bring their children in for routine medical examination. We examined what GPs, doctors and nurses at mother-and-child clinics and midwives reported. A self-administered questionnaire focusing on practice as regards the matter of passive smoking and children was mailed to a representative sample of 1050 GPs, the senior midwives at Norway's 77 maternity departments, 492 senior public health nurses, and health personnel at 1024 mother-and-child clinics. The response rate varied from 71% (GPs) to 82% (senior midwives). 70% of the personnel at mother-and-child clinics less often than "always" ask about exposure to passive smoking. 60% of the senior midwives report that the department's personnel less than "to a large extent" allocate time to talk with parents about passive smoking. 40% of the GPs and 50% of the paediatricians say that they "never" bring up the matter of passive smoking when they examine small children and do not know whether members of the household smoke or not. The rest of the GPs bring up the matter in 46% of consultations and the rest of the paediatricians in 63% of consultations. When the child has symptoms that can be associated with passive smoking, the GPs discuss the parents' smoking habits in 88% of the consultations and paediatricians in 100% of consultations. Only to a small extent do health personnel use their opportunities of motivating parents to change their smoking habits for the sake of the health of their children. Smoking is only brought up by professionals as a matter routine when the children develop symptoms of exposure to tobacco smoke.


Palmitoylation of Hepatitis C Virus NS2 Regulates Its Subcellular Localization and NS2-NS3 Autocleavage.
Hepatitis C virus (HCV) nonstructural protein 2 (NS2) is a multifunctional protein implicated in both HCV RNA replication and virus particle assembly. NS2-encoded cysteine protease is responsible for autoprocessing of NS2-NS3 precursor, an essential step in HCV RNA replication. NS2 also promotes HCV particle assembly by recruiting envelope protein 2 (E2) to the virus assembly sites located at the detergent-resistant membranes (DRM). However, the fundamental mechanism regulating multiple functions of NS2 remains unclear. In this study, we discovered that NS2 is palmitoylated at the position 113 cysteine residue (NS2/C113) when expressed by itself in cells and during infectious-HCV replication. Blocking NS2 palmitoylation by introducing an NS2/C113S mutation reduced NS2-NS3 autoprocessing and impaired HCV RNA replication. Replication of the NS2/C113S mutant was restored by inserting an encephalomyocarditis virus (EMCV) internal ribosome entry site (IRES) between NS2 and NS3 to separate the two proteins independently of NS2-mediated autoprocessing. These results suggest that NS2 palmitoylation is critical for HCV RNA replication by promoting NS2-NS3 autoprocessing. The NS2/C113S mutation also impaired infectious-HCV assembly, DRM localization of NS2 and E2, and colocalization of NS2 with Core and endoplasmic reticulum lipid raft-associated protein 2 (Erlin-2). In conclusion, our study revealed that two major functions of NS2 involved in HCV RNA replication and virus assembly, i.e., NS2-NS3 autoprocessing and E2 recruitment to the DRM, are regulated by palmitoylation at NS2/C113. Since S-palmitoylation is reversible, NS2 palmitoylation likely allows NS2 to fine tune both HCV RNA replication and infectious-particle assembly.IMPORTANCE Chronic infection with hepatitis C virus (HCV) is a major cause of severe liver diseases responsible for nearly 400,000 deaths per year. HCV NS2 protein is a multifunctional regulator of HCV replication involved in both viral-genome replication and infectious-virus assembly. However, the underlying mechanism that enables the protein to participate in multiple steps of HCV replication remains unknown. In this study, we discovered that NS2 palmitoylation is the master regulator of its multiple functions, including NS2-mediated self-cleavage and HCV envelope protein recruitment to the virus assembly sites, which in turn promote HCV RNA replication and infectious-particle assembly, respectively. This newly revealed information suggests that NS2 palmitoylation could serve as a promising target to inhibit both HCV RNA replication and virus assembly, representing a new avenue for host-targeting strategies against HCV infection.


The status of lactoferrin and total iron binding capacity of human parotid saliva in Sjögren's syndrome.
Sjögren's syndrome (SS) is chronic salivary gland disorder characterized by a reduction in salivary and lacrimal secretion. Elevation in salivary lactoferrin has been reported in SS patients. Fluctuation in the iron binding capacity of lactoferrin has been associated with cellular damage. The purpose of this study was to compare the levels of salivary lactoferrin, total iron, and iron binding capacity in Sjögren's syndrome (SS) patients and healthy controls. SDS-PAGE was used to examine the presence of lactoferrin in 102 patients and 20 healthy controls. A colorimetric assay was used to examine the level of total salivary iron and iron binding capacity in patients and controls. A higher number of SS patients exhibited elevated levels of lactoferrin as compared to controls (86% vs. 20%, respectively). No significant difference was observed in the mean level of total iron in the saliva between patients and controls (12.6 micrograms/100 ml vs. 11.1 micrograms/100 ml, respectively). However, the total iron binding capacity of lactoferrin was significantly lower among SS patients than healthy controls (38.2 micrograms/100 ml vs. 61.8 micrograms/100 ml, respectively), p = 0.019. The overall results of this study suggest a possible impairment of the iron binding capacity of saliva in SS patients. Such impairment may contribute to the cellular damage of the salivary glands observed in SS patients.


Rapid differentiation between livestock-associated and livestock-independent Staphylococcus aureus CC398 clades.
Staphylococcus aureus clonal complex 398 (CC398) isolates cluster into two distinct phylogenetic clades based on single-nucleotide polymorphisms (SNPs) revealing a basal human clade and a more derived livestock clade. The scn and tet(M) genes are strongly associated with the human and the livestock clade, respectively, due to loss and acquisition of mobile genetic elements. We present canonical single-nucleotide polymorphism (canSNP) assays that differentiate the two major host-associated S. aureus CC398 clades and a duplex PCR assay for detection of scn and tet(M). The canSNP assays correctly placed 88 S. aureus CC398 isolates from a reference collection into the human and livestock clades and the duplex PCR assay correctly identified scn and tet(M). The assays were successfully applied to a geographically diverse collection of 272 human S. aureus CC398 isolates. The simple assays described here generate signals comparable to a whole-genome phylogeny for major clade assignment and are easily integrated into S. aureus CC398 surveillance programs and epidemiological studies.


Exploring Competency-Based Medical Education Through the Lens of the UME-GME Transition: A Qualitative Study.
Competency-based medical education (CBME) represents a shift to a paradigm with shared definitions, explicit outcomes, and assessments of competence. The groundwork has been laid to ensure all learners achieve the desired outcomes along the medical education continuum using the principles of CBME. However, this continuum spans the major transition from undergraduate medical education (UME) to graduate medical education (GME) that is also evolving. This study explores the experiences of medical educators working to use CBME assessments in the context of the UME-GME transition and their perspectives on the existing challenges. This study used a constructivist-oriented qualitative methodology. In-depth, semistructured interviews of UME and GME leaders in CBME were performed between February 2019 and January 2020 via Zoom. When possible, each interviewee was interviewed by 2 team members, one with UME and one with GME experience, which allowed follow-up questions to be pursued that reflected the perspectives of both UME and GME educators more fully. A multistep iterative process of thematic analysis was used to analyze the transcripts and identify patterns across interviews. The 9 interviewees represented a broad swath of UME and GME leadership positions, though most had an internal medicine training background. Analysis identified 4 overarching themes: mistrust (a trust chasm exists between UME and GME); misaligned goals (the residency selection process is antithetical to CBME); inadequate communication (communication regarding competence is infrequent, often unidirectional, and lacks a shared language); and inflexible timeframes (current training timeframes do not account for individual learners' competency trajectories). Despite the mutual desire and commitment to move to CBME across the continuum, mistrust, misaligned goals, inadequate communication, and inflexible timeframes confound such efforts of individual schools and programs. If current efforts to improve the UME-GME transition address the themes identified, educators may be more successful implementing CBME along the continuum.


Effect of varying feedstock-pretreatment chemistry combinations on the formation and accumulation of potentially inhibitory degradation products in biomass hydrolysates.
A variety of potentially inhibitory degradation products are produced during pretreatment of lignocellulosic biomass. Qualitative and quantitative interrogation of pretreatment hydrolysates is paramount to identifying potential correlations between pretreatment chemistries and microbial inhibition in downstream bioconversion processes. In the present study, corn stover, poplar, and pine feedstocks were pretreated under eight different chemical conditions, which are representative of leading pretreatment processes. Pretreatment processes included: 0.7% H(2)SO(4), 0.07% H(2)SO(4), liquid hot water, neutral buffer solution, aqueous ammonia, lime, lime with oxygen pressurization, and wet oxidation. Forty lignocellulosic degradation products resulting from pretreatment were analyzed using high performance liquid chromatography in combination with UV spectroscopy or tandem mass spectrometry detection (HPLC-PDA-MS/MS) and ion chromatography (IC). Of these compounds, several have been reported to be inhibitory, including furfural, hydroxymethyl furfural, ferulic acid, 3,4-dihydroxybenzaldehyde, syringic acid among others. Formation and accumulation of monitored compounds in hydrolysates is demonstrated to be a function of both the feedstock and pretreatment conditions utilized.


Alpha-carboxynucleoside phosphonates: direct-acting inhibitors of viral DNA polymerases.
Acyclic nucleoside phosphonates represent a well-defined class of clinically used nucleoside analogs. All acyclic nucleoside phosphonates need intracellular phosphorylation before they can bind viral DNA polymerases. Recently, a novel class of alpha-carboxynucleoside phosphonates have been designed to mimic the natural 2'-deoxynucleotide 5'-triphosphate substrates of DNA polymerases. They contain a carboxyl group in the phosphonate moiety linked to the nucleobase through a cyclic or acyclic bridge. Alpha-carboxynucleoside phosphonates act as viral DNA polymerase inhibitors without any prior requirement of metabolic conversion. Selective inhibitory activity against retroviral reverse transcriptase and herpesvirus DNA polymerases have been demonstrated. These compounds have a unique mechanism of inhibition of viral DNA polymerases, and provide possibilities for further modifications to optimize and fine tune their antiviral DNA polymerase spectrum.


Mechanism of centrosome positioning during the wound response in BSC-1 cells.
Locomoting cells are characterized by a pronounced external and internal anterior-posterior polarity. One of the events associated with cell polarization at the onset of locomotion is a shift of the centrosome, or MTOC, ahead of the nucleus. This position is believed to be of strategic importance for directional cell movement and cell polarity. We have used BSC-1 cells at the edge of an in vitro wound to clarify the causal relationship between MTOC position and the initiation of cell polarization. We find that pronounced cell polarization (the extension of a lamellipod) can take place in the absence of MTOC repositioning or microtubules. Conversely, MTOCs will reposition even after lamellar extension and cell polarization have occurred. Repositioning requires microtubules that extend to the cell periphery and is independent of selective detyrosination of microtubules extending towards the cell front. Significantly, MTOCs maintain, or at least attempt to maintain, a position at the cell's centroid. This is most clearly demonstrated in wounded monolayers of enucleated cells where the MTOC closely follows the centroid position. We suggest that the primary response to the would is the biased extension of a lamellipod, which can occur in the absence of microtubules and MTOC repositioning. Lamellipod extension leads to a shift of the cell's centroid towards the wound. The MTOC, in an attempt to maintain a position near the cell center, will follow. This will automatically put the MTOC ahead of the nucleus in the vast majority of cells. The nucleus as a reference for MTOC position may not be as meaningful as previously thought.


Xenobiotic Nucleic Acid (XNA) Synthesis by Phi29 DNA Polymerase.
Phi29 DNA polymerase (DNAP) is the replicative enzyme of the Bacillus subtilis bacteriophage Phi29. Its extraordinary processivity and its ability to perform isothermal amplification of DNA are central to many molecular biology applications, including high-sensitivity detection and large-scale production of DNA. We present here Phi29 DNAP as an efficient catalyst for the production of various artificial nucleic acids (XNAs) carrying backbone modifications such as 1,5-anhydrohexitol nucleic acid (HNA), 2'-deoxy-2'-fluoro-arabinonucleic acid (FANA), and 2'-fluoro-2'-deoxyribonucleic acid (2'-fluoro-DNA). A full protocol for the synthesis of HNA polymers by an exonuclease-deficient variant (D12A) of Phi29 DNAP plus a detailed guide for the design and test of novel XNA synthetase reactions performed by Phi29 DNAP are provided. © 2018 by John Wiley & Sons, Inc.


Smoke Exposure, Cytokine Levels, and Asthma Visits in Children Hospitalized for Bronchiolitis.
To determine if cigarette smoke exposure, marijuana smoke exposure, or cytokine levels at admission to the hospital for bronchiolitis are associated with follow-up visits for asthma. We enrolled a cohort of children aged 31 days to 2 years who were hospitalized with bronchiolitis from January 2013 to April 2014. Data included the results of a baseline survey about children's health and demographics, nasal wash samples, the results of a 6-month postdischarge follow-up survey, and a chart review. Nasal wash samples were tested for interleukin (IL)-6, IL-13, and tumor necrosis factor α (TNF-α); values were categorized for analysis. χ2, Fisher's exact, and Wilcoxon rank tests were done to test bivariable differences; all analyses were done using SAS. We approached 180 families for enrollment; 99 consented to participate, and 74% of these completed follow-up surveys. Half of those with high levels of IL-13 had follow-up visits for asthma, whereas only 4.2% of those with low levels had follow-up visits for asthma (P = .02). Marijuana exposure was reported for 12.5% (n = 7) of study participants. There was a significant association between marijuana exposure and TNF-α levels (P = .03). Our study revealed an association between IL-13 and follow-up visits for asthma in children who were hospitalized with bronchiolitis. We found an association between family-reported marijuana smoke exposure and detectable but lower levels of TNF-α. Further research is needed to study these relationships.


Genomic and phenotypic characterization of Xanthomonas cynarae sp. nov., a new species that causes bacterial bract spot of artichoke (Cynara scolymus L.).
A bacterial disease of artichoke (Cynara scolymus L.) was first observed in 1954 in Brittany and the Loire Valley, France. This disease causes water-soaked spots on bracts and depreciates marketability of the harvest. Ten strains of the pathogen causing bacterial spot of artichoke, previously identified as a member of the genus Xanthomonas, were characterized and compared with type and pathotype strains of the 20 Xanthomonas species using a polyphasic study including both phenotypic and genomic methods. The ten strains presented general morphological, biochemical and physiological traits and G+C content characteristic of the genus Xanthomonas. Sequencing of the 165 rRNA gene confirmed that this bacterium belongs to the genus Xanthomonas, and more precisely to the Xanthomonas campestris core. DNA-DNA hybridization results showed that the strains that cause bacterial spot of artichoke were 92-100% related to the proposed type strain CFBP 4188T and constituted a discrete DNA homology group that was distinct from the 20 previously described Xanthomonas species. The results of numerical analysis were in accordance with DNA-DNA hybridization data. Strains causing the bacterial bract spot of artichoke exhibited consistent determinative biochemical characteristics, which distinguished them from the 20 other Xanthomonas species previously described. Furthermore, pathogenicity tests allowed specific identification of this new phytopathogenic bacterium. Thus, it is concluded that this bacterium is a new species belonging to the genus Xanthomonas, for which the name Xanthomonas cynarae is proposed. The type strain, CFBP 4188T, has been deposited in the Collection Française des Bactéries Phytopathogènes (CFBP).


Daily experiences of hangover severity and food consumption in young adults.
Our aim was to determine whether alcohol hangover is associated with eating unhealthy foods (hot chips, soft drink) or healthy foods (fruit, vegetables). Daily diary study across 13 days (micro-longitudinal design). We examined a sample of 605 young adults (71% women; ages 17-25; mean age 19.91 [SD 1.86] years) who completed daily diaries in the university community and reported drinking alcohol at least twice during the 13-day study period. Each day, participants reported on their hangover severity, their consumption of fruit, vegetables, hot chips (French fries), and soft drink, and their alcohol consumption from the previous day. Linear mixed models were used to examine within-person associations between hangover severity and food consumption, by gender. Exploratory models also controlled for previous day alcohol consumption to acknowledge potential variability in hangover susceptibility. On days when participants reported higher severity of hangovers, they reported consuming more hot chips (β = .09, p = .001), more soft drink (β = .08, p = .001) and less fruit (β = -.06, p = .05). In our exploratory model controlling for previous day alcohol consumption, the predictive effect of hangover severity on hot chips remained (β = .08, p = .009) and significant interaction effects were observed between gender and previous day alcohol consumption on fruit (β = -.03, p = .003) and vegetable (β = -.03, p = .03) servings. Higher hangover severity may lead to greater intake of some unhealthy foods such as hot chips, an effect that may not be reduceable to those associated with alcohol consumption per se. Interventions that target excessive drinking primarily, but also emphasize the importance of a healthy diet, should be considered for this population.


An updated study of mortality among North American synthetic rubber industry workers.
This study evaluated mortality rates from leukemia and other diseases during the time period 1944 through 1998 among 17,924 men employed in the synthetic rubber industry. In this group, there were 6237 deaths, which is 14% fewer than the 7242 deaths expected based on general population rates. Numbers of observed versus expected deaths (shown hereafter as observed/expected) were 1608/1741 for all cancers combined, including 71/61 for leukemia, 53/53 for non-Hodgkin lymphoma (NHL*), and 26/27 for multiple myeloma. The higher than expected number of deaths from leukemia (16% increase) was concentrated in workers paid hourly who had started work 20 to 29 years earlier, had worked 10 or more years in the industry, and had worked in subgroups employed in polymerization, coagulation, maintenance labor, and laboratory operations. The overall higher leukemia mortality rate, as well as the higher rate in the subgroup of hourly workers who had 20 or more years since hire and 10 or more years worked, was not limited to a particular form of leukemia. Cumulative exposure to 1,3-butadiene (BD) was associated positively with all leukemias, with chronic myelogenous leukemia and, to a lesser extent, with chronic lymphocytic leukemia (CLL). Exposure to styrene or to dimethyldithiocarbamate (DMDTC) also was associated positively with leukemia. Exposures to these two agents were correlated with exposure to BD; data were limited on the independent effects of each of the three chemicals on leukemia. After controlling for the effects of BD, we found no consistent exposure-response relation between either styrene or DMDTC and all leukemias, chronic myelogenous leukemia, or CLL. However, a positive association between any exposure to DMDTC and leukemia persisted. The data from this study indicate that employment in the synthetic rubber industry is related causally to leukemia. Uncertainty remains about the specific agent or agents responsible for the association. The carcinogenic mechanisms through which BD, styrene, or DMDTC could cause leukemia in humans have not been established, and epidemiologic support for a leukemogenic role is limited for these agents. Styrene and DMDTC were associated positively with NHL. External support for this relation has not been reported from other epidemiologic studies. The study did not find any clear relation between exposure to BD, styrene, or DMDTC and multiple myeloma. Some subgroups of subjects had more than the expected number deaths from colorectal cancer, prostate cancer, and other diseases. These increases did not appear to be related to occupational exposure in the industry.


An integrative Tai Chi program for patients with breast cancer undergoing cancer therapy: study protocol for a randomized controlled feasibility study.
Breast cancer patients experience various side effects during cancer therapy, often resulting in reduced quality of life and poor adherence to treatment. A limited range of proven interventions has been developed to target such side effects. While Tai Chi offers benefits for the health and well-being of breast cancer survivors, the effectiveness of Tai Chi across the treatment continuum has not been evaluated. Improved patient education and support has been suggested as a priority for breast cancer care. This pilot study assesses the feasibility of a randomized controlled trial (RCT) to evaluate the effectiveness of "an integrative Tai Chi" (ANITA) program for breast cancer patients undergoing cancer therapy. This is a single-centre, two-arm feasibility RCT. Twenty-four patients with breast cancer who have undergone surgical treatment will be recruited from the Dunedin Hospital (New Zealand) over a 12-month period (from August 2017 to July 2018). Subject to informed consent, patients will be randomized to receive standard cancer treatment alone or standard cancer treatment plus the ANITA program, consisting of peer support, health education, and Tai Chi Ruler exercise. The program runs alongside the patient's adjuvant cancer therapy, which may include chemotherapy, radiation therapy, antibody treatment, and/or antihormonal therapy. Analysis in this study will focus on process evaluation of participant recruitment, retention, treatment fidelity, acceptability of the program, and occurrence of adverse events. Clinical outcomes (i.e., fatigue, sleep quality, anxiety and depression and quality of life) will be assessed at baseline, and at 12 weeks and 24 weeks post-randomization. Outcomes from this study will inform the feasibility and methodology for a future fully-powered RCT. Australian New Zealand Clinical Trials Registry with the identifier ACTRN12617000975392.


[Anemia in malignant tumor diseases. II. Tumor-induced loss of transferrin as a cause of the development of anemia based on a rat model].
The cellular uptake and lysosomal accumulation of 67Ga-labelled transferrin within tumors of different malignancy were examined using tissue fractionation and immunological techniques. As tumor models the slowly growing Morris hepatoma 5123 C, the moderately growing Novikoff hepatoma and the fast and aggressive Yoshida hepatoma AH130 were investigated. Isolation of subcellular fractions of tumor homogenates was performed by differential centrifugation and density-gradient centrifugation. The intracellular 67Ga-transferrin was found to be highly concentrated within the purified lysosomes. The transferrin within the lysosomal fraction was identified by radial immunodiffusion technique using monospecific antiserum. The accumulation of 67Ga-transferrin by the tumors resulted in a faster disappearance of 67Ga-transferrin from the blood. This loss of circulating 67Ga-transferrin correlated with the proliferation activity and the spread of the tumors. Since transferrin is indispensible for the utilization of iron by the heme-synthesizing red cell precursors, transferrin concentration in the blood is the limiting factor for the utilization of iron in hemoglobin synthesis. Thus, in a further series of experiments we investigated the development of anemia in tumor-bearing rats. With increasing tumor mass a progressive fall of hemoglobin concentration was found. The anemia was more severe in the faster growing Novikoff hepatoma than in the slowly growing Morris hepatoma. The most significant reduction of hemoglobin concentration was found in the very fast growing Yoshida hepatoma. After total tumor resection hemoglobin concentration and red blood cell count normalized completely within 6-8 weeks. We conclude from these data that the uptake of transferrin by the tumor cells results in a faster disappearance of transferrin from the blood.(ABSTRACT TRUNCATED AT 250 WORDS)


Compact device for in situ ultraviolet-visible spectrophotometric measurement of photocatalytic kinetics.
In this work, we have designed a compact device that can be easily integrated with Ultraviolet-Visible spectrophotometers, utilizing Light Emitting Diode technology for in situ spectrophotometric measurements of photocatalytic reactions. Using our device, we present the test results for the breakdown of amaranth dye with Degussa P25 powder and compare them with those obtained from a conventional arc discharge reactor. The results show that the reaction constants obtained using our device are practically equivalent to those acquired with a conventional reactor. However, our device significantly simplifies the experimental task by requiring less test solution volume and fewer user interventions while enabling in situ monitoring of the reaction kinetics. Overall, the proposed approach offers a convenient and efficient means of studying photocatalytic materials for dye degradation.


Complications After Anterior Cruciate Ligament Reconstruction and Their Relation to the Type of Graft: A Prospective Study of 958 Cases.
Complications and adverse events after anterior cruciate ligament (ACL) reconstruction are well known, but they have been underestimated in previous studies. To describe the complications and adverse events after ACL reconstruction within a 2-year follow-up and analyze them in relation to the type of graft. Cohort study; Level of evidence, 3. From 2000 to 2012, 958 patients with an isolated ACL injury underwent surgery by a single knee surgeon. ACL reconstruction was performed with the medial portal technique for the femoral tunnel and the use of bone-patellar tendon-bone (BPTB) or hamstring tendon graft. Patients were reviewed at 6 weeks and 3, 6, 12, and 24 months after surgery with the International Knee Documentation Committee score, plain radiographs, and the KT-1000 arthrometer. Of 958 patients enrolled, 147 (15%) were lost at last follow-up. The 2 groups (bone-patellar tendon-bone [n = 257] and hamstring [n = 554]) were similar regarding the mean age at the time of surgery and preoperative anterior laxity. The main complications were as follows: anterior knee pain (n = 130 of 811, 16%), stiffness (n = 72, 8.8%), secondary meniscal lesions (n = 59, 7.2%), pain attributed to fixation (n = 79, 9.7%), ACL rerupture (n = 47, 5.7%), contralateral ACL ruptures (n = 24, 3%), patellar fractures (n = 3, 0.3%), infections (n = 9, 1%), and thromboembolic complications (n = 5, 0.6%). There was no significant difference between the grafts with respect to the frequency of joint stiffness, secondary meniscal lesions, or anterior knee pain. During the first 2 postoperative years, the percentage of patients with anterior knee pain was higher in the patellar tendon group (23.3% vs 12.6%, P < .001); however, this difference was not significant after the 2-year interval (3.1% vs 2.5%, P = .63). The percentage of patients with a rerupture of the graft was significantly lower in the patellar tendon group than in the hamstring group (25 of 811 [3.1%] vs 57 of 811 [7%], P = .023). Similar results were recorded regarding the pain related to the hardware material (7 of 811 [0.8%] in the BPTB group vs 113 of 811 [13.9%] in the hamstring group, P = .001). The percentage of ACL ruptures contralateral to the repair was higher in the patellar tendon group (41 of 811 [5%] vs 17 of 811 [2%], P = .016). The total rate of complications after an ACL reconstruction was 39%, and the surgical revision rate for any reason was 28%. Problems with the hardware material were more frequent in the hamstring group, leading to an increased rate of surgical revision. Anterior knee pain was initially higher in the patellar tendon group, but there was no significant difference in a 2-year interval. The rerupture rate was statistically higher in the hamstring group.


Methodological Issues in the Use of Peer Sociometric Nominations with Middle School Youth.
Studies reporting sociometric assessments based on nominations have been characterized by important methodological inconsistencies when conducted in the middle school context. The purpose of this study was to examine (1) the possibility of a response bias when participants are provided with a long roster sorted alphabetically, (2) the impact of including or not other-sex peers in the voting population, and (3) the impact of including or not all the grademates in the voting population. Participants were 664 sixth graders from three middle schools. Peer nominations for sociometric items (i.e., like most and like least), as well as teacher ratings of antisocial behavior and records of academic performance, were collected. A sequence effect in peer nominations was found, suggesting that students whose names were listed higher on the rosters received more nominations than did students whose names were listed lower on the list. Moreover, results indicated that the nominations received from the other-sex grademates and from the grademates outside the classroom improved the predictive validity of the sociometric measure. The implications of these results for the use of sociometric assessment in middle schools are discussed.


Correlates of perceived care comfort with an EMS professional having a legal conviction.
The first objective was to examine the outcome of how comfortable a potential EMS-caller would be receiving care from an out-of-hospital-care EMS professional who might have a legal conviction. A second objective was to test for correlates that would explain this outcome. In the autumn of 2010, a structured phone survey was conducted. To maximize geographical representation across the contiguous United States, a clustered, stratified sampling strategy was used based upon US Postal Service zip codes. Of the 2,443 phone calls made, 1,051 (43%) full survey responses were obtained. Data cleaning efforts reduced the total to 929 in the final model regression analysis. Results revealed significant public discomfort in receiving care from EMS professionals who may have such a conviction. In addition, respondents who are less educated and older more strongly (1) agree that EMS professionals should have their licenses revoked for wrong doing; (2) agree EMS professionals should be screened before being hired; (3) perceive EMS credentials to be important; (4) support a lawsuit for improper care; and (5) are collectively less comfortable with being cared for by an EMS professional who may have a legal conviction. Reliable scales were found for future research use. There is significant public discomfort in receiving care from EMS professionals who may have a legal conviction. The results of this study provide increased impetus for the careful screening of EMS professionals before they are hired or allowed to be volunteers. Beyond this due diligence, the results serve as a reminder for increased EMS provider awareness of the importance of exhibiting professionalism when dealing with the public.


Fludarabine-based chemotherapy in untreated mantle cell lymphomas: an encouraging experience in 29 patients.
A prospective study to evaluate the role of fludarabine alone or in combination with idarubicin in untreated patients with mantle cell lymphoma (MCL). Twenty-nine untreated patients with mantle cell lymphoma were stochastically treated with intravenous fludarabine at a dose of 25 mg/m(2)/day for 5 days (11 patients) or with a combination of fludarabine and idarubicin (FLU-ID) (fludarabine 25 mg/m(2) i.v. on days 1 to 3 and idarubicin 12 mg/m(2) i.v. on day 1 (18 patients). For both regimens, cycles were given at three-week intervals for a total of six courses. According to the International Prognostic Index, the most part of high-intermediate and high risk factor patients were in the FLU-ID subset: 7 (39%) patients vs. 2 (18%) in the fludarabine alone subset. Of the 29 patients, 8 (28%) obtained a complete response and 10 (35%) a partial response, with an overall response rate of 63%. The remaining 11 (37%) patients did not respond to the therapy. The overall response rates were 64% (7 patients) in the fludarabine group and 61% (11 patients) in the FLU-ID group. The complete response rate was 27% (3 patients) for fludarabine and 28% (5 patients) for FLU-ID. The toxicity was mild in terms of neutropenia and infections, and no fatalities occurred due to drug-induced side effects. These results suggest the efficacy of fludarabine alone or in combination with idarubicin in MCL patients. It will be important to increase this experience and to assess other fludarabine-containing regimens, in particular with cyclophosphamide plus idarubicin and with mitoxantrone and or cyclophosphamide, to test the true role of this approach in MCL.


Elastic fiber proteins in the glomerular mesangium in vivo and in cell culture.
Glomerular capillaries of the mammalian kidney are exposed to high intraluminal hydrostatic pressures and require elastic constraint to maintain size, shape, and integrity. Previous morphological and functional studies indicated that the extracellular matrices of glomeruli, that is, basement membrane and mesangial matrix, contribute to glomerular resilience and mechanical stability. Immunofluorescence microscopy findings demonstrated elastic fiber components to be located in the renal vasculature, including glomeruli. The aim of this study was to clarify the exact glomerular localization, composition, and cellular production of these proteins. We examined the renal distribution of the elastic fiber proteins fibrillin-1, emilin, microfibril-associated glycoproteins (MAGPs) 1 and 2, latent transforming growth factor-binding protein-1 (LTBP-1), and elastin using immunohistology and immunoelectron microscopy of human, rat, and mouse kidneys. In mesangial cell cultures, we also studied the expression and extracellular deposition of such proteins by use of Northern blotting and immunocytochemistry. Fibrillin-1, emilin, MAGPs 1 and 2, and LTBP-1 were present in glomeruli of mouse, rat, and human kidney, where they were located predominantly in the mesangial extracellular matrix underlying glomerular endothelium and basement membrane. Several of these proteins, as well as elastin, were also expressed in the renal vasculature. While elastin localized to the glomerular vascular pole in afferent and efferent arterioles extending to Bowman's capsule, it was not found in the glomerular capillary tuft. Cultured mesangial cells of rat, mouse, and human kidneys expressed mRNAs of fibrillin-1, emilin, MAGP-2, and elastin, and the respective proteins localized within and outside of mesangial cells, as shown by immunocytochemistry. mRNA expression of fibrillin-1, emilin, and elastin was strong in quiescent mesangial cells; their gene expression was further up-regulated by transforming growth factor-beta1, while it was transiently reduced when cells were exposed to mitogenic 10% fetal calf serum and platelet-derived growth factor. These findings demonstrate that specific elastic fiber proteins are produced and secreted by mesangial cells. This process is regulated by growth factors. Their abundance in the extracellular matrix of the mesangium is in keeping with the concept that elastic fiber proteins contribute to the mechanical stability and elastic strength of the glomerular capillary tuft.


Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases.
Chronic osteomyelitis may recur if dead space management, after excision of infected bone, is inadequate. This study describes the results of a strategy for the management of deep bone infection and evaluates a new antibiotic-loaded biocomposite in the eradication of infection from bone defects. We report a prospective study of 100 patients with chronic osteomyelitis, in 105 bones. Osteomyelitis followed injury or surgery in 81 patients. Nine had concomitant septic arthritis. 80 patients had comorbidities (Cierny-Mader (C-M) Class B hosts). Ten had infected nonunions. All patients were treated by a multidisciplinary team with a single-stage protocol including debridement, multiple sampling, culture-specific systemic antibiotics, stabilisation, dead space filling with the biocomposite and primary skin closure. Patients were followed up for a mean of 19.5 months (12 to 34). Infection was eradicated in 96 patients with a single procedure and all four recurrences were successfully managed with repeat surgery. Adverse events were uncommon, with three fractures, six wound leaks and three unrelated deaths. Outcome was not dependant on C-M host class, microbial culture, wound leakage or presence of nonunion. This single-stage protocol, facilitated by the absorbable local antibiotic, is effective in the treatment of chronic osteomyelitis. It offers a more patient-friendly treatment compared with other published treatment options. Cite this article: Bone Joint J 2016;98-B:1289-96.


Formation of Minimal Third Phase in Ionic Liquid Extraction System with Trioctylphosphine Oxide and Its Possible Application to Extraction Concentration.
The third-phase formation behavior in ionic liquid (IL) extraction system using trioctylphosphine oxide (TOPO) was investigated. In the use of a relatively less-lipophilic IL, such as 1-butyl-3-methylimidazolium bis(trifluoromethanesulfonyl)imide (C4mimTf2N), the third phase was formed between the aqueous phase and the IL phase. The third phase seems to have a relatively high lipophilicity compared to the IL phase. The main components of the third phase were suggested as being (H3O)TOPO+, IL anion (Tf2N-), IL cation (C4mim+) and free TOPO. In addition, the third phase showed an extraction concentration ability for the Fe(III)-thiocyanato complex.


Geriatric Syndromes in Older Surgical Patients: A Literature Review.
With the ageing of the population, surgical wards are caring for an increased proportion of older patients. Geriatric syndromes are common in older hospitalised medical and hip fracture patients and are important predictors of poor outcomes in these groups, however the extent of presenting and hospital acquired geriatric syndromes in other older inpatients is less clear. This systematic literature review aimed to identify the proportion of patients aged 60 or older, cared for in usual-care surgical wards, who presented with and/or developed geriatric syndromes. Observational studies in English were identified through searches in CINAHL and Medline databases from 1985-2012. Studies of hip fracture patients and those requiring surgical intensive care (eg cardiac surgery) were excluded. The review included 25 studies. The majority of studies reported on the incidence of post-operative delirium, which ranged from 2% to 51% and varied with the type of surgery. The prevalence of depression at pre-admission screening varied from 9% to 29%. No studies reported on functional decline. Estimates of falls, malnutrition, pressure ulcers and urinary incontinence were limited by the small number of studies. These findings indicate the need for further studies to improve the understanding of geriatric syndromes in older surgical patients in usual-care wards.


Streptococcus suis infection in Hong Kong: an emerging infectious disease?
We conducted a 31-month retrospective review of all laboratory-confirmed Streptococcus suis infections admitted to public hospitals in Hong Kong. Strain identification, serotyping and antibiotic susceptibility tests were conducted on S. suis isolates. Twenty-one sporadic cases were identified, comprising 18 (86%) males and 3 (14%) females. About half were patients aged 65 years. More cases occurred during summer. Occupational exposure was documented in five (24%) cases. The estimated annual incidence was 0.09/100 000 in the general population and 32/100 000 in people with occupational exposure to pigs and raw pork. The primary clinical manifestations were meningitis (48%), septicaemia (38%) and endocarditis (14%). The case-fatality rate was 5%. All available isolates from 15 patients were serotype 2, sensitive to penicillin, ampicillin, ceftriaxone, but resistant to tetracycline. Injury prevention and proper handling of pigs or raw pork should be advocated to both at-risk occupational groups and the general population.


Influences of niobium pentoxide on roughness, hydrophilicity, surface energy and protein absorption, and cellular responses to PEEK based composites for orthopedic applications.
To improve the bio-performances of polyetheretherketone (PEEK) for orthopedic applications, submicro-particles of niobium pentoxide (Nb2O5) were synthesized using a sol-gel method, and PEEK/Nb2O5 composites (PNC) with a Nb2O5 content of 25v% (PNC25) and 50v% (PNC50) were fabricated by utilizing a process of pressing-sintering. The results showed that the Nb2O5 particles were not only dispersed in the composites but also exposed on the surface of the composites, which formed submicro-structural surfaces. In addition, the hydrophilicity, surface energy, surface roughness and absorption of proteins of the composites were improved with increasing Nb2O5 content. Moreover, the release of Nb ions with the highest concentration of 5.01 × 10-6 mol L-1 from the composite into the medium displayed no adverse effects on cell proliferation and morphology, indicating no cytotoxicity. Furthermore, compared with PEEK, the composites, especially PNC50, obviously stimulated adhesion and proliferation as well as osteogenic differentiation of bone mesenchymal stem cells of rats. The results suggested that the incorporation of Nb2O5 submicro-particles into PEEK produced novel bioactive composites with improved surface properties, which played important roles in regulating cell behaviors. In conclusion, the composites, especially PNC50 with good cytocompatibility and promotion of cellular responses, exhibited great potential as implantable materials for bone repair.


[Medical and social aspects of causes of neglected lung cancer at the primary health care level].
A technology of managing the treatment- and diagnostic process, based on automation and algorithms for adopting decisions, has been introduced at outpatient center No. 9 in Barnaul.


13C magic-angle spinning NMR studies of bathorhodopsin, the primary photoproduct of rhodopsin.
Magic-angle spinning NMR spectra have been obtained of the bathorhodopsin photointermediate trapped at low temperature (less than 130 K) by using isorhodopsin samples regenerated with retinal specifically 13C-labeled at positions 8, 10, 11, 12, 13, 14, and 15. Comparison of the chemical shifts of the bathorhodopsin resonances with those of an all-trans-retinal protonated Schiff base (PSB) chloride salt show the largest difference (6.2 ppm) at position 13 of the protein-bound retinal. Small differences in chemical shift between bathorhodopsin and the all-trans PSB model compound are also observed at positions 10, 11, and 12. The effects are almost equal in magnitude to those previously observed in rhodopsin and isorhodopsin. Consequently, the energy stored in the primary photoproduct bathorhodopsin does not give rise to any substantial change in the average electron density at the labeled positions. The data indicate that the electronic and structural properties of the protein environment are similar to those in rhodopsin and isorhodopsin. In particular, a previously proposed perturbation near position 13 of the retinal appears not to change its position significantly with respect to the chromophore upon isomerization. The data effectively exclude charge separation between the chromophore and a protein residue as the main mechanism for energy storage in the primary photoproduct and argue that the light energy is stored in the form of distortions of the bathorhodopsin chromophore.