Cultivating interprofessional practice in New Zealand: an inter-sectorial approach to developing interprofessional education.
The World Health Organization (WHO) challenges health providers to commit to and champion interprofessional education (IPE) and interprofessional collaboration (IPC), arguing that IPE promotes IPC, which in turn improves health outcomes. Providing opportunities for students to engage in IPE, which occurs when current or future practitioners learn from, with, and about one another, ensures that health providers are in line with the WHO imperative of 2010. This paper describes the process of developing and implementing an undergraduate IPE initiative within a large New Zealand district health board, Counties Manukau Health, which provides clinical placements for over 500 students annually. This initiative involved 2 half-day interprofessional workshops attended by 123 students from seven disciplines. The impact of the interprofessional learning on students' perceptions and their confidence in relation to teamwork, communication, and interprofessional interaction were evaluated. Overall, students had a positive view of interprofessional communication and teamwork, and their opinion of relationships with other professionals improved following participation in the workshops.


Cumulative frequency distribution in East Asian facial widths using the facial golden mask.
Many studies have been published on the clinical importance and attractiveness of a face. On the other hand, Asian faces give an impression that is not polished owing to their pronounced cheekbone and mandible. There have already been many studies in progress pertaining to measurements and analyses of Asian facial structure; however, the authors would like to contribute to such research by providing practical analytical data and distributional patterns of the widths of their faces showing how wide their faces are. The facial golden mask was applied to 1000 facial photographs of Korean college students, of whom 500 were males and 500 were females.The horizontal ratios (HR) of the mid- and lower faces of each student were calculated against the facial golden mask. The results were divided into 3 groups according the degrees of the HR for further analyses: group 1 (HR = 1.0), group 2 (HR > 1.0), and group 3 (HR < 1.0). We obtained an S-shaped cumulative frequency distribution graph for young Koreans per sex, per midface, and per lower face. The graph is dense at the center and is shifted to the right, signifying that the Koreans' midfaces and lower faces are wider than that of the facial golden mask. Conclusion reached in this study is that the faces of Koreans are wider than those of the facial golden mask as commonly perceived; thus, it is expected that graphs for the cumulative frequency of the distribution will be used extensively in the future.


Stability of perovskite solar cells: issues and prospects.
Even though power conversion efficiency has already reached 25.8%, poor stability is one of the major challenges hindering the commercialization of perovskite solar cells (PSCs). Several initiatives, such as structural modification and fabrication techniques by numerous ways, have been employed by researchers around the world to achieve the desired level of stability. The goal of this review is to address the recent improvements in PSCs in terms of structural modification and fabrication procedures. Perovskite films are used to provide a broad range of stability and to lose up to 20% of their initial performance. A thorough comprehension of the effect of the fabrication process on the device's stability is considered to be crucial in order to provide the foundation for future attempts. We summarize several commonly used fabrication techniques - spin coating, doctor blade, sequential deposition, hybrid chemical vapor, and alternating layer-by-layer. The evolution of device structure from regular to inverted, HTL free, and ETL including the changes in material utilization from organic to inorganic, as well as the perovskite material are presented in a systematic manner. We also aimed to gain insight into the functioning stability of PSCs, as well as practical information on how to increase their operational longevity through sensible device fabrication and materials processing, to promote PSC commercialization at the end.


Single cell network profiling (SCNP): mapping drug and target interactions.
Measuring target coverage of small molecule inhibitors is paramount-first, for selection of molecules to progress through the drug development process and second, once a candidate drug moves to clinical testing, for guiding dose/schedule selection. Single cell network profiling (SCNP) using multiparameter flow cytometry can measure compound effects on multiple signaling cascades in a cell-type-specific manner. We applied SCNP to a panel of compounds with reported inhibitory effects on Jak/Stat signaling using a novel system where modulation of multiple signaling cascades are simultaneously measured in discrete cell subsets in whole (ie, unfractionated) blood. Jak2 vs. Jak3 selectivity as well as "off-target" effects on other cell signaling pathways were measured using a combination of cytokines that target different white blood cell subsets, namely GM-CSF (monocytes/granulocytes), IL-2 (T cells), and CD40L (B cells). The compounds were then rank-ordered by potency and selectivity against the different pathways tested. Notably, SCNP performed in whole unfractionated blood compared to fractionated peripheral blood mononuclear cells (PBMC) from the same donors revealed potency loss for all compounds, with one exception. These studies show that SCNP can be used to efficiently measure a drug candidate's potency and selectivity in a physiologically relevant environment (eg, whole blood) and that robust IC(50) are attainable from rare subpopulations (<100 cells). The ability to generate in vitro IC(50) measurements in whole blood can be used not only for the preclinical selection of lead molecules, but also to determine the target plasma concentration for clinical studies and to measure target coverage after drug administration in early phase clinical trials. Knowledge of the compound plasma concentration necessary to achieve biochemical coverage permits rational design of clinical trials based on biologically active dose vs. the traditional maximum tolerated dose (MTD) design, which is better suited for cytotoxic, nontargeted drugs.


Deep vein thrombosis prophylaxis protocol--needs active enforcement.
Each hospital department tends to have its own DVT prophylaxis protocol generally based on the recommendations of the THRIFT consensus group. This is developed to help the junior medical staff to prescribe the appropriate prophylaxis according to risk assessment. However, adherence to the protocol tends to be haphazard unless actively enforced. This study is aimed at determining whether active enforcement of the protocol improves the uptake of prophylaxis.


Mismanagement of a hypochondriacal patient.
Hypochondriasis is a persistent preoccupation that despite appropriate medical evaluations and assurance of patient's physical health, the patient insists on having a serious disease. The case which is discussed in this article is a 39-years-old woman that hospitalized for half of her life and no one can perceive her disorder according to her assertions. The mentioned case is a "difficult patient" with fear of oxygen shortage and being choked (Pnigophobia) which leads to continuous tendency to wear oxygen device even during sleep. There is no benefit in exaggerating her condition for herself so there is no fictitious disorder considered. During the therapy she has been assured that she does not have a serious disease and she has learnt to decrease oxygen intake and breath with his mouth. The point that makes this study different from the others is that most of hypochondriacal patients have a fear of getting HIV, cancers, hepatitis and MS but our patient has phobia of pulmonary embolism.


Suppression of matrix degradation and amelioration of disc degeneration by a 970-nm diode laser via inhibition of the p38 MAPK pathway in a rabbit model.
Intervertebral disc degeneration (IVDD) mainly manifests as an imbalance between the synthesis and degradation of cellular and extracellular matrix (ECM) components. The cytokine interleukin (IL)-1β-induced inflammatory response of intervertebral discs causes ECM degradation. The aim of this study was to investigate the effects of a 970-nm diode laser therapy (DLT) on inflammatory cytokine IL-1β and ECM degradation proteinases in nucleus pulposus (NP) tissues in a puncture-induced rabbit IVDD model. Thirty-six New Zealand white rabbits were randomly divided into six groups: the normal group, IVDD group, laser group, sham laser group, IVDD + anisomycin (p38MAPK signaling pathway agonist), and laser + anisomycin group. Effects of laser on IVDD progression were detected using radiographic and magnetic resonance imaging. Hematoxylin and eosin, Alcian blue, safranin O-fast green staining, western blotting, and immunohistochemistry staining were performed for the histological analysis and molecular mechanism underlying protection against puncture-induced matrix degradation in NP tissues by DLT. DLT reduced the degree of disc degeneration in the gross anatomy of the disc and increased the T2-weighted signal intensity of NP. Inflammatory cytokine IL-1β levels in the disc were significantly reduced after DLT suppressed the matrix-degrading proteinases MMP13 and ADAMTS-5 and upregulated the protein expression of collagen II and aggrecan. Moreover, it inhibited the p38MAPK signaling pathway in NP tissues in a puncture-induced rabbit IVDD model. DLT reduced puncture-induced overexpression of inflammatory cytokines, mainly IL-1β, thus inhibiting matrix degeneration of NP tissues and ameliorating IVDD. This may be related to inhibition of the p38 MAPK signaling pathway.


Urgent thoracotomy for penetrating chest trauma: analysis of 158 patients of a single center.
Penetrating injuries to the chest present a frequent and challenging problem, but the majority of these injuries can be managed non-\operatively. The aim of this study was to describe the incidence of penetrating chest trauma and the ultimate techniques used for operative management, as well as the diagnosis, complications, morbidity and mortality. A retrospective 9-year review of patients who underwent an operative procedure following penetrating chest trauma was performed. The mechanism of injury, gender, age, physiological and outcome parameters, including injury severity score (ISS), chest abbreviated injury scale (AIS) score, lung injury scale score, concomitant injuries, time from admission to operating room, transfusion requirement, indications for thoracotomy, intra-operative findings, operative procedures, length of hospital stay (LOS) and rate of mortality were recorded. A total of 1123 patients who were admitted with penetrating thoracic trauma were investigated. Of these, 158 patients (93 stabbings, 65 gunshots) underwent a thoracotomy within 24 h after the penetrating trauma. There were 146 (92.4%) male and 12 (7.6%) female patients, and their mean age was 25.72 9.33 (range, 15–54) years. The mean LOS was 10.65 8.30 (range, 5–65) days. Patients admitted after a gunshot had a significantly longer LOS than those admitted with a stab wound (gunshot, 13.53 9.92 days; stab wound, 8.76 6.42 days, p < 0.001). Patients who died had a significantly lower systolic blood pressure (SBP) on presentation in the emergency room (42.94 36.702 mm Hg) compared with those who survived (83.96 27.842 mm Hg, p = 0.001). The overall mortality rate was 10.8% (n = 17). Mortality for patients with stab wounds was 8/93 (8.6%) compared with 9/65 (13.8%) for patients with gunshot wounds (p = 0.29). Concomitant abdominal injuries (p = 0.01), diaphragmatic injury (p = 0.01), ISS (p = 0.001), chest AIS score (p < 0.05), ongoing output (p = 0.001), blood transfusion volume (p < 0.01) and SBP (p = 0.001) were associated with mortality. Penetrating injuries to the chest requiring a thoracotomy are uncommon, and lung-sparing techniques have become the most frequently used procedures for lung injuries. The presence of associated abdominal injuries increased the mortality five-fold. Factors that affected mortality were ISS, chest AIS score, SBP, ongoing chest output, blood transfusion volume, diaphragmatic injury and associated abdominal injury.


Quantum chemical calculations predict biological function: the case of T cell receptor interaction with a peptide/MHC class I.
A combination of atomic correlation statistics and quantum chemical calculations are shown to predict biological function. In the present study, various antigenic peptide-Major Histocompatibility Complex (pMHC) ligands with near-identical stereochemistries, in complexation with the same T cell receptor (TCR), were found to consistently induce distinctly different quantum chemical behavior, directly dependent on the peptide's electron spin density and intrinsically expressed by the protonation state of the peptide's N-terminus. Furthermore, the cumulative coordination difference of any variant in respect to the native peptide was found to accurately reflect peptide biological function and immerges as the physical observable which is directly related to the immunological end-effect of pMHC-TCR interaction.


Novel image processing methods for the analysis of calcium dynamics in glial cells.
Calcium (Ca(2+)) waves and Ca(2+) oscillations within cells initiate a wide range of physiological processes including control of cell signaling, gene expression, secretion, and cell migration. A thorough analysis of Ca(2+) waves in glial cells provides information not only about the subcellular location of signaling processing events but also about nonneuronal or intercellular signaling pathways, their timing, routes, spatial domains, and coordination. In this study, three novel image processing methods have been applied to the study of Ca(2+) dynamics in cells. These bring additional information to the methods already available in the literature, providing insight into the analysis of calcium dynamics in fluorescence recordings and defining bidimensional maps that give a complete and detailed description of calcium intracellular behavior. The application of these processing methods to glial cells highlighted the complex 2-D Ca(2+) dynamics phenomena, the location of calcium uptake and release microdomains on the endoplasmic reticulum, and the correlation between different calcium signals inside the cell. A perinuclear zone acting as a filter and regulator of intracellular calcium waves was detected: it acts as a controller of calcium fluxes between the cytoplasm and the nucleus.


Developmental regulation of glial cell phagocytic function during Drosophila embryogenesis.
The proper removal of superfluous neurons through apoptosis and subsequent phagocytosis is essential for normal development of the central nervous system (CNS). During Drosophila embryogenesis, a large number of apoptotic neurons are efficiently engulfed and degraded by phagocytic glia. Here we demonstrate that glial proficiency to phagocytose relies on expression of phagocytic receptors for apoptotic cells, SIMU and DRPR. Moreover, we reveal that the phagocytic ability of embryonic glia is established as part of a developmental program responsible for glial cell fate determination and is not triggered by apoptosis per se. Explicitly, we provide evidence for a critical role of the major regulators of glial identity, gcm and repo, in controlling glial phagocytic function through regulation of SIMU and DRPR specific expression. Taken together, our study uncovers molecular mechanisms essential for establishment of embryonic glia as primary phagocytes during CNS development.


New glaucoma drainage implants available to glaucoma surgeons.
Glaucoma drainage device (GDD) implantation surgery is commonly performed by glaucoma specialists to treat complex and refractory glaucomas. Relative safety and efficacy data from randomized controlled trials conducted in the last two decades have sparked the interest in GDDs as possible surgical options earlier in the course of the disease than has traditionally been practiced. However, until recently, advances in the design and techniques of GDD surgery have fallen short of this increasing interest. Most recently, new GDDs that possess novel design features have become available to glaucoma specialists. Two of these new devices are the Ahmed ClearPath and the Paul glaucoma implant. These devices have demonstrated promising outcomes that are comparable to those of traditional implants. Additionally, given their unique respective features, these devices may streamline surgical technique due to ease of insertion and afford better safety and efficacy outcomes in certain patients. The recent introduction of new GDDs has been long awaited by glaucoma surgeons. Although early results are promising, long-term data and comparison of outcomes to those of traditional filtering surgery and commonly implanted devices are needed before these devices can be the new standard of care in glaucoma tube shunt surgery.


Environmental factors in helicopter operations.
The environmental problems affecting aircrew are partly those which all soldiers face, such as noise, heat and cold, and partly peculiar to the medium and the vehicle in which aircrew train and fight, such as disorientation and decompression. The cockpit environment of the modern helicopter is luxurious in comparison with many of its predecessors, yet most of the adverse effects of flight on the man still pertain. The result can, predictably, be acute and disastrous, resulting in an accident produced by severe disorientation, or chronic, producing insidious fatigue and performance decrement, which may also result in an accident. One particular stressor may be dominant in a given situation, but generally, many separate factors act simultaneously to produce their results.


Functional CeOx nanoglues for robust atomically dispersed catalysts.
Single-atom catalysts1 make exceptionally efficient use of expensive noble metals and can bring out unique properties1-3. However, applications are usually compromised by limited catalyst stability, which is due to sintering3,4. Although sintering can be suppressed by anchoring the metal atoms to oxide supports1,5,6, strong metal-oxygen interactions often leave too few metal sites available for reactant binding and catalysis6,7, and when exposed to reducing conditions at sufficiently high temperatures, even oxide-anchored single-atom catalysts eventually sinter4,8,9. Here we show that the beneficial effects of anchoring can be enhanced by confining the atomically dispersed metal atoms on oxide nanoclusters or 'nanoglues', which themselves are dispersed and immobilized on a robust, high-surface-area support. We demonstrate the strategy by grafting isolated and defective CeOx nanoglue islands onto high-surface-area SiO2; the nanoglue islands then each host on average one Pt atom. We find that the Pt atoms remain dispersed under both oxidizing and reducing environments at high temperatures, and that the activated catalyst exhibits markedly increased activity for CO oxidation. We attribute the improved stability under reducing conditions to the support structure and the much stronger affinity of Pt atoms for CeOx than for SiO2, which ensures the Pt atoms can move but remain confined to their respective nanoglue islands. The strategy of using functional nanoglues to confine atomically dispersed metals and simultaneously enhance their reactivity is general, and we anticipate that it will take single-atom catalysts a step closer to practical applications.


Natural and recombinant molecules of the cherry allergen Pru av 2 show diverse structural and B cell characteristics but similar T cell reactivity.
Cherry allergy is often reported in the context of allergy to other fruits of the Rosaceae family and pollinosis to trees because of cross-reactive allergens. Allergic reactions to cherry are reported by 19-29% of birch pollen-allergic patients. Pru av 2, identified as a thaumatin-like protein (TLP) from sweet cherry, was recognized by the majority of cherry-allergic patients in immunoblotting. In order to investigate the structural characteristics and the immunoglobulin (Ig)E- and T cell reactivity of cherry-derived TLP, recombinant Pru av 2 was expressed in Escherichia coli and natural Pru av 2 was purified. Parallel-His and FLAG expression vectors were used for recombinant production of Pru av 2 in the cytoplasm and the periplasm of E. coli. Natural Pru av 2 was purified from fresh cherries and verified by N-terminal sequencing. Structural characterization was performed using circular dichroism (CD) measurements, and the biologic activity was measured in a glucanase assay. Using cherry-specific sera, the IgE-binding ability of recombinant and natural Pru av 2 was investigated in IgE-ELISA and the T cell reactivity was studied in proliferation assays. Results Natural Pru av 2 revealed thaumatin-like structural features and bound IgE of 50% of cherry-allergic patients. It was demonstrated to be enzymatically active. Recombinant Pru av 2 expressed in the cytoplasm of E. coli exhibited a slightly different folding compared with the natural protein. It was not recognized by IgE from cherry-allergic subjects, but retained the ability to stimulate T lymphocytes. Periplasmic recombinant Pru av 2 was able to bind an anti-grape TLP antibody and cherry-specific IgE. We prepared two recombinant model TLPs from cherry, and compared their molecular characteristics as well as their IgE-binding activity and T cell interactions in relation to the natural counterpart. The cytoplasmic recombinant Pru av 2 can be used as a hypoallergenic variant in allergen-specific immunotherapy, whereas the periplasmic protein can be included in a component-resolved diagnosis.


Association between phospholipids and free cholesterol in high-density lipoprotein and the response to hepatitis C treatment in Japanese with genotype 1b.
Pegylated interferon and ribavirin combination therapy is the standard treatment for patients with chronic hepatitis C (CHC), but treatment failure can be difficult to predict. We and others have reported a relation between lipid values and sustained viral responses in patients with CHC. However, the relationship between lipid values and treatment failure has not been previously reported. The present study investigated the association between the profiles of phospholipids and free cholesterol (FC), the main constitutive ingredients of the surface of lipoprotein, classified according to particle size and hepatitis C treatment, and determined the usefulness of these parameters for predicting the outcome of treatment. Fifty-five patients with CHC (33 men and 22 women) were included in the study. The serum total cholesterol, triglyceride, phospholipids, and FC levels in the lipoprotein subclasses were determined using high-performance liquid chromatography with gel permeation columns, enabling the lipoproteins to be classified into 13 subclasses according to particle size. According to a univariate analysis, the treatment failure group had a significantly higher serum phospholipid level overall in the high-density lipoprotein (HDL) and medium HDL fractions as well as a higher serum FC level in the HDL fraction and all HDL subclass fractions compared with the corresponding values in the non-nonvirological response group. Higher serum phospholipid and FC concentrations in the HDL subclasses were predictive of a failure to respond in patients with genotype 1b.


Reliability and accuracy of a goniometer mobile device application for video measurement of the functional movement screen deep squat test.
The squat is a fundamental movement of many athletic and daily activities. Methods to clinically assess the squat maneuver range from simple observation to the use of sophisticated equipment. The purpose of this study was to examine the reliability of Coach's Eye (TechSmith Corp), a 2-dimensional (2D) motion analysis mobile device application (app), for assessing maximal sagittal plane hip, knee, and ankle motion during a functional movement screen deep squat, and to compare range of motion values generated by it to those from a Vicon (Vicon Motion Systems Ltd) 3-dimensional (3D) motion analysis system. Twenty-six healthy subjects performed three functional movement screen deep squats recorded simultaneously by both the app (on an iPad [Apple Inc]) and the 3D motion analysis system. Joint angle data were calculated with Vicon Nexus software (Vicon Motion Systems Ltd). The app video was analyzed frame by frame to determine, and freeze on the screen, the deepest position of the squat. With a capacitive stylus reference lines were then drawn on the iPad screen to determine joint angles. Procedures were repeated with approximately 48 hours between sessions. Test-retest intrarater reliability (ICC3,1) for the app at the hip, knee, and ankle was 0.98, 0.98, and 0.79, respectively. Minimum detectable change was hip 6°, knee 6°, and ankle 7°. Hip joint angles measured with the 2D app exceeded measurements obtained with the 3D motion analysis system by approximately 40°. Differences at the knee and ankle were of lower magnitude, with mean differences of 5° and 3°, respectively. Bland-Altman analysis demonstrated a systematic bias in the hip range-of-motion measurement. No such bias was demonstrated at the knee or ankle. The 2D app demonstrated excellent reliability and appeared to be a responsive means to assess for clinical change, with minimum detectable change values ranging from 6° to 7°. These results also suggest that the 2D app may be used as an alternative to a sophisticated 3D motion analysis system for assessing sagittal plane knee and ankle motion; however, it does not appear to be a comparable alternative for assessing hip motion. 3.


Postoperative ctDNA detection predicts relapse but has limited effects in guiding adjuvant therapy in resectable stage I NSCLC.
To date, identifying resectable stage I non-small cell lung cancer (NSCLC) patients likely to benefit from adjuvant therapy (ADT) remains a major challenge. Previous studies suggest that circulating tumor DNA (ctDNA) is emerging as a promising biomarker for NSCLC. However, the effectiveness of ctDNA detection in guiding ADT for resectable stage I NSCLC patients remains elusive. This study aimed to elucidate the role of ctDNA detection in estimating prognosis and guiding ADT for resectable stage I NSCLC patients. Individual patient data and ctDNA results data were collected from 270 patients across four independent cohorts. The detection of ctDNA was conducted at 3 days to 1 month after surgery. The endpoint for this study was relapse-free survival (RFS) and overall survival (OS). Of the 270 resectable stage I NSCLC patients, 9 patients with ctDNA-positive and 261 patients with ctDNA-negative. We found that the risk of recurrence was significantly lower in the ctDNA-negative group compared to the ctDNA-positive group(HR=0.11, p<0.0001). However, there is no difference in the risk of death between the two groups (p =0.39). In the ctDNA-positive group, there were no significant differences in RFS between patients who received ADT and patients who did not receive ADT (p =0.58). In the ctDNA-negative group, those who received ADT had a worse RFS in comparison with those who did not receive ADT (HR=2.36, p =0.029). No difference in OS was seen between patients who received ADT and patients who did not receive ADT in both the ctDNA-positive group and the ctDNA-negative group (All p values>0.05). Furthermore, there was no difference in RFS and OS between patients who received chemotherapy-based or tyrosine kinase inhibitor-based ADT and patients who did not receive ADT in both the ctDNA-positive group and the ctDNA-negative group (All p values>0.05). Postoperative ctDNA detection can be a prognostic marker to predict recurrence but has limited effects in guiding ADT for resectable stage I NSCLC. Future prospective investigations are needed to verify these results.


[Screening PIAS2-interacting proteins in the mouse using the yeast two-hybrid system].
To screen and identify PIAS2-interacting proteins from the mouse spermatogonial cDNA library using the yeast two-hybrid system, and to investigate the action mechanism of PIAS2 in spermatogenesis. With pGBKT7-PIAS2 as a bait plasmid, the positive clones interacting with pGBKT7-PIAS2 were screened from the mouse spermatogonial cDNA library, the inserted fragments were sequenced and underwent bioinformatic analysis, and their interaction was verified using the yeast two-hybrid system. Through screening, sequencing, homology analysis and yeast two-hybrid verification, we obtained 8 different candidate proteins interacting with PIAS2, including Cyfip2, Psmb3, Nmel, nischarin, Ints10, Nsun5, Gnb211 and Ndufaf3. Eight different genes were successfully obtained using the yeast two-hybrid system, and their encoding proteins interacted with PIAS2, which might be related with male fertility regulation. Our findings have offered some new clues to the action mechanism of PIAS2 in spermatogenesis.


Faculty wellness in academic medicine: Addressing stressors in the workplace.
Burnout is widely regarded as a syndrome resulting from chronic occupational stress. While physician burnout has been the subject of extensive research, physician wellness has been proposed as an alternative framework for understanding physician distress. The purpose of this qualitative study was to understand the organizational context of faculty wellness within an academic health care system. Semi-structured interviews were conducted with 24 chairs of clinical and non-clinical departments in a US university school of medicine. Chairs described several system-level factors perceived to interfere with faculty wellness such as a stricter regulatory environment, the loss of professional autonomy, the up or out promotion system, limitless hours, and the rise of shadow work. While all chairs articulated some degree of responsibility for the wellness of their faculty, some said they lacked the skills or knowledge of resources to fully engage in this role. Findings from this study are consistent with recent research on physician burnout, which has pivoted from describing burnout as an individual responsibility to including the professional, organizational, and societal factors which likely contribute to physician job satisfaction and well-being. As health care organizations, including academic medical centers, move toward systems-based solutions for physician occupational health, it will be incumbent upon organizational leaders to make administrative decisions favoring physician wellness.


Biphasic potassium contractures in frog muscle fibers.
Potassium-induced contractures were studied in single fibers from the semitendinosus muscle of Rana pipiens. Contractures elicited by solutions containing 60-117 mM potassium and 120 mM chloride were biphasic, consisting of a rapid initial contraction with a duration at 23 degrees C of less than 1 sec followed by a slow response with a duration of many seconds. At 13 degrees C, the initial response was greatly prolonged so that the two responses virtually fused into a single smooth contracture. Membrane potential in high potassium, high chloride solutions underwent a transient peak depolarization, probably as a result of time-dependent changes in membrane conductance during depolarization. It is proposed that this complex time course of depolarization gives rise to the biphasic contracture response.


Ribosome biogenesis and the translation process in Escherichia coli.
Translation, the decoding of mRNA into protein, is the third and final element of the central dogma. The ribosome, a nucleoprotein particle, is responsible and essential for this process. The bacterial ribosome consists of three rRNA molecules and approximately 55 proteins, components that are put together in an intricate and tightly regulated way. When finally matured, the quality of the particle, as well as the amount of active ribosomes, must be checked. The focus of this review is ribosome biogenesis in Escherichia coli and its cross-talk with the ongoing protein synthesis. We discuss how the ribosomal components are produced and how their synthesis is regulated according to growth rate and the nutritional contents of the medium. We also present the many accessory factors important for the correct assembly process, the list of which has grown substantially during the last few years, even though the precise mechanisms and roles of most of the proteins are not understood.


[Conservative treatment of a traumatic biliopleural fistula].
Conservative management of a traumatic biliopleural fistula. A female patient, 13 years of age, developed a right-sided haemothorax after a stab wound in the right para-vertebral region. Pleural effusion reoccurred after thoracic drainage was stopped. Ten days after the injury, thoracic puncture enabled a diagnosis of biliopleural fistula to be made, confirmed by ERCP and CT-scan. The fistula closed after repeat thoracic drainage combined with prophylactic antibiotic therapy.


Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 Gene Editing Technique in Xenotransplantation.
Genetically modified pigs have been considered favorable resources in xenotransplantation. Microinjection of randomly integrating transgenes into zygotes, somatic cell nuclear transfer, homologous recombination, zinc finger nucleases, transcription activator-like effector nucleases, and most recently, clustered regularly interspaced short palindromic repeats-cas9 (CRISPR/Cas9) are the techniques that have been used to generate these animals. Here, we provide an overview of the CRISPR approaches that have been used to modify genes which are vital in improving xenograft survival rate, including cytidine monophosphate-N-acetylneuraminic acid hydroxylase, B1,4N-acetylgalactosaminyltransferase, isoglobotrihexosylceramide synthase, class I MHC, von Willebrand factor, C3, and porcine endogenous retroviruses. In addition, we will mention the importance of potential candidate genes which could be targeted using CRISPR/Cas9.


What physicians need to know about dreams and dreaming.
An overview of the current status of dream science is given, designed to provide a basic background of this field for the sleep-interested physician. No cognitive state has been more extensively studied and is yet more misunderstood than dreaming. Much older work is methodologically limited by lack of definitions, small sample size, and constraints of theoretical perspective, with evidence equivocal as to whether any special relationship exists between rapid eye movement (REM) sleep and dreaming. As the relationship between dreams and REM sleep is so poorly defined, evidence-based studies of dreaming require a dream report. The different aspects of dreaming that can be studied include dream and nightmare recall frequency, dream content, dreaming effect on waking behaviors, dream/nightmare associated medications, and pathophysiology affecting dreaming. Whether studied from behavioral, neuroanatomical, neurochemical, pathophysiological or electrophysiological perspectives, dreaming reveals itself to be a complex cognitive state affected by a wide variety of medical, psychological, sleep and social variables.


Retinoic acid-metabolizing enzyme cytochrome P450 26A1 promotes skin carcinogenesis induced by 7,12-dimethylbenz[a]anthracene.
Elevated expression of the retinoic acid-metabolizing enzyme cytochrome P450 26A1 (CYP26A1) has been demonstrated to have an oncogenic function in carcinogenesis. In order to address the oncogenic capacity of CYP26A1 in vivo, transgenic mice that ubiquitously overexpressed CYP26A1 driven by the cytomegalovirus promoter were generated in the present study. Since the growth of these animals was normal for ≤15 months and they presented no evident abnormalities, a two-stage skin carcinogenesis analysis was performed. In the CYP26A1 transgenic mice, papilloma formation was observed within 7 weeks after administration of the carcinogen 7,12-dimethylbenz[a]anthracene (DMBA). Development of papillomas in these animals was significantly accelerated when compared with that observed in the control mice following treatment with DMBA in combination with the chemical tumor promoter 12-O-tetradecanoylphorbol-13-acetate. In addition, constitutive expression of CYP26A1 increased the susceptibility of these mice to the generation of squamous cell carcinomas caused by treatment with the carcinogen alone. It is thus concluded that CYP26A1 expression promotes skin carcinogenesis initiated by DMBA.


Participants' assessments of the continuing educational program with the delivery mode of a periodontal alliance.
To evaluate the effectiveness of the periodontal continuing educational delivery mode via a periodontal alliance. An innovative continuing educational delivery mode via a periodontal alliance has been conducted using a periodontal alliance of 30 hospitals in 18 provinces of China. This delivery mode integrates several instructional methods, including lectures, case presentations, and interactive question and answer sessions, all of which were conducted through online platforms. The effectiveness of the mode was evaluated via a questionnaire that was administered to the participants. The questionnaire consisted of 13 closed-ended questions and 2 open-ended questions. Of the 450 participants, 343 (76%) returned the questionnaire. Of the returned surveys, more than 92% provided positive feedback regarding the instructional methods of the program, stating that the techniques helped them study more efficiently and saved them time and money. More than 85% of the participants were satisfied with the instructional content and more than 90% of the participants considered the educational value of the program to be high, as it helped them identify gaps in knowledge, promoted their ability to establish treatment plans, and encouraged them to network with one another and thereby establish a supportive environment. With respect to the responses to the open-ended questions, the participants claimed that the most useful aspects of the program were related to time and cost savings. The most frequent feedback with respect to improving the program was to include hands-on courses and to divide the program into different levels. The participants responded positively to the program. The periodontal alliance delivery mode was determined to be an effective way to improve the quality of continuing dental education.


Mitomycin trabeculectomy: the microsurgical sponge difference.
A reproducible method for mitomycin application during glaucoma surgery is necessary to compare clinical results among investigators. To evaluate the potential reliability in drug delivery characteristics, mitomycin absorption and release from microsurgical sponges was studied. Four brands of commercially available sponges were compared using a 0.5 mg/ml concentration of mitomycin. First, the maximum volume each sponge could absorb was measured. Second, 0.2 ml was applied to each sponge and then the expansion width was measured. Finally, 0.2 ml was applied to each sponge, the sponge was placed on filter paper, and then the amount (by weight) each sponge released during a 31/2-min period was measured. The volume absorbed was similar for each brand; the means ranged from 0.44 to 0.52 ml. The expansion width was variable between the brands; the means ranged from 4.0 to 10.4 mm. The amount released to filter paper was also variable between the brands; the means ranged from 19 to 54 mg. The difference in delivery characteristics suggests that the microsurgical sponge may be an important variable in mitomycin application. In absence of a standardized method, more detailed descriptions about specific mitomycin techniques are needed.


Prevention of liquid-diet-induced damages on submandibular glands by selenium supplementation in rats.
This study was designed to explore the protective effects of selenium on submandibular glands of rats that were maintained on liquid diet. The animals kept on liquid diet for 10 days following 20 days of solid diet, had severe degeneration on both acinar and ductal cells: pycnotic nuclei, enlarged granular endoplasmic reticulum, swollen mitochondria with separated cristae, reduction of secretory granules and abundant lipid droplets were observed. Body and gland weights of these animals were found to decrease significantly compared to those of control group given solid diet for 30 days. The animals that were fed 20 days with solid diet + 10 days liquid diet and also given selenium 0.4 mg/kg for 30 days, did not have any remarkable sign of degeneration on submandibular glands, and their gland weights significantly increased when compared to the animals fed with liquid diet without selenium supplementation. Submandibular glands of the group that was maintained on solid diet for 30 days and supplemented with selenium in drinking water were found to be normal. They showed consistent gain in both body and gland weights almost equal to that of control group. As a result, we assume that adding selenium in liquid diet can prevent the detrimental effects of liquid diet consumption on submandibular glands.


Knockdown of DEAD-box RNA helicase 52 (DDX52) suppresses the proliferation of melanoma cells in vitro and of nude mouse xenografts by targeting c-Myc.
The ATP-dependent protein DEAD-box RNA helicase 52 (DDX52) is an important regulator in RNA biology and has been implicated in the development of prostate and lung cancer. However, its biological functions and clinical importance in malignant melanoma (MM) are still unclear. Understanding the potential mechanism underlying the regulation of MM progression by DDX52 might lead to novel therapeutic strategies. The aim of the present study was to investigate the role of DDX52 in the regulation of MM progression and its clinical relevance. DDX52 expression in normal and MM tissues was evaluated by GEO analysis and immunohistochemistry. The effects of DDX52 on cell growth were evaluated in MM cells with downregulated DDX52 expression. In this study, we found that DDX52 was markedly overexpressed in MM tissues compared with nontumor tissues and was associated with shorter overall survival in patients; therefore, DDX52 might be a prognostic marker in MM. Downregulation of DDX52 expression in the MM cell lines A2058 and MV3 markedly inhibited cell proliferation and colony formation. Additionally, knockdown of DDX52 in MM cells caused significant regression of established tumors in nude mice and delayed the onset time. Moreover, downregulation of DDX52 markedly suppressed c-Myc mRNA and protein expression, and an RNA immunoprecipitation assay confirmed the association between DDX52 and c-Myc. Restoration of c-Myc expression partly rescued the effects of DDX52 deficiency in MM cells. In conclusion, our study found that DDX52 mediated oncogenesis by promoting the transcriptional activity of c-Myc and could be a therapeutic target in MM.


Identification of ARKL1 as a Negative Regulator of Epstein-Barr Virus Reactivation.
Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication. Lytic reactivation starts with derepression of the Zp promoter controlling BZLF1 gene expression, which binds and is activated by the c-Jun transcriptional activator. Here, we identified the cellular Arkadia-like 1 (ARKL1) protein as a negative regulator of Zp and EBV reactivation. Silencing of ARKL1 in the context of EBV-positive gastric carcinoma (AGS) cells, nasopharyngeal carcinoma (NPC43) cells, and B (M81) cells led to increased lytic protein expression, whereas overexpression inhibited BZLF1 expression. Similar effects of ARKL1 modulation were seen on BZLF1 transcripts as well as on Zp activity in Zp reporter assays, showing that ARKL1 repressed Zp. Proteomic profiling of ARKL1-host interactions identified c-Jun as an ARKL1 interactor, and reporter assays for Jun transcriptional activity showed that ARKL1 inhibited Jun activity. The ARKL1-Jun interaction required ARKL1 sequences that we previously showed mediated binding to the CK2 kinase regulatory subunit CK2β, suggesting that CK2β might mediate the ARKL1-Jun interaction. This model was supported by the findings that silencing of CK2β, but not the CK2α catalytic subunit, abrogated the ARKL1-Jun interaction and phenocopied ARKL1 silencing in promoting EBV reactivation. Additionally, ARKL1 was associated with Zp in reporter assays and this was increased by additional CK2β. Together, the data indicate that ARKL1 is a negative regulator of Zp and EBV reactivation that acts by inhibiting Jun activity through a CK2β-mediated interaction.IMPORTANCE Epstein-Barr virus (EBV) maintains a life-long infection due to the ability to alternate between latent and lytic modes of replication and is associated with several types of cancer. We have identified a cellular protein (ARKL1) that acts to repress the reactivation of EBV from the latent to the lytic cycle. We show that ARKL1 acts to repress transcription of the EBV lytic switch protein by inhibiting the activity of the cellular transcription factor c-Jun. This not only provides a new mechanism of regulating EBV reactivation but also identifies a novel cellular function of ARKL1 as an inhibitor of Jun-mediated transcription.


Efficacy and safety of pimecrolimus cream 1% in adult patients with vitiligo: results of a randomized, double-blind, vehicle-controlled study.
Vitiligo is an acquired, pigmentary skin disorder which is disfiguring and difficult to treat. In an earlier open label study in adult patients with vitiligo, pimecrolimus cream 1% was reported to have similar efficacy as clobetasol propionate 0.05%. We performed a double-blind, intrapatient comparison of pimecrolimus cream 1% with placebo cream. Twenty adult Caucasians with symmetrical vitiligo (predominantly on extremities, none in the face) were treated b.i.d. for 6 months left/right with pimecrolimus/vehicle (N = 10) or vehicle/pimecrolimus (N = 10), respectively. Primary efficacy endpoint was the size of the target lesion at month 6 and secondary efficacy endpoint was re-pigmentation. Treatment with pimecrolimus cream 1% or vehicle resulted in no significant change in mean target lesion size. Modest repigmentation (1-25%) was noted with pimecrolimus at month 2 in 12 of 17 patients (vehicle: 9 of 17 patients). Afterwards, the number of patients who experienced an improvement of pigmentation steadily decreased (3 of 14 patients with pimecrolimus and 2 of 14 with placebo at month 6). Treatment was well tolerated. There were no treatment-related adverse events, no induction of skin atrophy nor any other application site side effects. In this group of adult patients with symmetrical vitiligo, treatment of body lesions (except face) with pimecrolimus cream 1% could not be shown to be effective.


[Epidemiology of liver cirrhosis morbitity and mortality in Iceland.].
The mortality from liver cirrhosis in Iceland is the lowest in the Western world. To study the epidemiology of liver cirrhosis mortality and morbitity in Iceland and to obtain a reliable separation between alcoholic cirrhosis (AC) and non alcoholic cirrhosis (NAC) by using multiple data sources. The study included the whole population of Iceland. Mortality was studied through death certificate data for the period 1951-1990 and morbidity (clinical incidence) through hospital, autopsy and biopsy records for the period 1971-1990. 1) The average mortality for AC in age group 20 years and older was 8.6 and for NAC 19.2 per 106 per year and the average clinical incidence was 22.1 for AC and 25.9 for NAC. 2) In the morbitity study 44% were due to AC. In the mortality study 24% were due to AC but the data suggested an underreporting of AC for males at a rate of 30%. 3) There was a significant decrease in AC mortality with time but no change in NAC. 4) Alcohol consumption per inhabitant over 15 years increased from 2.1 to 4.9 litre (130%) during the period 1951-1990. The incidence of cirrhosis in Iceland is very low for both AC and NAC accounting for only 0.2% of total deaths. The reasons are unknown. The low incidence of AC in Iceland is probably partly due to a low population alcohol consumption. The decreasing incidence of AC despite 130% increase in alcohol consumption is thought to be due to intensive treatment of alcoholism. A low prevalence of hepatitis B and C probably contributes to the low incidence of NAC.


The use of carbon suspension as an adjunct to wire localisation of impalpable breast lesions.
To determine the accuracy and therapeutic success of localisation of impalpable breast lesions by hookwire with additional lesion marking with carbon suspension to mark screen detected abnormalities requiring surgical excision. Retrospective review of all breast localisation procedures performed in our unit on women with a screen detected abnormality requiring excision over a 7 year period. One hundred and thirty eight women underwent breast localisation procedures. All of the mammographic abnormalities were excised at the initial surgical procedure. The benign to malignant ratio was 1:2. Pre-operative cytology was used to guide the extent of surgical excision, with clear margins in 70 of the 92 patients (75 percent) with malignancy. Twenty patients had further surgery: mastectomy in 7 and further local excision in 14. The localisation procedure was a therapeutic success in the local excision of malignancy in 73 of the 92 patients (79 percent) with malignancy. This method of localisation biopsy is an accurate technique for surgical excision of mammographically detected impalpable abnormalities. The surgeon is able to choose the site of surgical incision to give the best cosmetic result, the lesion is easier to identify at operation and the confidence that the abnormality has been excised is improved.


Differences in clinical trial patient attributes and outcomes according to enrollment setting.
During the last 25 years, National Cancer Institute (NCI) cooperative trial groups have extended trial networks from academic centers to include certain community and Veterans Health Administration (VHA) centers. We compared trial patients' attributes and outcomes by these enrollment settings. Studying 2,708 patients on one of 10 cooperative group, randomized lung trials at 272 institutions, we compared patient attributes by enrollment setting (ie, academic, community, and VHA affiliates). We used adjusted Cox regression to evaluate for survival differences by setting. Main member institutions enrolled 44% of patients; community affiliates enrolled 44%; and VHAs enrolled 12%. Patient attributes (ie, case-mix) of age, ethnicity, sex, and performance status varied by enrollment setting. After analysis was adjusted for patient case-mix, no mortality differences by enrollment setting were noted. Although trial patients with primarily advanced-stage lung cancer from nonacademic centers were older and had worse performance statuses than those from academic centers, survival did not differ by enrollment setting after analysis accounted for patient heterogeneity. An answer for whether long-term outcomes for patients at community and VHA centers affiliated with cooperative trial groups are equivalent to those at academic centers when care is delivered through NCI trials requires additional research among patients with longer survival horizons.


Specific histone-histone contacts are ruptured when nucleosomes unfold at low ionic strength.
The ordered unfolding of the nucleosome core within chromatin at low ionic strengths has been studied. The results show that, when nuclei are lysed gently in solutions of very low ionic strength, their constituent nucleosomes rupture at a major H2B-H4 binding site but remain unperturbed at the site of the H2A-H2B interaction. These conclusions are based on data which show that at least four separate but closely spaced H2B-H4 contacts, identifiable by contact-site cross-linking in intact nuclei, are broken when nuclei are suspended in very dilute buffers. Appropriate controls on purified nucleosomes monomers demonstrate that the H2B-H4 contacts being broken are indeed intranucleosomal. Sedimentation of nucleosomes in the ultracentrifuge at various salt concentrations reveals that a significant conformational transition occurs in the range of ionic strength over which the H2B-H4 binding site ruptures.


Indentation testing of human articular cartilage: effects of probe tip geometry and indentation depth on intra-tissue strain.
Experimental determination of intra-tissue deformation during clinically applicable rapid indentation testing would be useful for understanding indentation biomechanics and for designing safe indentation probes and protocols. The objectives of this study were to perform two-dimensional (2-D) indentation tests, using indenters and protocols that are analogous to those in clinically oriented probes, of normal adult-human articular cartilage in order to determine: (1) intra-tissue strain maps and regions of high strain magnitude, and (2) the effects on strain of indenter geometry (rectangular prismatic and cylindrical) and indentation depth (40-190 microm). Epifluorescence microscopy of samples undergoing indentation and subsequent video image correlation analysis allowed determination of strain maps. Regions of peak strain were near the "edges" of indenter contact with the cartilage surface, and the strain magnitude in these regions ranged from approximately 0.05 to approximately 0.30 in compression and shear, a range with known biological consequences. With increasing indentation displacement, strain magnitudes generally increased in all regions of the tissue. Compared to indentation using a rectangular prismatic tip, indentation with a cylindrical tip resulted in slightly higher peak strain magnitudes while influencing a smaller region of cartilage. These results may be used to refine clinical indenters and indentation protocols.


Gross photoreduction kinetics of mercury in temperate freshwater lakes and rivers: application to a general model of DGM dynamics.
Previous published measurements of mercury photoreduction are for net-photoreduction, since photooxidation processes occur simultaneously. In this research we combine continuous dissolved-gaseous mercury (DGM) analysis with a photoreactor and a quartz sparger in order to derive mercury gross photoreduction rate constants for UVB and UVA irradiations. The DGM concentration in each filter-sterilized freshwater was measured at 5 min intervals over a period of 23 h. Photoreduction proceeded for the initial 200 min, after which, reducible mercury was depleted in the sample. Substantial losses in DOC fluorescence were observed during the incubations for UVA radiation but not for UVB; therefore, UVB photoreduction dynamics are not linked to a loss in DOC fluorescence. Pseudo first-order reaction kinetics fit the data well (r2 > 0.87). The rate constants appear divided between lakes and rivers with the mean lake UVB rate constant (kUVB = 8.91 x 10(-5) s(-1)), significantly less than the mean rate constant (kUVB = 1.81 x 10(-4) s(-1)) for the river samples. However, while there were differences for the UVB rates between lakes and rivers, the mean and median rate constants for UVA in lakes (kUVA = 7.76 x 10(-5) s(-1)) did not differ significantly from the mean rate constant forthe river sites (kUVA = 1.78 x 10(-4) s(-1)). Here, we propose a model for mercury photoredox dynamics for both temperate lake and river systems. The lake model was validated using principal axis analysis to compare observed and predicted DGM data (n=279) from a variety of lake sites in Nova Scotia and Central Quebec. Principal axis analysis found a linear fit (correlation = 0.81; slope = 2.13) between predicted and observed environmental DGM values when log-normalized. The constant bias on the predicted values was attributed to estimates of available reducible mercury and the effect of DGM volatilization on observed data.


Biotechnological Advances to Improve Abiotic Stress Tolerance in Crops.
The major challenges that agriculture is facing in the twenty-first century are increasing droughts, water scarcity, flooding, poorer soils, and extreme temperatures due to climate change. However, most crops are not tolerant to extreme climatic environments. The aim in the near future, in a world with hunger and an increasing population, is to breed and/or engineer crops to tolerate abiotic stress with a higher yield. Some crop varieties display a certain degree of tolerance, which has been exploited by plant breeders to develop varieties that thrive under stress conditions. Moreover, a long list of genes involved in abiotic stress tolerance have been identified and characterized by molecular techniques and overexpressed individually in plant transformation experiments. Nevertheless, stress tolerance phenotypes are polygenetic traits, which current genomic tools are dissecting to exploit their use by accelerating genetic introgression using molecular markers or site-directed mutagenesis such as CRISPR-Cas9. In this review, we describe plant mechanisms to sense and tolerate adverse climate conditions and examine and discuss classic and new molecular tools to select and improve abiotic stress tolerance in major crops.


Lapabot: a compact telesurgical robot system for minimally invasive surgery: part I. System description.
The applications of robotic minimally invasive surgery (MIS) have widened, providing new advantages such as augmented dexterity and telesurgery. However, current commercial robotic laparoscopic surgical systems still have aspects to be improved such as heavy and bulky systems not suitable for agile operations, large rotational radii of robot manipulator arms, limited remote control capacity, and absence of force feedback. We have developed a robotic laparoscopic surgical system that features compact slave manipulators. The system can simultaneously operate one laparoscope arm and up to four instrument arms. The slave robot is controlled remotely through an Ethernet network and is ready for telesurgery. The developed surgical robot has sufficient workspace to perform general MIS and has been shown to provide acceptable motion tracking control performance.


Staging laparoscopy in digestive cancers.
BACKGROUND. Laparoscopy and laparoscopic ultrasonography may assist in the more accurate staging of digestive cancers. We assessed the diagnostic value of staging laparoscopy in patients with cancers of lower esophagus, stomach, liver, biliary tract, pancreas and colon. MATERIAL AND METHOD. Extended staging laparoscopy, laparoscopic ultrasonography and peritoneal cytology were performed in 165 patients with primary digestive cancers, admitted between January 2006 and December 2008 at three tertiary referral hospitals participating in the study. Staging laparoscopy was immediately followed by open surgery in 63 patients without distant metastases or with uncertain primary tumor resectability, and in 20 colorectal cancer patients with resectable hepatic metastases. The sensibility, sensitivity and diagnostic accuracy of staging laparoscopy for distant metastases and tumor resectability were assessed against the findings on open surgery and the final pathological report. RESULTS. An unnecessary laparotomy was avoided in 36 of the 99 patients (36.4%) without distant metastases on imaging pre-therapeutic staging. The staging laparoscopy sensitivity for distant metastases varied between 66% and 100% and the diagnostic accuracy between 87% for the lower esophageal cancer and 100% for the biliary tract tumors. The overall morbidity of staging laparoscopy was 2.5% and the mortality 0. CONCLUSION. Staging laparoscopy avoids unnecessary laparotomies and changes the therapeutic plan in a significant number of patients. It can be performed just before the planned surgery or as a separate diagnostic procedure. The laparoscopy indications in digestive cancers are changing fast, with ongoing new developments in cancer treatment and laparoscopic technology.


A SERS-active microfluidic device with tunable surface plasmon resonances.
A surface-enhanced Raman scattering (SERS)-active microfluidic device with tunable surface plasmon resonances is presented here. It is constructed by silver grating substrates prepared by two-beam laser interference of photoresists and subsequent metal evaporation coating, as well as PDMS microchannel derived from soft lithography. By varying the period of gratings from 200 to 550 nm, surface plasmon resonances (SPRs) from the metal gratings could be tuned in a certain range. When the SPRs match with the Raman excitation line, the highest enhancement factor of 2×10(7) is achieved in the SERS detection. The SERS-active microchannel with tunable SPRs exhibits both high enhancement factor and reproducibility of SERS signals, and thus holds great promise for applications of on-chip SERS detection.


Injectable Immunotherapeutic Hydrogel Containing RNA-Loaded Lipid Nanoparticles Reshapes Tumor Microenvironment for Pancreatic Cancer Therapy.
Pancreatic cancer immunotherapy is becoming a promising strategy for improving the survival rate of postsurgical patients. However, the low response rate to immunotherapy suggests a low number of antigen-specific T cells and a high number of immunosuppressive tumor-associated macrophages in the pancreatic tumor microenvironment. Herein, we developed an in situ injectable thermosensitive chitosan hydrogel loaded with lipid-immune regulatory factor 5 (IRF5) mRNA/C-C chemokine ligand 5 (CCL5) siRNA (LPR) nanoparticle complexes (LPR@CHG) that reprogram the antitumoral immune niche. The LPR@CHG hydrogel upregulates IRF5 and downregulates CCL5 secretion, which contribute to a significant increase in M1 phenotype macrophages. Tumor growth is controlled by effective M1 phenotype macrophage that initiate T cell-mediated immune responses. Overall, the LPR@CHG hydrogel is expected to be a meaningful immunotherapy platform that can reshape the immunosuppressive tumor microenvironment and improve the efficacy of current pancreatic immunotherapies while minimizing systemic toxicity.


Metabolism of diphenylhydantoin (phenytoin) during pregnancy.
Plasma levels of diphenylhydantoin (DPH) and the 24 hour urinary excretion of both DPH and its major metabolite 5-(p-hydroxyphenyl)-phenylhydantoin (HPPH) were measured serially during pregnancy in a group of five unselected epileptic patients. Plasma DPH levels fell and on average were some 40 per cent lower at term than they had been in early pregnancy. With one exception, the patients were well controlled during pregnancy but two patients who regularly had plasma DPH levels below 10 microgram/ml both suffered seizures in the puerperium. There was no convincing change in the excretion of either DPH or HPPH which together accounted for less than half the administered dose. Gestational length exceeded 41 weeks in 4 of the 5 patients studied but all were delivered of normal healthy infants, of average birthweight, with no congenital defects or clotting disorders.


Interaction of Lyapunov vectors in the formulation of the nonlinear extension of the Kalman filter.
When applied to strongly nonlinear chaotic dynamics the extended Kalman filter (EKF) is prone to divergence due to the difficulty of correctly forecasting the forecast error probability density function. In operational forecasting applications ensemble Kalman filters circumvent this problem with empirical procedures such as covariance inflation. This paper presents an extension of the EKF that includes nonlinear terms in the evolution of the forecast error estimate. This is achieved starting from a particular square-root implementation of the EKF with assimilation confined in the unstable subspace (EKF-AUS), that is, the span of the Lyapunov vectors with non-negative exponents. When the error evolution is nonlinear, the space where it is confined is no more restricted to the unstable and neutral subspace causing filter divergence. The algorithm presented here, denominated EKF-AUS-NL, includes the nonlinear terms in the error dynamics: These result from the nonlinear interaction among the leading Lyapunov vectors and account for all directions where the error growth may take place. Numerical results show that with the nonlinear terms included, filter divergence can be avoided. We test the algorithm on the Lorenz96 model, showing very promising results.


Virtual or In-Person: A Mixed Methods Survey to Determine Exercise Programming Preferences during COVID-19.
A survey was conducted to identify barriers and facilitators to engaging in virtual and in-person cancer-specific exercise during COVID-19. A theory-informed, multi-method, cross-sectional survey was electronically distributed to 192 individuals with cancer investigating preferences towards exercise programming during COVID-19. Respondents had previously participated in an exercise program and comprised two groups: those who had experience with virtual exercise programming ('Virtual') and those who had only taken part in in-person exercise ('In-Person'). Quantitative data were summarized descriptively. Qualitative data were thematically categorized using framework analysis and findings were mapped to an implementation model. The survey completion response rate was 66% (N = 127). All respondents identified barriers to attending in-person exercise programming during COVID-19 with concerns over the increased risk of viral exposure. Virtual respondents (n = 39) reported: (1) feeling confident in engaging in virtual exercise; and (2) enhanced motivation, accessibility and effectiveness as facilitators to virtual exercise. In-Person respondents (n = 88) identified: (1) technology as a barrier to virtual exercise; and (2) low motivation, accessibility and exercise effectiveness as barriers towards virtual exercise. Sixty-six percent (n = 58) of In-Person respondents reported that technology support would increase their willingness to exercise virtually. With appropriately targeted support, perceived barriers to accessing virtual exercise-including motivation, accessibility and effectiveness-may become facilitators. The availability of technology support may increase the engagement of individuals with cancer towards virtual exercise programming.


Extracorporeal shock wave therapy (ESWT) in patients with chronic proximal plantar fasciitis: a 2-year follow-up.
The aim of this study was to compare the effect of extracorporeal shock wave therapy (ESWT) in patients with chronically painful proximal plantar fasciitis with a further conventional conservative treatment. Forty-seven patients (49 feet) with a previously unsuccessful nonsurgical treatment of at least 6 months were randomized to two groups. Heel cups had to be worn throughout the study. Group 1 (25 heels) was treated immediately with three sessions of ESWT (3000 shock waves/session of 0.2 mJ/mm2) at weekly intervals. The patients of group 2 (24 heels) continued nonsurgical treatment (iontophoresis with diclofenac and an oral nonsteroidal anti-inflammatory drug) for 12 weeks. After this period they were treated using the protocol of group 1. No significant difference of pain and walking time after further nonsurgical treatment (3 months) was seen in group 2. At 12 weeks after ESWT, the pain estimation on the visual analogue scale (VAS) for activities of daily living diminished significantly by 62.9% in group 1 and by 63.0% in group 2. The comfortable walking time had increased significantly in both groups. Two years after ESWT, pain during activities of daily living decreased by 94% in group 1 and by 90% in group 2 on the VAS and the comfortable walking time had increased significantly in both groups.


Nursing Care Management of Responsive Behaviors for Persons Living With Dementia in Acute Care Settings: An Integrative Review.
The current integrative review was performed to understand how acute care nurses manage responsive behaviors among persons living with dementia (PLWD) in acute care settings. Eight studies were included, and three themes were developed: Person-Centered Approach, Non-Person-Centered Approach, and Facilitators and Barriers to Care Approaches. Nurses expressed difficulties in caring for hospitalized PLWD due to lack of knowledge of dementia care, pressure to work more efficiently, and prioritization of acute medical concerns. Nurses frequently used nonpharmacological approaches that required less time spent with patients. Results suggest that nurses in acute care settings require further education regarding dementia and person-centered care approaches for PLWD. Nursing management can support nurses' learning needs through education and policies to improve patient outcomes. [Journal of Gerontological Nursing, 49(2), 19-25.].


Expanding role of lipid II as a target for lantibiotics.
Lipid II is an essential cell-wall precursor required for the growth and replication of both Gram-positive and Gram-negative bacteria. Compounds that use lipid II to selectively target bacterial cells for destruction represent an important class of antibiotics. Clinically, vancomycin is the most important example of an antibiotic that operates in this manner. Despite being considered the 'antibiotic drug of last resort', significant bacterial resistance to vancomycin now manifests itself worldwide. In this paper we review recent progress made in understanding the lipid II-associated antibacterial characteristics of various naturally occurring compounds, with particular focus on the lantibiotic peptides.


[A case of liver metastasis of pancreatic duct carcinoma successfully treated with gemcitabine].
We report a patient in whom systemic chemotherapy using gemcitabine was effective against liver metastases of pancreatic cancer. A 72-year-old woman underwent pancreatoduodenectomy with lymphadenectomy and partial resection of the portal vein following a diagnosis of pancreatic cancer, and her postoperative course was uneventful. The diagnosis was stage III anaplastic ductal carcinoma (t2n1P0H0M0). One year and 3 months after the operation, however, her serum level of carbohydrate antigen 19-9 (CA19-9) was found to be elevated, and CT examination revealed a mass in the liver that was diagnosed as liver that was metastases. Systemic chemotherapy was performed with a regimen of gemcitabine 600 mg/m2/week for 3 weeks, followed by a week rest, for the first three courses. On and after fourth course, gemcitabine 1,000 mg/m2/week was administered. The serum CA19-9 level was down from 882 U/ml to normal after 5 courses of chemotherapy and CT examination revealed that liver metastases had completely vanished. Although no evidence of deterioration was observed, the patient died of infectious pneumonia 10 months after recurrence. The prognosis of liver metastases of pancreatic cancer is quite unfavorable. However, if remission is achieved with gemcitabine, the patient has the possibility to obtain a better outcome.


Closed system with agent-specific vaporizers and nitrous oxide.
Through judicious use of nitrous oxide the closed system can be quite effectively used with currently available equipment including both agent-specific direct-reading percentage vaporizers and suitable devices for the measurement of end-tidal concentrations of oxygen, carbon dioxide and anaesthetic agents. It is only necessary to think in terms of required volumes of fresh gases and vapours added to the system as well as the appropriate concentrations of oxygen and anaesthetic in the respired mixture. When used as described the inspired concentration of nitrous oxide in the closed system should never exceed 50% (usually about 40%). Therefore nitrous oxide will not pose the threat of hypoxaemia unless misused. Experience in teaching this method during the previous decade supports a belief that learning the use of a truly closed circle absorption anaesthesia system is fundamentally important to the development of clinical skills and also facilitates understanding of basic concepts related to respiratory physiology and the uptake and distribution of inhalation anaesthetics. It follows that students and residents should be introduced to this method in the early weeks of their learning experience.


Effects of flavonoid mixtures on the transport of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) through Caco-2 monolayers: an in vitro and kinetic modeling approach to predict the combined effects on transporter inhibition.
This study describes and kinetically models the effect of flavonoid mixtures on PhIP transport through Caco-2 monolayers. Previously it was shown that quercetin, luteolin, naringenin and myricetin increase the apical to basolateral PhIP transport in Caco-2 monolayers. In this study, apigenin was shown to exert a similar effect with an apparent K(i) value of 10.8 microM. Additional experiments revealed that several binary flavonoid mixtures and one mixture containing all five model flavonoids increased the apical to basolateral PhIP transport through the Caco-2 monolayer. Assuming competitive inhibition of the apparent active transporter by the flavonoids and concentration-additivity for their inhibiting effect, the kinetic model previously developed to describe the effect of the individual flavonoids on PhIP transport, could be extended and adequately describes the experimental values obtained for the flavonoid mixtures. We conclude that combinations of flavonoids increase the transport of PhIP and do so by interacting in an additive way with the active transport of PhIP. This flavonoid-mediated increase in PhIP transport through Caco-2 monolayers may point at a possible increased bioavailability of PhIP in the presence of flavonoid mixtures in the in vivo situation. This would imply an adverse effect of these supposed beneficial food ingredients.


Noncovalent PEG Coating of Nanoparticle Drug Carriers Improves the Local Pharmacokinetics of Rectal Anti-HIV Microbicides.
Antiretroviral drug nanocarriers hold great promise for developing anti-human immunodeficiency virus (HIV) rectal microbicides. However, challenges remain, namely, concerning which properties are more suited for enhancing colorectal distribution and retention of microbicide compounds. In this work, we developed and assessed the in vitro and in vivo performance of poly(lactic- co-glycolic acid) (PLGA)-based nanoparticles (NPs) as carriers for the model drug efavirenz (EFV). We particularly focused on the effect of noncovalent poly(ethylene glycol) coating of PLGA NPs (PEG-PLGA NPs) conferring a mucus-diffusive behavior on the pharmacokinetics (PK) of EFV following rectal administration to mice. Drug-loaded PLGA NPs and PEG-PLGA NPs (200-225 nm) were obtained by nanoprecipitation. Both types of systems were able to retain native antiretroviral activity of EFV in vitro, while featuring lower cytotoxicity against different epithelial cell lines and HIV target cells. Also, PLGA NPs and PEG-PLGA NPs were readily taken up by colorectal cell lines and mildly reduced EFV permeation while increasing membrane retention in Caco-2 and Caco-2/HT29-MTX cell monolayer models. When administered intrarectally to CD-1 mice in phosphate-buffered saline (pH 7.4), EFV-loaded PEG-PLGA NPs consistently provided higher drug levels in colorectal tissues and lavages, as compared to free EFV or drug-loaded PLGA NPs. Mean values for the area-under-the-curve between 15 min and 12 h following administration were particularly higher for PEG-PLGA NPs in distal and middle colorectal tissues, with relative bioavailability values of 3.7 and 29, respectively, as compared to free EFV (2.2 and 6.0 over PLGA NPs, respectively). Systemic exposure to EFV was reduced for all treatments. NPs were further shown safe after once-daily administration for 14 days, as assessed by histological analysis of colorectal tissues and chemokine/cytokine assay of rectal lavages. Overall, PEG-PLGA NPs demonstrated to be safe carriers for rectal microbicide drug delivery and able to provide enhanced local PK that could be valuable in preventing rectal HIV transmission.


Simple semi-permanent blockade against rigid varus foot in a case with spasticity: possible practical benefits in ambulatory adults.
A 55-year-old ambulatory woman with hemiplegia and varus foot deformity had several problems in her daily life, including load pain and stance instability in the affected foot, easy fatigue of the non-paralysed leg, low back pain, neck stiffness and rapid shoe-rubber wear on the deformed side. We began repeated focal blockades using botulinum toxin to the tibialis posterior muscle to control varus spasticity. Distant influences presenting in the whole body were relieved soon after the first blockade, and shoe wear also stopped. Although, neither the deformed appearance nor foot contact pattern on walking changed in the initial period after beginning the blockade, the foot contact pattern revealed gradual improvement over several years. Generally, surgical correction is indicated for the treatment of deformed feet. The present case suggests that, in case of varus-deformed foot with some spastic elements, trial of focal blockade for varus spasticity may be worthwhile.


Ursodeoxycholic acid ameliorates fructose-induced metabolic syndrome in rats.
The metabolic syndrome (MS) is characterized by insulin resistance, dyslipidemia and hypertension. It is associated with increased risk of cardiovascular diseases and type-2 diabetes. Consumption of fructose is linked to increased prevalence of MS. Ursodeoxycholic acid (UDCA) is a steroid bile acid with antioxidant, anti-inflammatory activities and has been shown to improve insulin resistance. The current study aims to investigate the effect of UDCA (150 mg/kg) on MS induced in rats by fructose administration (10%) in drinking water for 12 weeks. The effects of UDCA were compared to fenofibrate (100 mg/kg), an agonist of PPAR-α receptors. Treatment with UDCA or fenofibrate started from the 6th week after fructose administration once daily. Fructose administration resulted in significant increase in body weight, elevations of blood glucose, serum insulin, cholesterol, triglycerides, advanced glycation end products (AGEs), uric acid levels, insulin resistance index and blood pressure compared to control rats. Moreover, fructose increased oxidative stress in aortic tissues indicated by significant increases of malondialdehyde (MDA), expression of iNOS and reduction of reduced glutathione (GSH) content. These disturbances were associated with decreased eNOS expression, increased infiltration of leukocytes and loss of aortic vascular elasticity. Treatment with UDCA successfully ameliorated the deleterious effects of fructose. The protective effect of UDCA could be attributed to its ability to decrease uric acid level, improve insulin resistance and diminish oxidative stress in vascular tissues. These results might support possible clinical application of UDCA in MS patients especially those present with liver diseases, taking into account its tolerability and safety. However, further investigations on human subjects are needed before the clinical application of UDCA for this indication.


Metabolomic signatures associated with weight gain and psychosis spectrum diagnoses: A pilot study.
Psychosis spectrum disorders (PSDs), as well as other severe mental illnesses where psychotic features may be present, like bipolar disorder, are associated with intrinsic metabolic abnormalities. Antipsychotics (APs), the cornerstone of treatment for PSDs, incur additional metabolic adversities including weight gain. Currently, major gaps exist in understanding psychosis illness biomarkers, as well as risk factors and mechanisms for AP-induced weight gain. Metabolomic profiles may identify biomarkers and provide insight into the mechanistic underpinnings of PSDs and antipsychotic-induced weight gain. In this 12-week prospective naturalistic study, we compared serum metabolomic profiles of 25 cases within approximately 1 week of starting an AP to 6 healthy controls at baseline to examine biomarkers of intrinsic metabolic dysfunction in PSDs. In 17 of the case participants with baseline and week 12 samples, we then examined changes in metabolomic profiles over 12 weeks of AP treatment to identify metabolites that may associate with AP-induced weight gain. In the cohort with pre-post data (n = 17), we also compared baseline metabolomes of participants who gained ≥5% baseline body weight to those who gained <5% to identify potential biomarkers of antipsychotic-induced weight gain. Minimally AP-exposed cases were distinguished from controls by six fatty acids when compared at baseline, namely reduced levels of palmitoleic acid, lauric acid, and heneicosylic acid, as well as elevated levels of behenic acid, arachidonic acid, and myristoleic acid (FDR < 0.05). Baseline levels of the fatty acid adrenic acid was increased in 11 individuals who experienced a clinically significant body weight gain (≥5%) following 12 weeks of AP exposure as compared to those who did not (FDR = 0.0408). Fatty acids may represent illness biomarkers of PSDs and early predictors of AP-induced weight gain. The findings may hold important clinical implications for early identification of individuals who could benefit from prevention strategies to reduce future cardiometabolic risk, and may lead to novel, targeted treatments to counteract metabolic dysfunction in PSDs.


Characterisation of aqueous waste produced during the clandestine production of amphetamine following the Leuckart route utilising solid-phase extraction gas chromatography-mass spectrometry and capillary electrophoresis with contactless conductivity detection.
Chemical waste from the clandestine production of amphetamine is of forensic and environmental importance due to its illegal nature which often leads to dumping into the environment. In this study, 27 aqueous amphetamine waste samples from controlled Leuckart reactions performed in Germany, the Netherlands, and Poland were characterised to increase knowledge about the chemical composition and physicochemical characteristics of such waste. Aqueous waste samples from different reaction steps were analysed to determine characteristic patterns which could be used for classification. Conductivity, pH, density, ionic load, and organic compounds were determined using different analytical methods. Conductivity values ranged from 1 to over 200 mS/cm, pH values from 0 to 14, and densities from 1.0 to 1.3 g/cm3 . A capillary electrophoresis method with contactless conductivity detection (CE-C4 D) was developed and validated to quantify chloride, sulphate, formate, ammonium, and sodium ions which were the most abundant ions in the investigated waste samples. A solid-phase extraction sample preparation was used prior to gas chromatography-mass spectrometry analysis to determine the organic compounds. Using the characterisation data of the known samples, it was possible to assign 16 seized clandestine waste samples from an amphetamine production to the corresponding synthesis step. The data also allowed us to draw conclusions about the synthesis procedure and used chemicals. The presented data and methods could support forensic investigations by showing the probative value of synthesis waste when investigating the illegal production of amphetamine. It can also act as starting point to develop new approaches to tackle the problem of clandestine waste dumping.


The Evolving Role and Impact of Integrating Pharmacists into Primary Care Teams: Experience from Ontario, Canada.
The movement to integrate pharmacists into a primary care team-based settings is growing in countries such as Canada, the United States, the United Kingdom, and Australia. In the province of Ontario in Canada, almost 200 pharmacists have positions within interdisciplinary primary care team settings, including Family Health Teams and Community Health Centers. This article provides a narrative review of the evolving roles of pharmacists working in primary care teams, with a focus on evidence from Ontario, as well as drawing from other jurisdictions around the world. Pharmacists within primary care teams are uniquely positioned to facilitate the expansion of the pharmacist's scope of practice, through a collaborative care model that leverages, integrates, and transforms the medication expertise of pharmacists into a reliable asset and resource for physicians, as well as improves the health outcomes for patients and optimizes healthcare utilization.


Elite athletes: is survival shortened in boxers?
Moderate exercise and intense physical training are associated with increased life expectancy (LE). Boxing is characterized by intentional and repetitive head blows, sometimes causing brain injury, possibly reducing LE. We examined a sample of male athletes born between 1860 and 1930 selected from the international "hall of fame" inductees in baseball (n = 154), ice hockey (n = 130), tennis (n = 83), football (n = 81), boxing (n = 81), track and field (n = 59), basketball (n = 58), swimming (n = 37) and wrestling (n = 32). In boxing, we analyzed the number of disputed bouts/rounds and career records. Sports were also analyzed according to physiological demand and occurrence and kind of contact (intentional, unintentional). The Kaplan-Meier product limit method was used to compare survival curves (significance: p <or= 0.05). Median LE of the samples was 76.0 yrs and no differences were observed in different sports, although it was lower in boxers (73.0 yrs) and higher in tennis players (79.0 yrs). Sports of different physiological demand were similar in respect to LE. No differences in LE were found related to occurrence and kind of impact. Similar LE was found in boxers of different weight or career records. In conclusion, this study indicates that LE in top-level athletes is unaffected by the type of discipline, and not related to physiological demand and intentional contact.


[Mechanism of selenium protecting against free radical damages during myocardial ischemia/reperfusion in rats].
To investigate the mechanism of selenium (Se) protecting against free radical damages during myocardial ischemia/reperfusion (I/R) in rats. All rats were separated into three groups: control, organic Se and inorganic Se supplemented groups. Myocardial I/R was established by operation in all three groups. Biochemical assays, atomic absorption spectrophotometry, RT-PCR and cDNA sequence scanning were performed to examine the changes in myocardial MDA level, GSH-Px activity and gene expression, GSH-Px cDNA nucleotide sequence, as well as Se and Ca2+ and Mg2+ concentrations in the heart muscle during I/R. The administration of Se for 7 days did not significantly change the content of Se in the plasma and blood cells. In the two Se-supplemented groups, after reperfusion for 30 minutes, myocardial Se concentration and GSH-Px activity were increased significantly, and GSH-Px expression was elevated with a normal cDNA sequence, and at the same time, MDA contents in the two Se-supplemented groups were lower than that in the control group. Se supplementation can protect against free radical damages during myocardial I/R by increasing myocardial Se content and improving both the expression and activity of GSH-Px.


Long Non-Coding RNA Generated from CDKN1A Gene by Alternative Polyadenylation Regulates p21 Expression during DNA Damage Response.
Alternative Polyadenylation (APA) is an emerging mechanism for dynamic changes in gene expression. Previously, we described widespread APA occurrence in introns during the DNA damage response (DDR). Here, we show that a DNA damage activated APA event occurs in the first intron of CDKN1A , inducing an alternate last exon (ALE)-containing lncRNA. We named this lncRNA SPUD (Selective Polyadenylation Upon Damage). SPUD localizes to polysomes in the cytoplasm and is detectable as multiple isoforms in available high throughput studies. SPUD has low abundance compared to the CDKN1A full-length isoform and is induced in cancer and normal cells under a variety of DNA damaging conditions in part through p53 transcriptional activation. RNA binding protein (RBP) HuR and the transcriptional repressor CTCF regulate SPUD levels. SPUD induction increases p21 protein, but not CDKN1A full-length levels, affecting p21 functions in cell-cycle, CDK2 expression, and cell viability. Like CDKN1A full-length isoform, SPUD can bind two competitive p21 translational regulators, the inhibitor calreticulin and the activator CUGBP1; SPUD can change their association with CDKN1A full-length in a DDR-dependent manner. Together, these results show a new regulatory mechanism by which a lncRNA controls p21 expression post-transcriptionally, highlighting lncRNA relevance in DDR progression and cellcycle.


Immunoregulatory properties of mouse limbal stem cells.
Stem cells have been demonstrated in nearly all adult mammalian tissues and play a vital role in their physiological renewal and healing after injury. Due to their irreplaceable role in tissue repair, these cells had to develop mechanisms protecting them from deleterious inflammatory immune reactions and ensuring their increased resistance to various apoptosis-inducing agents. In this study, we demonstrate that a population of mouse limbal cells highly enriched for cells expressing markers and characteristics of limbal stem cells (LSCs) suppresses in a dose-dependent manner the proliferation of lymphocytes elicited by mitogens or TCR-triggering and significantly inhibits the production of proinflammatory cytokines by activated T cells. The suppression was mediated by soluble factor(s) and did not affect early cell activation. LSCs were even more suppressive than mesenchymal stem cells or natural regulatory T cells. In addition, the cells expressing markers and characteristics of LSC had significantly higher levels of mRNA for Fas ligand and for the antiapoptotic molecules Mcl-1, XIAP, and survivin than other limbal cell populations. LSCs were also more resistant to staurosporin-induced apoptotic cell death and to cell-mediated cytotoxic reaction than other limbal cells. Collectively, these results suggest that SC isolated from fresh adult limbal tissue possess immunomodulatory properties and inhibit proinflammatory immune reactions. Simultaneously, these cells express high levels of mRNA for antiapoptotic molecules, which can protect them against cell-mediated cytotoxic reactions and various apoptosis-inducing agents.


Translation, Validity, and Reliability of the Indonesian Version of the Anterior Cruciate Ligament-Return to Sport After Injury Scale.
The Anterior Cruciate Ligament-Return to Sport After Injury (ACL-RSI) scale measures athletes' emotion, confidence, and risk appraisal when returning to sports after an anterior cruciate ligament (ACL) injury and/or ACL reconstruction (ACLR). To translate the ACL-RSI into the Indonesian language and to assess its validity and reliability in Indonesian-speaking patients after ACLR. Cohort study (diagnosis); Level of evidence, 2. After a forward-and-backward translation procedure, the validity and reliability of the Indonesian version of the ACL-RSI (I-ACL-RSI) were investigated. Patients who had undergone ACLR at a single hospital were asked to complete 4 questionnaires: I-ACL-RSI, Injury-Psychological Readiness to Return to Sport, Tampa Scale of Kinesiophobia, and International Knee Documentation Committee. After a 2-week interval, patients were asked to complete the I-ACL-RSI a second time. Following the COSMIN reporting guidelines (Consensus-Based Standards for the Selection of Health Measurement Instruments), we determined construct validity using hypothesis testing, as well as test-retest reliability, internal consistency, floor and ceiling effects, and measurement error. Of 200 eligible patients, 102 (51%) were included in the analysis. All predefined hypotheses on correlations between the I-ACL-RSI and the other questionnaires were confirmed, indicating good construct validity. An intraclass correlation coefficient of 0.90 (2-way random, type agreement) was found for the first and second I-ACL-RSI scores, indicating good test-retest reliability. A Cronbach α of 0.95 indicated good internal consistency, and no floor or ceiling effects were found. The standard error of measurement was 3.9, with the minimal detectable change calculated as 10.9 points at the individual level and 1.1 points at the group level. Based on the study findings, the I-ACL-RSI can be considered a valid and reliable questionnaire for Indonesian-speaking patients after ACL injury and/or ACLR.


Two subsets of human CD4+ T helper cells differing in kinetics and capacities to produce interleukin 2 and interferon-gamma can be defined by the Leu-18 and UCHL1 monoclonal antibodies.
Human CD4+ T helper cells were separated into CD4+45R+ and CD4+45R- cells. When stimulated with the polyclonal activator staphylococcal enterotoxin A in the presence of autologous monocytes, these two subsets exhibited a striking difference in production of interleukin 2 (IL2) and interferon-gamma (IFN-gamma). While the CD4+45R- subset produced maximal amounts of IL2 within 24 h and IFN-gamma within 72 h, the CD4+45R+ subset produced no IL2 within 24 h and merely marginal amounts of IFN-gamma as assayed after 24 to 96 h. This discrepancy between the subsets was found when the cells were stimulated by other accessory cell-dependent activators and by the accessory-independent combination of the calcium ionophore A23187 and the phorbol ester 12-O-tetradecanoylphorbol 13-acetate as well. The inability of the CD4+45R+ cells to produce IL2 during the first day of culture was not due to any modulation of either the CD4 or the CD45R antigens, as purified CD4+45R+ cells obtained by negative panning selection with the reciprocal UCHL1 monoclonal antibody responded in a similar manner as the positively selected sorted CD4+45R+ cells. Analysis of the kinetics of IL2 production by the two T helper cell subsets clearly demonstrated that the IL2 recorded after 1 day of culture was entirely produced by the CD4+45R- cells, whereas the CD4+45R+ cells produced IL2 during and after the second day of culture. This discrepancy in kinetics was not due to an increased absorption of IL2 by the CD4+45R+ cells during the first day of culture.(ABSTRACT TRUNCATED AT 250 WORDS)


Gene Network Analysis of Glucose Linked Signaling Pathways and Their Role in Human Hepatocellular Carcinoma Cell Growth and Survival in HuH7 and HepG2 Cell Lines.
Cancer progression may be affected by metabolism. In this study, we aimed to analyze the effect of glucose on the proliferation and/or survival of human hepatocellular carcinoma (HCC) cells. Human gene datasets regulated by glucose were compared to gene datasets either dysregulated in HCC or regulated by other signaling pathways. Significant numbers of common genes suggested putative involvement in transcriptional regulations by glucose. Real-time proliferation assays using high (4.5 g/L) versus low (1 g/L) glucose on two human HCC cell lines and specific inhibitors of selected pathways were used for experimental validations. High glucose promoted HuH7 cell proliferation but not that of HepG2 cell line. Gene network analyses suggest that gene transcription by glucose could be mediated at 92% through ChREBP in HepG2 cells, compared to 40% in either other human cells or rodent healthy liver, with alteration of LKB1 (serine/threonine kinase 11) and NOX (NADPH oxidases) signaling pathways and loss of transcriptional regulation of PPARGC1A (peroxisome-proliferator activated receptors gamma coactivator 1) target genes by high glucose. Both PPARA and PPARGC1A regulate transcription of genes commonly regulated by glycolysis, by the antidiabetic agent metformin and by NOX, suggesting their major interplay in the control of HCC progression.


A pilot study of cerebrovascular reactivity autoregulation after pediatric cardiac arrest.
Improved survival after cardiac arrest has placed greater emphasis on neurologic resuscitation. The purpose of this pilot study was to evaluate the relationship between cerebrovascular autoregulation and neurologic outcomes after pediatric cardiac arrest. Children resuscitated from cardiac arrest had autoregulation monitoring during the first 72h after return of circulation with an index derived from near-infrared spectroscopy in a pilot study. The range of mean arterial blood pressure (MAP) with optimal vasoreactivity (MAPOPT) was identified. The area under the curve (AUC) of the time spent with MAP below MAPOPT and MAP deviation below MAPOPT was calculated. Neurologic outcome measures included placement of a new tracheostomy or gastrostomy, death from a primary neurologic etiology (brain death or withdrawal of support for neurologic futility), and change in the Pediatric Cerebral Performance Category score (ΔPCPC). Thirty-six children were monitored. Among children who did not require extracorporeal membrane oxygenation (ECMO), children who received a tracheostomy/gastrostomy had greater AUC during the second 24h after resuscitation than those who did not (P=0.04; n=19). Children without ECMO who died from a neurologic etiology had greater AUC during the first 48h than did those who lived or died from cardiovascular failure (P=0.04; n=19). AUC below MAPOPT was not associated with ΔPCPC when children with or without ECMO were analyzed separately. Deviation from the blood pressure with optimal autoregulatory vasoreactivity may predict poor neurologic outcomes after pediatric cardiac arrest. This experimental autoregulation monitoring technique may help individualize blood pressure management goals after resuscitation.