Cancer trends in Sweden until 2010.
To arrive at a reasonable estimate of the total need for radiotherapy, the various descriptions of population trends and measures of cancer trends must be studied concurrently. Incidence and mortality are well documented by official statistics. All prognoses are based on these measures, the official population statistics, and the 1989 population prognosis from Statistics Sweden. Incidence, mortality, and prevalence may be considered either individually or together as indirect measures of the need for radiotherapy at different stages for different types of cancer. Incidence, ie, the number of cases of disease onset during a given period, shows the indirect need for curative radiotherapy, eg, for breast cancer, laryngeal cancer, gynecological tumor types, and head and neck cancer. The projected average annual mean increase in total incidence is 1.0%. Mortality may be used as an indirect measure of the need for palliative treatment for recurring cancer, eg, for bone metastases, prostate cancer, lung cancer, or breast cancer. The mean increase is estimated at 0.9% per year. Likewise, prevalence can be an indirect measure of the need for palliative treatment for cancer diseases of a chronic nature, eg, prostate cancer and multiple myeloma. The total mean increase per year has been estimated at 2.0%. The total need for radiotherapy in the future should be viewed against the background of all these descriptive measures. Assessment must also consider numerous other factors that directly influence need. A change in the indications for treatment can quickly increase the need for radiotherapy, eg, the benefits of radiotherapy for noninvasive breast cancer are currently being studied. Even a change in the indications for surgical intervention for small tumors in the breast influence the need for primary curative radiotherapy in this large group of patients. Likewise, a shift in staging the primary diagnosis, eg, in head and neck cancer, and changes in fractionation (hyperfractionation) may substantially influence need. This is addressed further in another section of the report. The largest single group of cancer patients who receive radiotherapy are those with bone metastases (25% of the total). The size of this group, and thereby the potential unsatisfied need, is largely unknown since no statistics show the prevalence of metastases in the population. This group is comprised mainly of patients that were primarily diagnosed with prostate cancer, breast cancer, and lung cancer. Concerning lung cancer, incidence trends probably provide the best measure of changes in the number of bone metastases over time. The annual increase in incidence has been estimated at 1.5%. As for breast cancer and prostate cancer, mortality trends provide more information about trends in the number of bone metastases. Both types of cancer increased by 1.9% per year. Chapter 6 presents the types of cancer for which radiotherapy is usually given. The projected trends show that each of these cancer diagnoses, except lung cancer in men and cervical cancer in women, are expected to increase in number until the year 2010. Prevalence is expected to increase even more, particularly cancer in the rectum, breast, and prostate. Also, the number of cases of non-Hodgkin's lymphoma is expected to nearly double by 2010.


Estrogen-induced recovery of autonomic function after middle cerebral artery occlusion in male rats.
Several studies have provided evidence to suggest that estrogen results in a significant reduction (approximately 50%) in the size of the ischemic zone in the middle cerebral artery occlusion (MCAO) model of stroke in a rat. The current study was done to demonstrate whether this estrogen-induced reduction in infarct size is associated with normalization of the autonomic dysfunction observed in an acute model of stroke in male rats. Experiments were done in anesthetized (thiobutabarbitol sodium; 100 mg/kg) male Sprague-Dawley rats instrumented to record baseline and reflex changes in cardiovascular and autonomic parameters. Estrogen was intravenously administered 30 min before, immediately before, or 30 min after MCAO. Estrogen administration resulted in a recovery of autonomic function and prevented the detrimental changes in autonomic tone observed following a stroke. In addition, infarct size was significantly increased in the presence of the estrogen antagonist ICI-182,780. These results suggest that both pre- or poststroke estrogen administration prevents or reverses acute stroke-induced autonomic dysfunction and that endogenous estrogen levels in males can contribute to this neuroprotection.


Draft Genome Sequences of Listeria monocytogenes Serotype 4b Strains 944 and 2993 and Serotype 1/2c Strains 198 and 2932.
Listeria monocytogenes is a foodborne pathogen and the causative agent of listeriosis among humans and animals. The draft genome sequences of L. monocytogenes serotype 4b strains 944 and 2993 and serotype 1/2c strains 198 and 2932 are reported here.


Recovery of Macro and Micro-Nutrients by Hydrothermal Carbonization of Septage.
In this study, septic tank waste (i.e., septage) was hydrothermally carbonized (HTC) in order to recover macro and micronutrients, while tracking the fate of residual heavy metals. Three different HTC temperatures (i.e., 180, 220, and 260 °C) at autogenous pressures and two reaction times (i.e., 30 and 120 min) were applied on both solid and liquid septages. Hydrochar and HTC process liquids were characterized using ICP, CHNS, and UV-vis spectroscopy. Treatment at 260 °C for 120 min maximized ammonia recovery, producing a liquid with 1400 mg/L of ammonia. Overall, about 70% of available nitrogen ended up in the liquid phase as nitrate or ammonia. Solid hydrochars show potential for fertilizer use, with high phosphorus content of 100-130 kg/tonne. It was found that heavy metals mainly remained in the solid phase, although the concentrations of heavy metals are mostly lower than U.S. EPA regulation for biosolids with the exception of selenium.


Predictors of Septic Arthritis in the Adult Population.
Septic arthritis is a devastating condition; well-established criteria for diagnosis exist in the pediatric population, but not for adults. This study evaluated patient factors and laboratory parameters that may be associated with the diagnosis of septic arthritis in adults. A total of 458 knee aspirates for suspected septic arthritis were evaluated with serum and synovial leukocyte counts and differentials as well as Kocher criteria for pediatric septic arthritis. Twenty-two patients (4.8%) had septic arthritis confirmed by a positive synovial fluid culture. Erythrocyte sedimentation rate (ESR) and serum white blood cell (WBC) counts were not statistically different between the 2 groups, with 64% of septic arthritis patients having a normal serum WBC count and 77% being afebrile. Mean synovial fluid WBC count was 26,758 cells/µL and 70,581 cells/µL in the nonseptic and septic groups, respectively. The likelihood ratio for a synovial fluid WBC count greater than 65,000 cells/µL was 2.8 (95% confidence interval, 1.2-6.7). Evaluation receiver operating characteristic curves using synovial WBC counts resulted in a significant area under the curve of 0.66 (P=.02). To achieve 90% specificity, a WBC cutoff of 64,000 cells/µL was required with a corresponding sensitivity of 40%. There was no significant difference in the synovial cell differential of 80% vs 90% in diagnosing infection. Synovial fluid WBC count greater than 64,000 cells/µL yielded the optimal combination of sensitivity and specificity. Polymorphonuclear leukocytes, ESR, serum WBC count, fever, and weight-bearing status were not significant predictors of septic arthritis. This study demonstrates the limited utility of Kocher criteria in the adult population and the importance of synovial leukocyte counts. [Orthopedics. 2016; 39(4):e657-e663.].


Recent Advances in the Core-Annulation of Naphthalene Diimides.
This review focuses on describing all known synthetic strategies leading to core-annulation of naphthalene diimides (NDIs). Strategies presented involve the formation of four-, five- and six-membered ring annulations bearing different heteroatomic and carbocyclic derivatives, including annulenes. The core-annulation method opens the possibility for obtaining designer molecules with tuneable electronic characteristics such as a reduced energy band gap, and enhanced intermolecular overlap of π-systems that improve electronic coupling between molecules-which is highly desirable for charge transport properties summarised in the final pages for applications in electronic devices such as organic field-effect transistors (OFETs) and organic photovoltaic (OPV) cells. Molecular recognition in pH and fluoride sensing, or as a DNA probe, are some of additional applications of core-annulated NDIs presented here. Additionally, recent advances in core modification of NDIs are presented, opening an entire new chemical avenue to be explored. Finally, the outlook on the future prospect of annulated NDIs in various applications is summarised.


Environmental Control of Astrocyte Pathogenic Activities in CNS Inflammation.
Genome-wide studies have identified genetic variants linked to neurologic diseases. Environmental factors also play important roles, but no methods are available for their comprehensive investigation. We developed an approach that combines genomic data, screens in a novel zebrafish model, computational modeling, perturbation studies, and multiple sclerosis (MS) patient samples to evaluate the effects of environmental exposure on CNS inflammation. We found that the herbicide linuron amplifies astrocyte pro-inflammatory activities by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), and X-box binding protein 1 (XBP1). Indeed, astrocyte-specific shRNA- and CRISPR/Cas9-driven gene inactivation combined with RNA-seq, ATAC-seq, ChIP-seq, and study of patient samples suggest that IRE1α-XBP1 signaling promotes CNS inflammation in experimental autoimmune encephalomyelitis (EAE) and, potentially, MS. In summary, these studies define environmental mechanisms that control astrocyte pathogenic activities and establish a multidisciplinary approach for the systematic investigation of the effects of environmental exposure in neurologic disorders.


[Angiocardiographic and clinical development of Carpentier's mitral rings].
Carpentier's ring was inserted in the mitral annulus of 79 patients suffering from mitral valve disease. 49 other patients also underwent surgery on other cardiac valves and are not considered in the present study. The mean follow up time was 19.5 months. The total hospital and late mortality in the isolated ring series was 3.8%. Clinical and hemodynamic improvement was evident postoperatively. The preoperative functional class (NYHA) of the patients was: I, 11.39%; II, 45.5%; III, 34.1%; IV, 8.86% respectively. The postoperative class was: I, 86.8%; II, 7.9%; III, 3.9%; and IV, 1.3% respectively. Postoperative hemodynamic and angiocardiographic evaluation was done in 27 patients. Mean pulmonary artery pressure fell from 49.8 +/- 2.4 mm. Hg to 38 +/- 2 mm. Hg. Mitral regurgitation present preoperatively in 66.6% of cases was present in residual form in only 18.5%. Atrial enlargement was moderate in 42.1% and severe in 57.9% before operation, and 80.3 moderate and 19.7 severe after operation. Tromboembolic accidents occurred in 2 patients (2.2%) both with severe atrial enlargement and atrial fibrillation pre and postoperatively. We conclude that Carpentier's ring is a valid alternative in the surgery of mitral valve disease.


Post-partum leucocytic activity and its relationship to caesarian section and retained placenta.
The activity of the leucocytes of 30 cows during 10 days after parturition is described. A comparison is made between the activity of leucocytes of 10 cows after normal parturition, 10 cows after caesarian section and 10 cows with retained placenta. When compared with normal parturition, caesarian section does not have a negative influence on the activity of the leucocytes during the puerperal period, during which time however the activity of leucocytes of cows with retained placenta is strongly decreased.


Amelanotic melanoma in a patient with oculocutaneous albinism.
Oculocutaneous albinism is a genetically heterogeneous, autosomal recessive group of disorders characterized by a generalized decreased or absence of melanin pigment in the eyes, hair, and skin. These patients have a greater sensitivity to UV radiation and a predisposition to skin tumors, mainly squamous cell carcinoma and basal cell carcinomas, and to a lesser extent malignant melanomas. Melanoma can be one of the most challenging cancers to diagnose in patients with albinism. We report an uncommon clinical presentation of melanoma, an amelanotic melanoma in the right supraciliar region in a patient with oculocutaneous albinism. The clinical presentation was an erythematous, scaly and ill-defined plaque. The skin biopsy revealed a lentigo maligna melanoma. Amelanotic melanomas are one of the two most difficult to diagnose subtypes of melanoma, together with the nevoid type. Melanoma in oculocutaneous albinism patients are often amelanotic, which makes their clinical diagnosis very difficult. These patients should be examined in the dermatology department at least once a year and it is recommended to have a high index of suspicion.


Identification of extensive coronary artery disease: incremental value of exercise Tl-201 SPECT to clinical and stress test variables.
The ability of the size of a total myocardial perfusion defect (MPD) to detect extensive coronary artery disease (CAD) is currently suboptimal with exercise thallium 201 single photon emission computed tomography (SPECT). To improve its performance, exercise electrocardiography and indirect scintigraphic markers of extensive CAD were proposed (increased right ventricular Tl-201 uptake, lung-to-heart [L/H] ratio, and left ventricular transient ischemic dilation ratio). We aimed to determine the additive value of these criteria for the detection of extensive CAD. The population included 338 patients who underwent exercise Tl-201 SPECT and coronary angiography. Patients were classified as having extensive CAD (left main, multivessel, or 1-vessel proximal left anterior descending CAD) or limited CAD (1-vessel disease other than proximal left anterior descending CAD or no CAD). First, Tl-201 SPECT provided higher diagnostic value than exercise electrocardiography. Second, age, percent target heart rate achieved, total MPD, and L/H ratio were independent predictors of extensive CAD. Third, visually estimated abnormal right ventricular Tl-201 uptake did not present additional information. Fourth, L/H ratio presented a higher diagnostic accuracy than left ventricular transient ischemic dilation ratio. With exercise Tl-201 SPECT, age, percent target heart rate achieved, total MPD, and L/H ratio were independent predictors of extensive CAD.


[Interferon-Gamma Release Assays in the diagnosis of latent tuberculosis infection in clinical situations].
Until recently, the basic test to identify latent tuberculosis infection (LTBI) was the tuberculin skin test, despite its limitations in the form of low sensitivity and specificity. Currently, Interferon Gamma Release Assays from peripheral blood are used for a rapid diagnosis of LTBI and measurement of the interferon gamma (IFN-g) levels secreted by specific T cells stimulated with Mycobacterium tuberculosis antigens. Detection of LTBI is important in the control of people potentially at risk of TB disease, such as people remaining in close contact with BK (+) tb patient and for patients evaluated for biological treatment. The paper presents the value of IGRA in three selected clinical situations: in two cases of latent tuberculosis infection and in one case of active tuberculosis.


A costimulatory function for T cell CD40.
CD40 plays a significant role in the pathogenesis of inflammation and autoimmunity. B cell CD40 directly activates cells, which can result in autoantibody production. T cells can also express CD40, with an increased frequency and amount of expression seen in CD4(+) T lymphocytes of autoimmune mice, including T cells from mice with collagen-induced arthritis. However, the mechanisms of T cell CD40 function have not been clearly defined. To test the hypothesis that CD40 can serve as a costimulatory molecule on T lymphocytes, CD40(+) T cells from collagen-induced arthritis mice were examined in parallel with mouse and human T cell lines transfected with CD40. CD40 served as effectively as CD28 in costimulating TCR-mediated activation, including induction of kinase and transcription factor activities and production of cytokines. An additional enhancement was seen when both CD40 and CD28 signals were combined with AgR stimulation. These findings reveal potent biologic functions for T cell CD40 and suggest an additional means for amplification of autoimmune responses.


The determination of linear and angular penetration of the femoral head into the acetabular component as an assessment of wear in total hip replacement: a comparison of four computer-assisted methods.
We have compared four computer-assisted methods to measure penetration of the femoral head into the acetabular component in total hip replacement. These were the Martell Hip Analysis suite 7.14, Rogan HyperOrtho, Rogan View Pro-X and Roman v1.70. The images used for the investigation comprised 24 anteroposterior digital radiographs and 24 conventional acetate radiographs which were scanned to provide digital images. These radiographs were acquired from 24 patients with an uncemented total hip replacement with a follow-up of approximately eight years (mean 8.1; 6.3 to 9.1). Each image was measured twice by two blinded observers. The mean annual rates of penetration of the femoral head measured in the eight-year single image analysis were: Martell, 0.24 (SD 0.19); HyperOrtho, 0.12 (SD 0.08); View Pro-X, 0.12 (SD 0.06); Roman, 0.12 (SD 0.07). In paired analysis of the six-month and eight-year radiographs: Martell, 0.35 (SD 0.22); HyperOrtho, 0.15 (SD 0.13); View Pro-X, 0.11 (SD 0.06); Roman, 0.11 (SD 0.07). The intra- and inter-observer variability for the paired analysis was best for View Pro-X and Roman software, with intraclass correlations of 0.97, 0.87 and 0.96, 0.87, respectively, and worst for HyperOrtho and Martell, with intraclass correlations of 0.46, 0.13 and 0.33, 0.39, respectively. The Roman method proved the most precise and the most easy to use in clinical practice and the software is available free of charge. The Martell method showed the lowest precision, indicating a problem with its edge detection algorithm on digital images.


Characterization of subfractions of autolysosomes isolated from rat liver after leupeptin treatment.
Autolysosomes were isolated from leupeptin-treated rat liver (Furuno, K., Ishikawa, T., & Kato, K. (1982) J. Biochem. 91, 1943-1950). They were disrupted by hypotonic treatment and subfractionated by centrifugation in a discontinuous sucrose gradient into three distinct parts: the membranes, the soluble contents, and the insoluble remnants. The content fraction contained the bulk of the activities of lysosomal enzymes with a protein yield of about 36%. The membrane fraction, representing about 5% of protein of the autolysosomes, had a high specific activity of acid phosphatase. In SDS-polyacrylamide gel electrophoretic analysis, the autolysosomal membranes showed protein profiles similar to those of normal lysosomal membranes. The aggregates of partially digested cellular components, including organelles, in the autolysosomes were recovered as granular materials with a very high density (designated as the remnant fraction). This fraction accounted for more than half of protein of the autolysosomes but contained little of the activities of lysosomal enzymes. Lipid analyses revealed that the autolysosomes were poor in lipids because the lipid content of the insoluble remnants was very low. Measurements of the rate of protein degradation in vitro in the crude lysosomal fraction and the isolated autolysosomes from leupeptin-treated rat liver showed that proteolysis was suppressed within the autolysosomes. It was suggested that lipids of sequestered cellular components were preferentially digested within the autolysosomes due to the inhibition of proteolytic activity by leupeptin, and the resulting massive accumulation of proteins was responsible for the enhanced autolysosomal density.


Loss of Rho-GDIα sensitizes podocytes to lipopolysaccharide-mediated injury.
Nephrotic syndrome is a disease of glomerular permselectivity that can arise as a consequence of heritable or acquired changes to the integrity of the glomerular filtration barrier. We recently reported two siblings with heritable nephrotic syndrome caused by a loss of function mutation in the gene ARHGDIA, which encodes for Rho guanine nucleotide dissociation inhibitor-α (GDIα). GDIs are known to negatively regulate Rho-GTPase signaling. We hypothesized that loss of GDIα sensitizes podocytes to external injury via hyperactivation of Rho-GTPases and p38 MAPK. We examined the response of cultured podocytes with and without knockdown of GDIα to LPS injury by assessing the levels of phospho-p38 as well as the degree of synaptopodin loss. GDIα knockdown podocytes showed more pronounced and sustained p38 phosphorylation in response to LPS compared with control podocytes, and this was blunted significantly by the Rac1 inhibitor. In LPS-treated control podocytes, synaptopodin degradation occurred, and this was dependent on p38, the proteasome, and cathepsin L. In GDIα knockdown podocytes, the same events were triggered, but the levels of synaptopodin after LPS treatment were significantly lower than in control podocytes. These experiments reveal a common pathway by which heritable and environmental risk factors converge to injure podocytes, from Rac1 hyperactivation to p38 phosphorylation and synaptopodin degradation via the ubiquitin-proteasome pathway and cathepsin L.


Physically demanding situations as predictors of disability pensioning with soft tissue rheumatism among persons 30-39 years old in Norway, 1981-90.
Physically demanding work is a predictor of disability pensioning with musculoskeletal diseases. Being a parent is probably also physically demanding. Having manual work and being a parent will be analyzed as possible predictors of becoming a disability pensioner with soft tissue rheumatism (DPSTR) after controlling for level of education, employment, number of hours worked, income, age, sex, and marital status. In this prospective study based on census data of persons 30-39 years old in 1980, predictors of becoming DPSTR during the followup period 1981-90 were identified by logistic regression analysis. Manual work was a predictor for becoming DPSTR for both men and women, while being a parent was neither a risk factor nor a protective factor for becoming DPSTR. Being employed was a predictor of becoming DPSTR for married women, but a protective factor for unmarried women and all men. Low level of education and being married or divorced were predictors of becoming DPSTR for both men and women. Working part time and having low income were predictors of becoming DPSTR among men. Physically demanding employment, but not a physically demanding private life, predicts becoming DPSTR. This may reflect that factors concerning a patient's private life are not taken into account when evaluating whether or not a disability pension should be granted, at least not for patients with uncertain medical conditions.


Development and validation of the PROMIS Pediatric Sleep Disturbance and Sleep-Related Impairment item banks.
To develop and evaluate the measurement properties of child-report and parent-proxy versions of the Patient-Reported Outcomes Measurement Information System (PROMIS) Pediatric Sleep Disturbance and Sleep-Related Impairment item banks. A national sample of 1104 children (8-17 years old) and 1477 parents of children 5-17 years old was recruited from an internet panel to evaluate the psychometric properties of 43 sleep health items. A convenience sample of children and parents recruited from a pediatric sleep clinic was obtained to provide evidence of the measures' validity; polysomnography data were collected from a subgroup of these children. Factor analyses suggested two dimensions: sleep disturbance and daytime sleep-related impairment. The final item banks included 15 items for Sleep Disturbance and 13 for Sleep-Related Impairment. Items were calibrated using the graded response model from item-response theory. Of the 28 items, 16 are included in the parallel PROMIS adult sleep health measures. Reliability of the measures exceeded 0.90. Validity was supported by correlations with existing measures of pediatric sleep health and higher sleep disturbance and sleep-related impairment scores for children with sleep problems and those with chronic and neurodevelopmental disorders. The sleep health measures were not correlated with results from polysomnography. The PROMIS Pediatric Sleep Disturbance and Sleep-Related Impairment item banks provide subjective assessments of child's difficulty falling and staying asleep as well as daytime sleepiness and its impact on functioning. They may prove useful in the future for clinical research and practice. Future research should evaluate their responsiveness to clinical change in diverse patient populations.


Effects of endothelin on peptide-dependent cyclic adenosine monophosphate accumulation along the nephron segments of the rat.
We investigated the tubular action of endothelin in rat nephron segments. The effects of endothelin on arginine vasopressin (AVP)-, parathyroid hormone-, glucagon-, calcitonin-, and isoproterenol-dependent cAMP accumulation were studied. The following nephron segments were microdissected: glomerulus (Gl), proximal convoluted tubule (PCT), cortical and medullary thick ascending limbs of Henle's loop (cTAL and mTAL, respectively), cortical collecting duct (CCD), outer medullary collecting duct (OMCD), and inner medullary collecting duct (IMCD). Endothelin dose dependently (10(-8)-10(-10)M) inhibited AVP-dependent cAMP accumulation in CCD, OMCD, and IMCD. This effect was independent of the presence or absence of phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, Ca channel blocker nicardipine, or indomethacin, but was abolished in the presence of protein kinase C inhibitor H-7. Protein kinase C stimulator dioctanoyl glycerol mimicked the effect of endothelin. On the other hand, endothelin had no inhibitory effect on AVP-dependent cAMP accumulation in cTAL or mTAL, parathyroid hormone-dependent cAMP accumulation in Gl and PCT, or glucagon-, calcitonin-, and isoprotereol-dependent cAMP accumulation in OMCD. We conclude that endothelin specifically inhibits AVP-dependent cAMP accumulation in CCD, OMCD, and IMCD through activating protein kinase C. This effect possibly has a role in maintaining urine volume to counteract the decrease in GFR caused by endothelin itself.


A new morphological trait in forensic identification - middle phalangeal hair (MPH).
Middle phalangeal hairs (MPH) are present on the dorsal aspect of the middle phalange of the fingers except for the thumb. The MPH have been of interest to anthropologists, human biologists, clinicians, geneticists and anatomists in the past as a morphological trait of the human body. The anthropological value of MPH is well established in studying population variations, with implications for age, ancestry and sex differences. We are of the opinion that MPH may be used significantly for forensic identification purposes along with other morphological characteristics of the human body. MPH can be one of the individualistic features in comparing the ante-mortem and post-mortem records in mass fatality incidents and in establishing identity in forensic casework pertaining to CCTV images of the hand.


Application of statistical process control in healthcare improvement: systematic review.
To systematically review the literature regarding how statistical process control--with control charts as a core tool--has been applied to healthcare quality improvement, and to examine the benefits, limitations, barriers and facilitating factors related to such application. Original articles found in relevant databases, including Web of Science and Medline, covering the period 1966 to June 2004. From 311 articles, 57 empirical studies, published between 1990 and 2004, met the inclusion criteria. A standardised data abstraction form was used for extracting data relevant to the review questions, and the data were analysed thematically. Statistical process control was applied in a wide range of settings and specialties, at diverse levels of organisation and directly by patients, using 97 different variables. The review revealed 12 categories of benefits, 6 categories of limitations, 10 categories of barriers, and 23 factors that facilitate its application and all are fully referenced in this report. Statistical process control helped different actors manage change and improve healthcare processes. It also enabled patients with, for example asthma or diabetes mellitus, to manage their own health, and thus has therapeutic qualities. Its power hinges on correct and smart application, which is not necessarily a trivial task. This review catalogs 11 approaches to such smart application, including risk adjustment and data stratification. Statistical process control is a versatile tool which can help diverse stakeholders to manage change in healthcare and improve patients' health.


The in vitro antibacterial activity of ceftriaxone against Streptococcus pyogenes is unrelated to penicillin-binding protein 4.
The in vitro activities of penicillin and ceftriaxone were compared against 29 strains of Streptococcus pyogenes with the result that ceftriaxone showed greater activity than penicillin. The morphological changes induced by 1/2 and 1x MIC concentrations of penicillin and ceftriaxone, respectively, were very similar using scanning electron microscopy. Competitive binding studies using 'cold' penicillin or ceftriaxone as inhibitors of radiolabeled penicillin binding demonstrated that ceftriaxone had a very low affinity for penicillin binding protein (PBP) 4 compared to that of penicillin. Since ceftriaxone had greater antibacterial activity, this suggests that PBP 4 may not be important to the in vitro activity of ceftriaxone. In contrast, the IC50 for ceftriaxone was much lower (> 200 fold) for PBPs 2 and 3 compared to PBP 4, suggesting greater avidity of these high molecular mass PBPs for ceftriaxone. These data may at least in part explain the superior in vitro activity of ceftriaxone compared to penicillin against S. pyogenes. These data, together with the observation that PBP 1 was saturated at a lower concentration of penicillin than any of the other PBPs, suggest that the inhibition of PBPs 1, 2, and 3 mediates the bactericidal activity of beta-lactam antibiotics against group A streptococci.


[Gastrocolic fistula. Diagnosis by endoscopy].
We present a case of gastrocolic fistula secondary to a benign gastric ulcer. In our Knowledge, this is the first reported case with an endoscopic diagnosis using the video-system; we did a complementary upper radiological series with oral contrast. This patient was treated with a subtotal gastrectomy and primary closure of the colonic defect.


The GATA-Type Transcription Factor Csm1 Regulates Conidiation and Secondary Metabolism in Fusarium fujikuroi.
GATA-type transcription factors (TFs) such as the nitrogen regulators AreA and AreB, or the light-responsive TFs WC-1 and WC-2, play global roles in fungal growth and development. The conserved GATA TF NsdD is known as an activator of sexual development and key repressor of conidiation in Aspergillus nidulans, and as light-regulated repressor of macroconidia formation in Botrytis cinerea. In the present study, we functionally characterized the NsdD ortholog in Fusarium fujikuroi, named Csm1. Deletion of this gene resulted in elevated microconidia formation in the wild-type (WT) and restoration of conidiation in the non-sporulating velvet mutant Δvel1 demonstrating that Csm1 also plays a role as repressor of conidiation in F. fujikuroi. Furthermore, biosynthesis of the PKS-derived red pigments, bikaverin and fusarubins, is de-regulated under otherwise repressing conditions. Cross-species complementation of the Δcsm1 mutant with the B. cinerea ortholog LTF1 led to full restoration of WT-like growth, conidiation and pigment formation. In contrast, the F. fujikuroi CSM1 rescued only the defects in growth, the tolerance to H2O2 and virulence, but did not restore the light-dependent differentiation when expressed in the B. cinerea Δltf1 mutant. Microarray analysis comparing the expression profiles of the F. fujikuroi WT and the Δcsm1 mutant under different nitrogen conditions revealed a strong impact of this GATA TF on 19 of the 47 gene clusters in the genome of F. fujikuroi. One of the up-regulated silent gene clusters is the one containing the sesquiterpene cyclase-encoding key gene STC1. Heterologous expression of STC1 in Escherichia coli enabled us to identify the product as the volatile bioactive compound (-)-germacrene D.


Traumatic bilateral hip dislocation with bilateral sciatic nerve palsy.
Bilateral hip dislocation rarely occurs. In this paper, a case of bilateral hip dislocation associated with bilateral sciatic nerve palsy resulted from a road traffic accident is reported. Both hips were emergently reduced under general anaesthesia. Acetabular reconstruction was done bilaterally due to the unstable hips. The patient subsequently developed heterotopic ossification and avascular necrosis on the left hip and underwent total hip arthroplasty. The sciatic nerve on the right side achieved complete recovery but that on the left side only partly recovered and was augmented by tendon transfer. Such injuries are serious and one should be aware of the complications because they can resurface and so patients should be followed up for a long time. To the best of our knowledge, this kind of injury has not been reported in the English language literature.


Silencing of AJAP1 expression by promoter methylation activates the Wnt/β-catenin signaling pathway to promote tumor proliferation and metastasis in salivary adenoid cystic carcinoma.
Salivary adenoid cystic carcinoma (SACC) is a unique malignant tumor of the salivary gland with poor prognosis, which is not effective with chemotherapy and targeted drugs. Therefore, it is important to explore the molecular mechanism underlying SACC invasion and metastasis to develop novel therapeutic strategies and targets in clinical research. Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were performed to detect the expression of Adherens Junctions Associated Protein 1 (AJAP1). Methylation-specific PCR was used to evaluate the methylation of the AJAP1 promoter. AJAP1 was overexpressed or knocked down by lentivirus-mediated transfection. Kaplan-Meier analysis was conducted to create a survival curve and the log-rank test was used to analyze the overall survival (OS). The prognostic correlation was assessed using univariate and multivariate Cox regression analyses. Co-immunoprecipitation (Co-IP) was utilized to pull down the possible binding protein of AJAP1 and laser scanning confocal microscopy was applied to detect the subcellular localization of AJAP1, E-cadherin, and β-catenin. Cell viability, colony formation, wound healing, and Transwell invasion assays were performed to evaluate the function of AJAP1 in vitro. A subcutaneous xenograft assay in nude mice was performed to verify the function of AJAP1 in vivo. AJAP1 was downregulated in SACC tumors and was closely related to SACC lymph node/distant metastasis, which was an independent risk factor for SACC prognosis. Methylation-specific PCR confirmed that high methylation of the AJAP1 promoter was the main cause of its silencing. Overexpression or knockdown of AJAP1 in SACC cells could significantly inhibit or promote the proliferation, invasion, and metastasis of SACC cells, respectively, in both the in vitro and in vivo experiments. Mechanically, we found that AJAP1 binds to E-cadherin and β-catenin to form a complex in cytomembrane, reducing the nuclear translocation of β-catenin and blocking the Wingless/Integrated/β-catenin (Wnt/β-catenin) signaling pathway to play a suppressive role in cancer. In conclusion, these results suggest that the downregulation of AJAP1 protein expression may play a certain role in progression and metastasis of SACC. Our study indicates that AJAP1 may be a potential prognostic molecular marker and therapeutic target for SACC.


A possible association between ZNRD1 and aspirin-induced airway bronchoconstriction in a Korean population.
The etiology of aspirin-exacerbated respiratory disease (AERD) has been attributed to the combination of environmental and genetic risk factors. Although widely investigated in various diseases associated with immune dysfunction, the human zinc ribbon domain containing 1 (ZNRD1) gene is thought to play a role in the pathogenesis of AERD by altering the mechanisms involved in disease development. We selected 6 single-nucleotide polymorphisms (SNPs) for genotyping from the International HapMap database in order to analyze the association between polymorphisms in ZNRD1 and AERD in a Korean asthma cohort. Genotyping was carried out using the TaqMan assay, and differences in genotype frequency distributions were analyzed using logistic regression models. Nominal associations were found between ZNRD1 rs1150740 and risk ofAERD via codominant and dominant genetic inheritance (P=.03; odds ratio, 1.14 [1.14-10.16]). The same polymorphism was found to be significantly associated with a decrease in forced expiratory volume in the first second of expiration, an important diagnostic marker of AERD, even after multiple testing corrections (P=.006, P(corr)=.03 in codominant and dominant models). These preliminary findings suggest a possible relationship between ZNRD1 and aspirin-induced respiratory dysfunctions in a Korean population and provide essential information on the etiology of AERD.


Melanoma cell adhesion molecule stimulates yes-associated protein transcription by enhancing CREB activity via c-Jun/c-Fos in hepatocellular carcinoma cells.
Dysfunction of the yes-associated protein (YAP) signaling pathway has previously been associated with liver tumorigenesis. Recently, the membrane protein melanoma cell adhesion molecule (MCAM) was identified as a novel, hepatocellular carcinoma (HCC)-specific YAP target protein that promotes carcinogenesis in HCC. However, whether MCAM conversely regulates YAP remains unknown. The aim of the current study was to demonstrate whether and how MCAM regulates YAP in HCC cells. The present study demonstrated that MCAM has a positive effect on the regulation of YAP activity and expression. Mechanistically, MCAM stimulated YAP transcription through its downstream effector c-Jun/c-Fos heterodimer. Gain and loss of function analysis by the present study indicated that c-Jun/c-Fos is capable of inducing cAMP response element-binding protein activation, which is a transcription factor that directly binds to the YAP promoter. Finally, it was identified that an impaired transformative phenotype in MCAM- or c-Jun/c-Fos-depleted HCC cells could be partially rescued by simultaneous overexpression of YAP, suggesting that YAP may function as a downstream effector of the MCAM-c-Jun/c-Fos signaling pathway. Collectively, a complete, positive, auto-regulatory loop was established by the present study, in which YAP is not only an upstream regulator, but also a downstream target of MCAM in HCC cells.


[The role of the hospital in the light of the new trends of medical education].
This article sets forth an innovative concept of the hospital's role today in keeping with both contemporary medical education and various national health service needs. After pointing out that the groundwork for a proper integration of training and service goals lies in the principles of medical preparation, the author emphasizes that although health care is provided in the home, in health centers, in outpatients clinics, and in general and specialized hospitals, the future physician's education is primarily the responsibility of universities, medical schools, and departments, which during the clinical phase of training become demonstration clinics atypical of the conditions at the many levels of health services. The combining of teaching and service-essential for the training of a better prepared professional, ready to handle any problem that might arise in the course of his career-is the keystone of this new approach. In other words, the author stresses "early student involvement in all levels of medical care within a particular health region, especially primary care, and a relatively lengthy period of work in direct relationship with the community hospital, supplemented by short periods in specialized hospitals or reference units."


How I treat type 2B von Willebrand disease.
Type 2B von Willebrand disease (VWD) is an inherited bleeding disorder caused by changes in von Willebrand factor (VWF) that enhance binding of VWF to GPIb on platelets. Although this disorder is seemingly well defined because of this single molecular defect, in reality type 2B VWD is a clinically heterogeneous disorder that can be difficult to identify and manage. Diagnostic criteria include a history of mucocutaneous bleeding, laboratory studies showing enhanced VWF binding of platelets and/or a 2B VWD genetic variant, and a family history consistent with autosomal dominant inheritance. Thrombocytopenia, although not always present, is common and can be exacerbated by physiologic stressors such as pregnancy. The mainstay of therapy for type 2B VWD is VWF replacement therapy. Adjunct therapies useful in other types of VWD, such as antifibrinolytics, are also used in type 2B VWD. 1-Desamino-8-d-arginine vasopressin (DDAVP) is controversial because of exacerbation of thrombocytopenia, but is, in practice, sometimes used for minor bleeding. Here we review the available evidence and provide 3 clinical cases to illustrate the intricacies of diagnosing type 2B VWD to describe the response to DDAVP and to review complexities and management during pregnancy.


[Preemptive analgesia produced with epidural analgesia administered prior to surgery].
The effect of epidural analgesia administered before or during surgery on postoperative pain relief using continuous epidural infusion of the mixture of local anesthetics and narcotics was studied. Ninety patients undergoing abdominal hysterectomy were randomly allocated to three groups; thirty patients of group 1 who received general anesthesia alone, thirty patients of group 2 with epidural analgesia 20 min before the end of surgery under general anesthesia and thirty patients of group 3 with epidural analgesia plus general anesthesia before surgery. Epidural analgesia was induced with 2% mepivacaine solution 15 ml without epinephrine in group 2 and 3, and in group 3 followed with 5 ml of the same solution at one-hour intervals. General anesthesia was induced with thiamylal and maintained with nitrous oxide, oxygen and sevoflurane. Immediately after surgery, 5 ml of the mixture of 0.225% bupivacaine and 0.0005% fentanyl was injected epidurally and followed with continuous infusion of the same mixture at the rate of 2.1 ml.h-1 over 24 h. Visual analogue score and Prince-Henry score were significantly less in group 3 than in group 1 and group 2 at 4 hours and 24 hours after surgery (P < 0.01, P < 0.05 respectively). These results suggest that postoperative continuous epidural analgesia is more effective if the entrance of noxious stimuli into the central neural system is prevented by preincisional epidural block.


On a spatially resolving USAXS instrument for operation at a third-generation synchrotron radiation source.
A point-collimation USAXS system based on the Bonse-Hart-diffractometer concept is proposed which takes advantage of a CCD detector to rapidly obtain two-dimensional SAXS data at both high spatial and angular resolution for a line of points on the sample. The method might typically be employed using Bonse-Hart crystal optics in the horizontal plane, encompassing the high-angular-resolution scan direction, and a condensing monochromator in the out-of-diffraction-plane direction as the basis for a pinhole SAXS camera in that plane. The new system is well suited to operation at an undulator beamline on a third-generation synchrotron radiation source. Other applications of the instrument include (i) both absorption and phase-contrast imaging/tomography, (ii) polycrystalline topography, (iii) high-resolution triple-crystal measurements and (iv) diffuse scattering measurements.


Changes of matrix metalloproteinase-9 level is associated with left ventricular remodeling following acute myocardial infarction among patients treated with trandolapril, valsartan or both.
Inhibition of the renin-angiotensin system (RAS) with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) can suppress left ventricular (LV) remodeling after acute myocardial infarction (AMI), possibly through the modifications of matrix metalloproteinase (MMP)-9. Whether LV remodeling is suppressed in association with MMP-9 suppression in post-AMI/-percutaneous coronary intervention (PCI) patients treated with ACE inhibitor and/or ARB was examined. The presence of any differences in LV remodeling and MMP-9 levels across the groups was also investigated. Sixty-five patients were initiated into each of 3 treatments; trandolapril, valsartan or a combination of both (half-dose-trandolapril plus half-dose-valsartan). Changes in MMP-9, LV end-diastolic and end-systolic volume index (LVEDVI and LVESVI) after 12 months were assessed. Overall, MMP-9 significantly decreased, although neither LVEDVI nor LVESVI increased significantly. DeltaMMP-9 was significantly correlated with DeltaLVEDVI (r=0.36) or DeltaLVESVI (r=0.39). In comparison, across groups, it was found that MMP-9, LVEDVI and LVESVI at 12 months were significantly lower in the combination therapy group than in the trandolapril group. There were no significant differences between the valsartan group and combination therapy group, or between the valsartan group and the trandolapril group. LV remodeling might be suppressed in association with MMP-9 suppression in AMI patients treated with PCI and regular dose or half-dose-combination of RAS inhibitors. Furthermore, a half-dose-combination might suppress LV remodeling more effectively than trandolapril alone.


siRNA delivery system based on magnetic nanovectors: Characterization and stability evaluation.
Gene therapy and particularly small interfering RNA (siRNA) is a promising therapeutic method for treatment of various human diseases, especially cancer. However the lack of an ideal delivery system limits its clinical applications. Effective anticancer drug development represents the key for translation of research advances into medicines. Previously we reported, the optimization of magnetic siRNA nanovectors (MSN) formulation based on superparamagnetic iron oxide nanoparticles (SPION) and chitosan for systemic administration. This work aimed at using rational design to further optimize and develop MSN. Therefore, formulated MSN were first purified, then their physical and chemical properties were studied mainly through capillary electrophoresis. 95% of siRNA was found enclosed within the purified MSN (pMSN). pMSN showed colloidal stability at pH 7.4, effective protection of siRNA against ribonuclease degradation up to 24 hours and few siRNA release (less than 10%) at pH 7.4. These findings push toward further evaluation studies in vitro and/or in vivo, indicating the appropriateness of pMSN for cancer theranostics.


Extensive right-sided endocarditis in double-chamber right ventricle presented with leukocytoclastic vasculitis.
Congenital heart disease is a risk factor for infective endocarditis (IE). Ventricular septal defects and ventricular outflow tract obstructions are this population's most common causes of endocarditis. We present a patient diagnosed with leukocytoclastic vasculitis, renal, and pulmonary involvement with right-sided IE as an etiology for vasculitis.


Sphingosylphosphorylcholine antagonizes proton-sensing ovarian cancer G-protein-coupled receptor 1 (OGR1)-mediated inositol phosphate production and cAMP accumulation.
Ovarian cancer G-protein-coupled receptor 1 (OGR1), previously proposed as a receptor for sphingosylphosphorylcholine (SPC), has recently been identified as a proton-sensing or extracellular pH-responsive G-protein-coupled receptor stimulating inositol phosphate production, reflecting the activation of phospholipase C. In the present study, we found that acidic pH stimulated cAMP accumulation, reflecting the activation of adenylyl cyclase, in addition to inositol phosphate production in OGR1-expressing cells. The cAMP response was hardly affected by the inhibition of phospholipase C. SPC inhibited the acidification-induced actions in a pH-dependent manner, while no OGR1-dependent agonistic action of SPC was observed. Thus, the dose-response curves of the proton-induced actions were shifted to the right in the presence of SPC regardless of stereoisoform. The antagonistic property was also observed for psychosine and glucosylsphingosine. In conclusion, OGR1 stimulation may lead to the activation of adenylyl cyclase in addition to phospholipase C in response to extracellular acidification but not to SPC. However, SPC and related lysolipids antagonize the proton-induced and OGR1-mediated actions.


Ketamine induces brain-derived neurotrophic factor expression via phosphorylation of histone deacetylase 5 in rats.
Ketamine shows promise as a therapeutic agent for the treatment of depression. The increased expression of brain-derived neurotrophic factor (BDNF) has been associated with the antidepressant-like effects of ketamine, but the mechanism of BDNF induction is not well understood. In the current study, we demonstrate that the treatment of rats with ketamine results in the dose-dependent rapid upregulation of Bdnf promoter IV activity and expression of Bdnf exon IV mRNAs in rat hippocampal neurons. Transfection of histone deacetylase 5 (HDAC5) into rat hippocampal neurons similarly induces Bdnf mRNA expression in response to ketamine, whereas transfection of a HDAC5 phosphorylation-defective mutant (Ser259 and Ser498 replaced by Ala259 and Ala498), results in the suppression of ketamine-mediated BDNF promoter IV transcriptional activity. Viral-mediated hippocampal knockdown of HDAC5 induces Bdnf mRNA and protein expression, and blocks the enhancing effects of ketamine on BDNF expression in both unstressed and stressed rats, and thereby providing evidence for the role of HDAC5 in the regulation of Bdnf expression. Taken together, our findings implicate HDAC5 in the ketamine-induced transcriptional regulation of Bdnf, and suggest that the phosphorylation of HDAC5 regulates the therapeutic actions of ketamine.


Edge-Terminated MoS2 Nanoassembled Electrocatalyst via In Situ Hybridization with 3D Carbon Network.
Transition metal dichalcogenides, especially MoS2 , are considered as promising electrocatalysts for hydrogen evolution reaction (HER). Since the physicochemical properties of MoS2 and electrode morphology are highly sensitive factor for HER performance, designed synthesis is highly pursued. Here, an in situ method to prepare a 3D carbon/MoS2 hybrid catalyst, motivated by the graphene ribbon synthesis process, is reported. By rational design strategies, the hybrid electrocatalysts with cross-connected porous structure are obtained, and they show a high HER activity even comparable to the state-of-the-art MoS2 catalyst without appreciable activity loss in long-term operations. Based on various physicochemical techniques, it is demonstrated that the synthetic procedure can effectively guide the formation of active site and 3D structure with a distinctive feature; increased exposure of active sites by decreased domain size and intrinsically high activity through controlling the number of stacking layers. Moreover, the importance of structural properties of the MoS2 -based catalysts is verified by controlled experiments, validating the effectiveness of the designed synthesis approach.


Axonal regeneration and sprouting following injury to the cerebral-buccal connective in the snail Achatina fulica.
Axonal sprouting and regeneration were studied in the land snail Achatina fulica following a unilateral crush to the cerebral-buccal connective. Both normal projection patterns and changes induced by injury were examined with axonal filling techniques. As expected, most staining was lost shortly after the crush when filling across the lesion site. Much of this decrease is attributable to the direct disruption of fiber pathways, but evidence also indicates that a limited amount of retraction of some neurites occurred during the first week. A subsequent, gradual increase in the numbers of stained elements culminated in supernumerary counts of fibers in many pathways and in some novel labeling of cell bodies. Maximum numbers of supernumerary fibers usually occurred 21-28 days after the lesion. Most of these extra neurites and cell bodies subsequently disappeared, and by day 35 the appearance of projections generally returned to within the ranges observed in normal, unlesioned animals. Together the results demonstrate the extent of neuritic regeneration, sprouting, and retraction that occurs in vivo within the gastropod nervous system following injury. The study also indicates the usefulness of such in vivo approaches to understand the long-term processes that contribute to the restoration of morphological and functional integrity.


Brain Tissue Oxygen and BOLD fMRI Under Different Levels of Neuronal Activity.
Localized increases in neuronal activity are supported by the hemodynamic response, which delivers oxygen to the brain tissue to support synaptic functions, action potentials and other neuronal processes. However, it remains unknown if changes in baseline neuronal activity, which are expected to reflect neuronal metabolic demand, alter the relationship between the local hemodynamic and oxygen behaviour. In order to better characterize this system, we examine here the relationship between brain tissue oxygen (PO2) and hemodynamic responses (BOLD functional MRI) under different levels of neuronal activity. By comparing the stimulus-evoked responses during different levels of baseline neuronal activity, the awake state vs isoflurane anesthesia, we were able to measure how a known change in neuronal demand affected tissue PO2 as well as the hemodynamic response to stimulation. We observed a high correlation between stimulus-evoked PO2 and BOLD responses in the awake state. Moreover, we found that the evoked PO2 and BOLD responses were still present despite the elevated tissue oxygen baseline and decreased baseline of neuronal activity under low concentration isoflurane, and that the magnitudes of these responses decreased by similar proportions but the relationship between these signals was distorted. Our findings point to distortion of the BOLD-PO2 relationship due to anesthesia. The feedback mechanism to adjust the level of brain tissue oxygen, as well as the correlation between BOLD and PO2 responses, are impaired even by a small dose of anesthetics.


Size hierarchy and stability in competitive plant populations.
A neighbourhood-based competition model for plant individuals is studied to evaluate how a hierarchical structure related to size may emerge in plant communities. It is shown by numerical simulations and linear stability analysis that many stable states exist in the hierarchical structure when both the total number of individuals and the degree of asymmetry of competition are high. When the hierarchical structures are self-organized by the dynamic instability of the homogeneous state due to non-linearity of competition, it is proved that these states are always locally stable. The relevance of the results to size structures in real plant communities (boreal forests vs tropical and temperate forests) is discussed. This is suggested to be the mechanism responsible for the coexistence of species in plant communities.


Rational Design of Single-Atom Site Electrocatalysts: From Theoretical Understandings to Practical Applications.
Atomically dispersed metal-based electrocatalysts have attracted increasing attention due to their nearly 100% atomic utilization and excellent catalytic performance. However, current fundamental comprehension and summaries to reveal the underlying relationship between single-atom site electrocatalysts (SACs) and corresponding catalytic application are rarely reported. Herein, the fundamental understandings and intrinsic mechanisms underlying SACs and corresponding electrocatalytic applications are systemically summarized. Different preparation strategies are presented to reveal the synthetic strategies with engineering the well-defined SACs on the basis of theoretical principle (size effect, metal-support interactions, electronic structure effect, and coordination environment effect). Then, an overview of the electrocatalytic applications is presented, including oxygen reduction reaction, hydrogen evolution reaction, oxygen evolution reaction, oxidation of small organic molecules, carbon dioxide reduction reaction, and nitrogen reduction reaction. The underlying structure-performance relationship between SACs and electrocatalytic reactions is also discussed in depth to expound the enhancement mechanisms. Finally, a summary is provided and a perspective supplied to demonstrate the current challenges and opportunities for rational designing, synthesizing, and modulating the advanced SACs toward electrocatalytic reactions.


Subcellular localization of alpha-tocopherol and its effect on RNA synthesis in perfused rabbit heart.
3H-tocopherol was administered by perfusion to rabbit hearts and rapidly entered the myocardial cells with an incorporation rate which was more evident inthe alpha-tocopherol deficient hearts than in the control hearts. During perfusion, the labelled alpha-tocopherol was slightly metabolized and 85% of the radioactivity was recovered as authentic alpha-tocopherol. The pattern of alpha-tocopherol distribution showed in both perfused hearts a significant binding of the radioactivity to the nuclei. The vitamin was also retained with high specific labelling in the mitochondria and in a lower degree in the microsomes and soluble fractions. Small amounts of radioactivity was found bound to the myofibrils. The study of the intranuclear distribution of tocopherol has revealed that the tocopherol-binding species were acidic nuclear macromolecules which exhibited characteristics of non-histone chromosomal proteins. Administration of alpha-tocopherol exhibited a positive effect on the stimulation of labelled RNA in the tocopherol-deficient perfused hearts. This was particularly evident at the nuclear level. The intracellular distribution of the vitamin and its ability to stimulate RNA synthesis in heart muscle can suggest a possible role of alpha-tocopherol in the regulation of gene activity.


Direct oral anticoagulants compared to vitamin K antagonist for the management of left ventricular thrombus.
Left ventricular (LV) thrombus is increasingly detected in patients with and without ischaemic heart disease due to the increased availability of cardiac magnetic resonance imaging. Risk factors include anterior ST elevation myocardial infarction, delayed reperfusion therapy, and non-ischaemic cardiomyopathy with severe LV systolic dysfunction. We aimed to report the characteristics and outcomes of patients with LV thrombus treated with either vitamin K antagonist (VKA) or direct oral anticoagulants (DOAC) with a view to describing differences in efficacy, specifically, subsequent thromboembolic events, thrombus resolution, and also side effects of therapy including clinically significant bleeding. We conducted a retrospective, observational cohort study of patients diagnosed with LV thrombus between 1 December 2012 and 30 June 2018 and treated with either DOAC or VKA. We recorded patient demographics, past medical history, prescribed medications, and baseline investigations. The primary outcomes were rates of thromboembolism and clinically significant bleeding, with secondary outcomes of thrombus resolution on repeat cardiac imaging, repeat hospitalization, and all-cause mortality. During the study period, 84 patients were diagnosed with and managed for LV thrombus. Of these, 62 received VKA and 22 DOAC including 13 prescribed rivaroxaban, eight apixaban, and one dabigatran. Most patients 75 (89%) were male with an average age of 62 ± 14 years. Ischaemic heart disease was the cause of LV impairment in 73 (87%) patients. Baseline characteristics were similar between groups at baseline. Most n = 55 (65%) were co-prescribed a single antiplatelet agent and 32 (38%) received dual-antiplatelet therapy. During an average follow-up of 3.0 ± 1.4 years, there were no statistically significant differences between VKA and DOAC in rates of stroke (2% vs. 0%, P = 0.55), other thromboemboli (2% vs. 0%, P = 0.55), or clinically significant bleeding (10% vs. 0%, P = 0.13). The average interval to cardiac imaging follow-up was 233 ± 251 days and was not different between groups (P = 0.83), and there was no difference in the rate of resolution of thrombus (76% vs. 65% P = 0.33). Rehospitalization (50% vs. 45%: P = 0.53) and all-cause mortality (10% vs. 14%; P = 0.61) were also similar. Our data suggest that DOACs are likely to be at least as effective and safe as VKA for stroke prevention in patients with LV thrombus and, despite their lack of a licence for this indication, are therefore likely to represent a reasonable and more convenient option for this setting. The optimal timing and type of anticoagulation for LV thrombus, as well as the role of screening for high-risk patients, should be tested in prospective, randomized trials.


Safety evaluation of eleven insecticides to Trichogramma nubilale (Hymenoptera: Trichogrammatidae).
The safety of 11 pesticides (indoxacarb, chlorfluazuron, azadirachtin, methoxyfenozide, rotenone, spinosad, acetamiprid, imidacloprid, chlorfenapyr, chlorpyrifos, and triazophos) to Trichogramma nubilale (Hymenoptera: Trichogrammatidae) was evaluated in this study. The acute toxicity to the adults was investigated using dry-film method. The influences of the pesticides on both parasitic ability and different developmental stages were studied using corn leaves residual method, rice moth egg card dipping method, and T. nubilale parasitized rice moth egg dipping method. Results showed that methoxyfenozide, azadirachtin, and indoxacarb were safe for the whole life cycle of T. nubilale. Chlorfluazuron, rotenone, and acetamiprid had different levels of impacts on different developmental stages, and they should be chosen to be used according to their safety time with reduced exposure levels. Rotenone was safe for the adults but it was harmful to the other stages, whose dosage should be reduced when it was used. Acetamiprid could be applied during the pupae stage. Finally, to avoid large kill, spinosad, chlorfenapyr, chlorpyrifos, triazophos, and imidacloprid should not be used as they were not safe for any development stage of T. nubilale.


Influenza HA subtypes demonstrate divergent phenotypes for cleavage activation and pH of fusion: implications for host range and adaptation.
The influenza A virus (IAV) HA protein must be activated by host cells proteases in order to prime the molecule for fusion. Consequently, the availability of activating proteases and the susceptibility of HA to protease activity represents key factors in facilitating virus infection. As such, understanding the intricacies of HA cleavage by various proteases is necessary to derive insights into the emergence of pandemic viruses. To examine these properties, we generated a panel of HAs that are representative of the 16 HA subtypes that circulate in aquatic birds, as well as HAs representative of the subtypes that have infected the human population over the last century. We examined the susceptibility of the panel of HA proteins to trypsin, as well as human airway trypsin-like protease (HAT) and transmembrane protease, serine 2 (TMPRSS2). Additionally, we examined the pH at which these HAs mediated membrane fusion, as this property is related to the stability of the HA molecule and influences the capacity of influenza viruses to remain infectious in natural environments. Our results show that cleavage efficiency can vary significantly for individual HAs, depending on the protease, and that some HA subtypes display stringent selectivity for specific proteases as activators of fusion function. Additionally, we found that the pH of fusion varies by 0.7 pH units among the subtypes, and notably, we observed that the pH of fusion for most HAs from human isolates was lower than that observed from avian isolates of the same subtype. Overall, these data provide the first broad-spectrum analysis of cleavage-activation and membrane fusion characteristics for all of the IAV HA subtypes, and also show that there are substantial differences between the subtypes that may influence transmission among hosts and establishment in new species.


Primary Cutaneous Apocrine Carcinoma and Syringocystadenoma Papilliferum Arising in Nevus Sebaceus: A Case Report and Review of the Literature.
Nevus sebaceus is a hamartomatous lesion characterized by epidermal, follicular, sebaceus, and apocrine gland abnormalities. Approximately 25% of affected individuals may develop benign or malignant secondary neoplasms within the preceding nevus sebaceus. Primary cutaneous apocrine carcinoma (PCAC) is a rare malignant skin tumor affecting elderly adults in their sixth decade of life. Histologically, PCAC appears as a dermal tumor displaying apocrine differentiation with decapitation secretion and malignant features. Secondary malignancy arising from nevus sebaceus is a rare complication, especially for apocrine carcinoma. To date, approximately 200 cases of PCAC have been reported in the literature, and only a few cases have developed PCAC on the scalp. Very few cases (approximately only 12) of PCACs developing in nevus sebaceus have been reported. Here, we report an extremely rare case of the coexistence of PCAC and syringocystadenoma papilliferum arising within nevus sebaceus of the scalp.


Treatment Outcomes of Mycobacterium avium Complex Lung Disease: A Systematic Review and Meta-analysis.
The advent of macrolides has led to therapeutic advances in the treatment of Mycobacterium avium complex lung disease (MAC-LD). The aim of this study was to elucidate the treatment outcomes of macrolide-containing regimens. We performed a systematic review and meta-analysis of published studies reporting treatment outcomes of macrolide-containing regimens for MAC-LD using the Medline, Embase, and Cochrane Library databases through 31 July 2016. The rates of treatment success, default from treatment, and adverse events of macrolide-containing regimens were assessed. Treatment success was defined as either 12 months of sustained culture negativity while on therapy or achievement of culture conversion and completion of the planned treatment without relapse. In total, 16 studies involving 1462 patients were included. The rate of treatment success was 60.0% (95% confidence interval [CI], 55.1%-64.8%). The proportion of patients who defaulted from the treatment was 16.0% (95% CI, 12.3%-19.7%). When a thrice-weekly dosing schedule was available, the default rate was 12.0% (95% CI, 8.9%-15.0%). Adverse events necessitating treatment discontinuation or dosage modification of macrolides were observed in 6.4% of patients (95% CI, 3.2%-9.5%), and decreased auditory acuity was the most common adverse event. Treatment outcomes of macrolide-containing regimens are relatively poor in terms of both the treatment success and default rates. The default rate could be reduced if a thrice-weekly dosing schedule is available. Clinicians should be aware of decreased auditory function as the most common adverse event associated with macrolide-containing regimens.


Hyperintense putaminal rim sign is not a hallmark of multiple system atrophy at 3T.
Hyperintense putaminal rim (HPR) on the T2-weighted imaging, which has been observed in our daily practice while reading 3T brain images, has been described as a finding typical of multiple system atrophy (MSA). We hypothesized that the HPR sign is not an exclusive hallmark of MSA at a high magnetic field strength, but rather may be a normal finding. Ten consecutive clinically healthy age-matched adults who showed recognizable HPR at 3T were subsequently examined on a 1.5T imaging system within 2 hours. MR examination included axial T2-weighted fast spin-echo (FSE), fluid attenuated inversion recovery (FLAIR) on a 3T scanner, and equivalent T2-weighted FSE at 1.5T. MR images were obtained parallel to the intercommissural plane. All the images were interpreted by 2 experienced neuroradiologists. All 10 subjects (3 men and 7 women; aged 52 +/- 6.1 years [range, 44-61 years], expressed as mean +/- SD) with the positive HPR sign on axial T2-weighted FSE at 3T had negative findings at 1.5T. Such hyperintense rim was also vague or absent on the 3T-FLAIR images. Our data suggest that the HPR at 3T scans is a nonspecific, normal finding. FLAIR may be helpful in discriminating between normal subjects and patients with MSA in case of isolated HPR at 3T.


Antitumor activity of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand.
To investigate the antitumor activity and safety of a novel recombinant mutant human tumor necrosis factor-related apoptosis-inducing ligand (rmh TRAIL). Antitumor activity of rmh TRAIL was evaluated by using several tumor cell lines by MTT assay in vitro, and by using a mouse xenograft model in vivo. rmh TRAIL-induced apoptosis in tumor cells was detected by cell death enzyme-linked immunosorbent assay (ELISA), TdT-mediated dUTP nick-end labeling (TUNEL) assay and flow cytometry. The safety of rmh TRAIL was also evaluated in several normal human cell lines. At the concentration of 0.32-1 000 ng/mL, rmh TRAIL remarkably inhibited the proliferation of 5 tumor cell lines from lung, colon, and breast cancer compared with wild type (wt TRAIL) in vitro, whereas at the concentration of 1 ng/mL-10 microg/mL, rmh TRAIL showed no or mild cytotoxicity in the normal cell lines. rmh TRAIL (3, 15 mg/kg, ip, once daily for 10 d) exerted a significant inhibition on the growth of xenograft tumor NCI-H460 in nude mice compared with the saline group (P<0.01), and was more potent than wt TRAIL, a positive control. The apoptosis of NCI-H460 cells was markedly induced in a concentration-dependent and time-dependent manner after rmh TRAIL treatment. The percentage of apoptotic cells induced by rmh TRAIL in NCI-H460 cells was significantly higher than that by wt TRAIL. rmh TRAIL provided potent antitumor activity in vivo and in vitro, whereas most normal human cells were resistant to rmh TRAIL. The results suggested that rmh TRAIL might be a useful anticancer agent in future.


Calciphylaxis in the Setting of Alcoholic Cirrhosis: Case Report and Literature Review.
Calciphylaxis can be a severe life-threatening dermatologic disease that is a known complication associated with end-stage renal disease. However, multiple non-uremic etiologies that are not yet well studied can cause calciphylaxis. We report a rare care of a 40-year-old female with history of alcoholic cirrhosis without any evidence of renal dysfunction who presents with calciphylaxis.


Childhood-onset inflammatory bowel diseases associated with mutation of Wiskott-Aldrich syndrome protein gene.
To screen primary immunodeficiency, Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD) among children with inflammatory bowel disease (IBD). This was a single-center retrospective study. Eighteen children with IBD were investigated. We analyzed their expression of Wiskott-Aldrich syndrome protein (WASP) in lymphocytes and superoxide generation in phagocytes using flow cytometry. When the expression of WASP or superoxide generation was low or absent, we performed genetic analysis to determine the cause of this. Eighteen patients were classified as having ulcerative colitis (n = 10), Crohn's disease (n = 5), or IBD-unclassified (n = 3). In total, three patients revealed low expression of WASP associated with a WAS gene c.1378 C>T p.Pro460Ser mutation, which has previously been reported as a pathogenic mutation in WAS and X-linked thrombocytopenia. However, with respect to the major symptoms of WAS, none of these three patients showed either thrombocytopenia or increased susceptibility to infection, but one patient showed generalized eczema. No CGD patients were discovered in this study. Despite the lack of typical clinical manifestations of WAS, low expression of WASP could be associated with the pathogenesis of a subtype of IBD patients.


Preheated composite resin used as a luting agent for indirect restorations: effects on bond strength and resin-dentin interfaces.
The aim of this study was to evaluate the effect of preheating composite resins used as luting agents for indirect restorations on microtensile bond strength (µTBS) and adhesive interfaces. Fifty sound extracted third molars were used. Ten experimental groups were formed with three different luting agents: one resin cement (RelyX ARC) and two composite resins (Venus and Z250 XT). The composite resins were tested both at room temperature and when preheated to 64°C. Restoration depth was tested using 2 or 4 mm-height indirect composite resin restorations, previously made on cylindrical molds. Adhesive and luting procedures were done under simulated pulpal pressure. After luting, the teeth were sectioned into beams with a cross-sectional area of 1 mm2 at the bonded interface, and tested in tension at 0.5 mm/min. The characteristics of the adhesive interfaces were observed under scanning electron microscopy (SEM). The µTBS data were analyzed using ANOVA and the Tukey test (α = 0.05). When luting 2 mm restorations, the composite resin Z250 XT, preheated or at room temperature, achieved significantly higher µTBS than did RelyX ARC. At this depth, Venus did not differ from the resin cement, and with the 4 mm restorations, only preheated Venus presented significantly higher µTBS than RelyX ARC. Preheating the composite resin resulted in thinner luting interfaces, with a more intimate interaction between luting agent and adhesive layer. Preheating composite resin for luting procedures may not improve µTBS, although it could be used to reduce material viscosity and improve restoration setting.


The Ca2+-induced methyltransferase xPRMT1b controls neural fate in amphibian embryo.
We have previously shown that an increase in intracellular Ca2+ is both necessary and sufficient to commit ectoderm to a neural fate in Xenopus embryos. However, the relationship between this Ca2+ increase and the expression of early neural genes has yet to be defined. Using a subtractive cDNA library between untreated and caffeine-treated animal caps, i.e., control ectoderm and ectoderm induced toward a neural fate by a release of Ca2+, we have isolated the arginine N-methyltransferase, xPRMT1b, a Ca2+-induced target gene, which plays a pivotal role in this process. First, we show in embryo and in animal cap that xPRMT1b expression is Ca2+-regulated. Second, overexpression of xPRMT1b induces the expression of early neural genes such as Zic3. Finally, in the whole embryo, antisense approach with morpholino oligonucleotide against xPRMT1b impairs neural development and in animal caps blocks the expression of neural markers induced by a release of internal Ca2+. Our results implicate an instructive role of an enzyme, an arginine methyltransferase protein, in the embryonic choice of determination between epidermal and neural fate. The results presented provide insights by which a Ca2+ increase induces neural fate.


Towards evidence based strength training: a comparison of muscle forces during deadlifts, goodmornings and split squats.
To ensure an efficient and targeted adaptation with low injury risk during strength exercises, knowledge of the participant specific internal loading conditions is essential. The goal of this study was to calculate the lower limb muscles forces during the strength exercises deadlifts, goodmornings and splits squats by means of musculoskeletal simulation. 11 participants were assessed performing 10 different variations of split squats by varying the step length as well as the maximal frontal tibia angle, and 13 participants were measured performing deadlift and goodmorning exercises. Using individualised musculoskeletal models, forces of the Quadriceps (four parts), Hamstrings (four parts) and m. gluteus maximus (three parts) were computed. Deadlifts resulted highest loading for the Quadriceps, especially for the vasti (18-34 N/kg), but not for the rectus femoris (8-10 N/kg), which exhibited its greatest loading during split squats (13-27 N/kg) in the rear limb. Hamstrings were loaded isometrically during goodmornings but dynamically during deadlifts. For the m. gluteus maximus, the highest loading was observed during split squats in the front limb (up to 25 N/kg), while deadlifts produced increasingly, large loading over large ranges of motion in hip and knee. Acting muscle forces vary between exercises, execution form and joint angle. For all examined muscles, deadlifts produced considerable loading over large ranges of motion, while split squats seem to be highly dependent upon exercise variation. This study provides key information to design strength-training programs with respect to loading conditions and ranges of motion of lower extremity muscles.


Hip kinetics during gait are clinically meaningful outcomes in young boys with Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is an X-linked genetic neuromuscular disorder characterized by progressive proximal to distal muscle weakness. The success of randomized clinical trials for novel therapeutics depends on outcome measurements that are sensitive to change. As the development of motor skills may lead to functional improvements in young boys with DMD, their inclusion may potentially confound clinical trials. Three-dimensional gait analysis is an under-utilized approach that can quantify joint moments and powers, which reflect functional muscle strength. In this study, gait kinetics, kinematics, spatial-temporal parameters, and timed functional tests were quantified over a one-year period for 21 boys between 4 and 8 years old who were enrolled in a multisite natural history study. At baseline, hip moments and powers were inadequate. Between the two visits, 12 boys began a corticosteroid regimen (mean duration 10.8±2.4 months) while 9 boys remained steroid-naïve. Significant between-group differences favoring steroid use were found for primary kinetic outcomes (peak hip extensor moments (p=.007), duration of hip extensor moments (p=.007), peak hip power generation (p=.028)), and spatial-temporal parameters (walking speed (p=.016) and cadence (p=.021)). Significant between-group differences were not found for kinematics or timed functional tests with the exception of the 10m walk test (p=.03), which improves in typically developing children within this age range. These results indicate that hip joint kinetics can be used to identify weakness in young boys with DMD and are sensitive to corticosteroid intervention. Inclusion of gait analysis may enhance detection of a treatment effect in clinical trials particularly for young boys with more preserved muscle function.


Developmental roles of Drosophila tRNA processing endonuclease RNase ZL as revealed with a conditional rescue system.
Drosophila RNase Z(L) (dRNaseZ) belongs to a family of endoribonucleases with a major role in tRNA 3'-end processing. The biochemical function of RNase Z(L) is conserved from yeast to human. Here we present a study of its biological function during Drosophila development. In flies, dRNaseZ provides a non-redundant function, as the RNZ(ED24) knockout (KO) mutation causes early larval lethality. Mosaic and conditional rescue techniques were employed to determine dRNaseZ requirements at later stages. We found that dRNaseZ activity is essential for all phases of fly development that involve cell division, including growth of adult tissue progenitors during larval and metamorphic stages, and gametogenesis in adults. At the cellular level, two major phenotypes were identified-cell growth deficiency in endoreplicating tissues and cell cycle arrest in mitotic tissues. While cell growth and proliferation are both dependant on protein synthesis, the two phenotypes displayed reliance on different dRNaseZ functions. We found that dRNaseZ KO completely blocks tRNA maturation without diminishing the abundance of mature tRNA molecules. Our data indicate that growth arrest of endoreplicating cells is primarily attributed to the relocation of the pool of mature tRNAs into the nuclei causing a decrease in translation efficiency. Mitotically dividing cells appear to be less dependent on translation machinery as they maintain their normal size when deprived of dRNaseZ activity, but rather display a cell cycle arrest at the G2-M transition.


Three-Year Follow-up of Conservative Treatments of Shoulder Osteoarthritis in Older Patients.
Little is known about the mid-term results of nonsurgical treatment for shoulder osteoarthritis (OA), especially in a Chinese population. This study sought to determine the efficacy of nonsurgical management in older patients with shoulder OA. A total of 129 conservatively treated unilateral shoulder OA patients who were older than 65 years were evaluated prospectively at the initial office visit and then subsequently at 3, 6, 12, 18, 24, and 36 months later. During the 36-month follow-up period, all patients could receive conventional therapy, such as nonsteroidal anti-inflammatory medication, corticosteroid injection, sodium hyaluronate, and education, at the discretion of treating physicians. Some patients received physiotherapy, rehabilitation training, and a shoulder strap to improve the range of motion and muscular strength training from a physical therapist. Parameters measured included comparative effectiveness of each therapeutic method, visual analog scale (VAS), Simple Shoulder Test (SST), and Short Form (36) Health Survey (SF-36) scores. At 3-year follow-up, most patients had a significant increase from their pretreatment values in pain, self-assessed shoulder function, mental health, and 5 of 8 SF-36 domains. The study showed a decline in SST and VAS at 6 and 12 months after an initial ascent at 3 months, and then it was rescued and continued at 3-year follow-up. Combined therapy could improve symptoms significantly. This study suggests that a conservative approach may be more appropriate and can produce satisfactory mid-term outcomes in selected cases. The findings of this study suggest that conservative treatments should be extended for longer than 12 months before the decision regarding shoulder arthroplasty is made. [Orthopedics. 2016; 39(4):e634-e641.].


A model to estimate the optimal sample size for microbiological surveys.
Estimating optimal sample size for microbiological surveys is a challenge for laboratory managers. When insufficient sampling is conducted, biased inferences are likely; however, when excessive sampling is conducted valuable laboratory resources are wasted. This report presents a statistical model for the estimation of the sample size appropriate for the accurate identification of the bacterial subtypes of interest in a specimen. This applied model for microbiology laboratory use is based on a Bayesian mode of inference, which combines two inputs: (ii) a prespecified estimate, or prior distribution statement, based on available scientific knowledge and (ii) observed data. The specific inputs for the model are a prior distribution statement of the number of strains per specimen provided by an informed microbiologist and data from a microbiological survey indicating the number of strains per specimen. The model output is an updated probability distribution of strains per specimen, which can be used to estimate the probability of observing all strains present according to the number of colonies that are sampled. In this report two scenarios that illustrate the use of the model to estimate bacterial colony sample size requirements are presented. In the first scenario, bacterial colony sample size is estimated to correctly identify Campylobacter amplified restriction fragment length polymorphism types on broiler carcasses. The second scenario estimates bacterial colony sample size to correctly identify Salmonella enterica serotype Enteritidis phage types in fecal drag swabs from egg-laying poultry flocks. An advantage of the model is that as updated inputs from ongoing surveys are incorporated into the model, increasingly precise sample size estimates are likely to be made.


Synthesis and biological activity of derivatives of ubiquinone: photoaffinity analogues containing the 4-azido-2-nitroanilino group.
The photoaffinity analogues of ubiquinone 2,3-dimethoxy-5-methyl-6-[2-[1-oxo-3-(4-azido-2-nitroanilino) propoxy]-3-methylbutyl]-1,4-benzoquinone (2'-ANAP-Q-1) and 2,3-dimethoxy-5-methyl-6-[3-[1-oxo-3-(4-azido-2-nitroanilino) propoxy]-3-methylbutyl]-1,4-benzoquinone (3'-ANAP-Q-1) have been synthesized. The required intermediate alcohols 2,3-dimethoxy-5-methyl-6-(2-hydroxy-3-methylbutyl)-1,4-benzoquinone and 2,3-dimethoxy-5-methyl-6-(3-hydroxy-3-methylbutyl)-1,4-benzoquinone were prepared in good yield from ubiquinone 1 by hydration of the side-chain double bond via hydroboration or acid catalysis, respectively. These alcohols were then coupled with 3-(4-azido-2-nitroanilino)propanoic acid, with p-toluenesulfonyl chloride in dry pyridine, to give 2'- and 3'-ANAP-Q-1. The synthetic methods presented should be of general utility in the preparation of derivatives of ubiquinone in which a reactive or reporter group is relatively close to the ubiquinone ring. By use of membrane vesicles prepared from a ubi-men-strain of Escherichia coli described previously [Wallace, B., & Young, I. G. (1977) Biochim. Biophys. Acta 461, 84-100], it has been shown that 2'- and 3'-ANAP-Q-1 substitute for ubiquinone 8 in the NADH, succinate, and D-lactate oxidase systems. Thus, these compounds may be of value in labeling respiratory chain proteins that interact with ubiquinone.


The influence of external stimulation in missing knowledge retrieval.
We investigated the effects of sensory reduction on the retrieval of information during tip-of-the-tongue (TOT) experiences. As conscious access results from severe competition in which external stimuli often have priority, we hypothesised that reducing external stimulation would allow individuals greater access to weakly activated inner knowledge. In Study 1, when participants experienced a TOT while answering a general knowledge question, they were given additional time to find the solution in a restricted (eyes closed + silence) or a non-restricted (eyes open + ambient noise) external stimulation environment. Results indicated that knowledge was more often retrieved when external stimulation was restricted than when not restricted. This result was replicated in a second study. Using an independent manipulation of the level of auditory and visual stimulation, Study 2 also indicated that the presence of visual stimulation was more disruptive for TOT resolution than the presence of auditory stimulation. Overall, the findings suggest that sensory restriction (especially of visual stimuli) facilitates the retrieval of weakly accessible knowledge through a greater processing of inner stimuli.


Clinical pharmacokinetics of cerebrospinal fluid.
The distribution of drugs into the cerebrospinal fluid has long been considered a challenging field of investigation in 2 major respects: (a) understanding how the physicochemical properties (molecular weight, pKa, plasma protein binding) of various molecules influence their movements across such a specific structure as the blood-brain barrier; and (b) defining the relationship between cerebrospinal fluid concentrations of various drugs and their central (side) effects. An attempt has been made to review the very dispersed information presently available to offer a clinically orientated picture of this area of pharmacokinetics. Drugs acting on the central nervous system (benzodiazepines, tricyclic antidepressants, anticonvulsants, opioids), antibacterial agents, cardiovascular drugs (beta-adrenoceptor blockers and digoxin), antineoplastic drugs (mainly methotrexate), and other miscellaneous agents (corticosteroids, cimetidine, methylxanthines) are reviewed. The available evidence seems to support the conclusion that only for methotrexate and antibacterial agents does knowledge of cerebrospinal fluid pharmacokinetics have direct therapeutic implications, while the mosaic of information available for other drugs does little more than provide a partially satisfactory picture.


Performance of unidimensional transient elastography in staging non-alcoholic steatohepatitis.
Transient elastography (TE) is a noninvasive method for predicting liver fibrosis, mainly validated in patients with viral hepatitis. Information is still limited concerning its performance in non-alcoholic steatohepatitis (NASH) patients. We aimed to assess the value of TE in the prediction of fibrosis stage in NASH as well as the factors determining the discordance between the TE-predicted and the biopsy-proven fibrosis stage in these patients. Liver biopsy and TE were performed on 72 consecutive NASH patients. Fibrosis, lobular inflammation, ballooning and steatosis were evaluated (Brunt system). Liver stiffness (LS) values ranged from 2.80 to 16.90 kPa. In the univariate analysis, LS was correlated with fibrosis (r=0.661; p<0.0001), steatosis (r=0.435, p<0.0001), ballooning (r=0.385; p=0.001) and lobular inflammation (r=0.364; p=0.002). In multivariate analysis, only fibrosis significantly correlated with LS (p<0.0001). The median (and range) LS values (kPa) according to the fibrosis stages were: 4.90 (2.80-7.30) for F0; 6.15 (4.80-12.50) for F1; 6.90 (3.30-16.90) for F2 and 14.00 (10.70-14.10) for F3, with significant difference between stages, except for F1-F2 (p=0.249). Cut off values were calculated for predicting each fibrosis stage: 5.3 kPa (AUROC=0.879) for F1; 6.8 kPa (AUROC=0.789) for F2; and 10.4 kPa (AUROC=0.978) for F3. Patients with false-positive results had a significantly higher ALT level than those with concordant results (p=0.039). In NASH patients, TE allows a reliable assessment and prediction of liver fibrosis, especially in advanced stages. Steatosis, ballooning and inflammation do not influence liver stiffness.


Posttraumatic GABA(A)-mediated [Ca2+]i increase is essential for the induction of brain-derived neurotrophic factor-dependent survival of mature central neurons.
A shift of GABA(A)-mediated responses from hyperpolarizing to depolarizing after neuronal injury leads to GABA(A)-mediated increase in [Ca2+](i). In addition, central neurons become dependent on BDNF for survival. Whether these two mechanisms are causally interrelated is an open question. Here, we show in lesioned CA3 hippocampal neurons in vitro and in axotomized corticospinal neurons in vivo that posttraumatic downregulation of the neuron-specific K-Cl cotransporter KCC2 leads to intracellular chloride accumulation by the Na-K-2Cl cotransporter NKCC1, resulting in GABA-induced [Ca2+](i) transients. This mechanism is required by a population of neurons to survive in a BDNF-dependent manner after injury, because blocking GABA(A)-depolarization with the NKCC1 inhibitor bumetanide prevents the loss of neurons on BDNF withdrawal. The resurgence of KCC2 expression during recovery coincides with loss of BDNF dependency for survival. This is likely mediated through BDNF itself, because injured neurons reverse their response to this neurotrophin by switching the BDNF-induced downregulation of KCC2 to upregulation.


Different roles of resilience in depressive patients with history of suicide attempt and no history of suicide attempt.
Suicidal ideation is modulated by several risk and protective factors. The aim of this study was to evaluate differences between patients with a history of suicide attempt and those with no such history, with special attention to depression, interpersonal sensitivity, humiliation, and resilience. One hundred consecutively admitted patients with an index depressive episode were recruited. The Brief Symptom Inventory, Humiliation Inventory, and Resilience Scale for Adult were administered. Scores for humiliation, interpersonal sensitivity, and depression were higher in subjects with history of suicide attempt, while higher scores for resilience were observed in the group with no such history. Different patterns of relationships among the variables of interest were found in the two groups. Resilience dimensions such as social resources and familial cohesion were strongly and negatively correlated with humiliation, interpersonal sensitivity, and depression in subjects with a past suicide attempt. Resilience factors can modulate and reduce the impact of suicide risk. Assessing risk and protective factors could enhance the ability to intervene appropriately.


Influence of high dietary vitamin E supplementation on egg production and plasma characteristics in hens subjected to heat stress.
1. The effects of different dietary concentrations of vitamin E (alpha-tocopherol acetate) were investigated in 2 experiments on laying hens exposed to chronic heat stress at 32 degrees C. 2. In the first experiment, egg production and plasma concentrations of calcium and egg yolk precursors were measured in 24 hens before, during and after a stress period of one week and fed on diets containing 10 or 500 mg vitamin E/kg. 3. In the second, larger experiment, egg production and food intake were measured in 300 hens housed in 2 temperature-controlled rooms and fed on diets containing 10, 125 or 500 mg vitamin E/kg. Birds in room 1 were stressed from 24 to 28 weeks of age and those in room 2 from 32 to 36 weeks. 4. In experiment 1, egg production and egg weight were significantly higher (72.6 vs 51.2%, P < 0.05 and 66.6 vs 63.1 g, P < 0.005 respectively) during and after the period of stress in the group given 500 mg vitamin E/kg. Plasma concentrations of calcium, vitellogenin (zinc) and VLDL (triglyceride) were also higher in this group. 5. In experiment 2, egg production was significantly higher (65.4 vs 56.2%, P < 0.05) during and after the period of heat stress in birds in room 1 fed on the diet containing 500 mg vitamin E/kg. Egg production was also higher (49.9% vs 44.7%) on this treatment during the stress period in room 2, though the difference was not significant (P < 0.10). Egg weight and food intake were unaffected by treatment in either room. 6. It is concluded that dietary supplementation with extra vitamin E can, at least in part, alleviate the adverse effects of chronic heat stress in laying hens, perhaps by maintaining the supply of egg precursors in plasma.


[Pharmacokinetic studies on the causes of increased neurotoxicity of lidocaine during heart surgery].
A high incidence of pathological EEG changes were registered following the treatment of arrhythmias using intravenous bolus injections of lidocaine during heart surgery with cardiopulmonary bypass. Lidocaine plasma concentrations were analysed by gas chromatography in order to detect reasons for this phenomenon. No dangerously high plasma levels of lidocaine were observed. The pharmacokinetic data show initially a larger volume of distribution and a shortening of distribution halflife. As causes for the increased neurotoxicity, a decrease of plasma binding and changed conditions for faster uptake by the brain are discussed. A reduction of lidocaine doses is recommended for this special clinical setting.


[Obtaining a specific antigen for the comparative testing of immunological methods in the diagnosis of Marek's disease].
Comparative studies were carried out on the diagnostic possibilities of immunological methods--precipitation in agar gel, immunofluorescence and indirect hemagglutination, as well as isolation of the virus through primary cellular cultures for the diagnosis of Marek's disease. For the purpose were obtained 9 series of specific antigens. The comparative studies were carried out on fowl and blood serums from different poultry yards, as well as from SPF chickens, experimentally infected with HPRS-16 strain. The results obtained justify a precipitation in agar gels as the most convenient for mass diagnosis of Marek's disease.