Decreased bone mineral density at the distal radius, but not at the lumbar spine or the femoral neck, in Japanese type 2 diabetic patients.
The purpose of this study is to assess the association between type 2 diabetes and bone mineral density. This study included 145 Japanese patients (64 men and 81 women) with type 2 diabetes and 95 non-diabetic control subjects (41 men and 54 women) of similar age. We measured bone mineral density (BMD) at the sites with different cortical/cancellous bone ratio (lumbar spine, femoral neck, and distal radius) using dual-energy X-ray absorptiometry. BMD and Z score at the distal radius were significantly lower in type 2 diabetic patients than those in control subjects, and in type 2 diabetic patients, the Z score at the distal radius was lower than that at their own lumbar spine and femoral neck. In type 2 diabetic patients, negative correlation between BMD and the mean HbA1c during the previous 2 years was found significantly at the distal radius in both genders and at the femoral neck in women. These results indicate the selective cortical bone loss in type 2 diabetes and suggest the importance of also determining BMD at the radius and keeping good metabolic control to prevent bone loss in type 2 diabetic patients.


[A case of papillary renal cell carcinoma mimicking a hemorrhagic renal cyst].
A right renal cyst was found in a 69-year-old man with stage IV chronic kidney disease on abdominal ultrasonography performed to investigate a right upper abdominal swelling. Aspiration cytology of the cyst revealed no malignancy, but malignancy could not be ruled out on magnetic resonance imaging because of the cyst's wall thickness and heterogeneous contents. At one-year of follow-up, emergent abdominal surgery was performed due to incidental perforation of ascending colon diverticulitis. At that time, cystic fenestration was performed because the large renal cyst obstructed the operative procedure. Pathological examination showed type-1 papillary renal cell carcinoma, and radical nephrectomy was performed after the patient's general condition improved. Hemodialysis was started after the operation, and there has been no disease recurrence for two years.


Effect of endurance training on ammonia and amino acid metabolism in humans.
Few studies examine ammonia and amino acid metabolism in response to endurance training. Trained humans generally experience less increase in plasma ammonia during either prolonged or intense exercise. This is probably a reflection of reduced ammonia production and release from the active muscle; it could be a reflection of decreased AMP deaminase activity, decreased glutamate dehydrogenase activity, and/or increased alanine and glutamine formation. Little is known regarding the associated enzyme systems in humans, but in experiments with animal models, aerobic training decreases AMP deaminase and increases the enzymes of amino acid transamination and oxidation.


Development and validation of a novel blending machine learning model for hospital mortality prediction in ICU patients with Sepsis.
Early prediction of hospital mortality is crucial for ICU patients with sepsis. This study aimed to develop a novel blending machine learning (ML) model for hospital mortality prediction in ICU patients with sepsis. Two ICU databases were employed: eICU Collaborative Research Database (eICU-CRD) and Medical Information Mart for Intensive Care III (MIMIC-III). All adult patients who fulfilled Sepsis-3 criteria were identified. Samples from eICU-CRD constituted training set and samples from MIMIC-III constituted test set. Stepwise logistic regression model was used for predictor selection. Blending ML model which integrated nine sorts of basic ML models was developed for hospital mortality prediction in ICU patients with sepsis. Model performance was evaluated by various measures related to discrimination or calibration. Twelve thousand five hundred fifty-eight patients from eICU-CRD were included as the training set, and 12,095 patients from MIMIC-III were included as the test set. Both the training set and the test set showed a hospital mortality of 17.9%. Maximum and minimum lactate, maximum and minimum albumin, minimum PaO2/FiO2 and age were important predictors identified by both random forest and extreme gradient boosting algorithm. Blending ML models based on corresponding set of predictors presented better discrimination than SAPS II (AUROC, 0.806 vs. 0.771; AUPRC 0.515 vs. 0.429) and SOFA (AUROC, 0.742 vs. 0.706; AUPRC 0.428 vs. 0.381) on the test set. In addition, calibration curves showed that blending ML models had better calibration than SAPS II. The blending ML model is capable of integrating different sorts of basic ML models efficiently, and outperforms conventional severity scores in predicting hospital mortality among septic patients in ICU.


The localization of cholecystokinin mRNA in embryonic striatal tissue grafts: further evidence for the presence of non-striatal cells.
We have studied by in situ hybridization histochemistry the mRNA expression of preprocholecystokinin (CCK) in grafts of foetal striatal tissue neurones implanted into the ibotenic acid lesioned adult rat neostriatum. Animals were studied at 30 and 90 days after implantation. Using a 35S-labelled 'antisense' oligonucleotide (45-mer) probe complementary to the rat CCK cDNA we observed a dense hybridization signal for CCK mRNA in the striatal eminence in developing embryos and in all the striatal grafts examined; no CCK mRNA expressing cells were found in the normal neonatal or adult rat neostriatum. However, CCK mRNA was heavily expressed in other areas of the host brain including the somatosensory cortex, the claustrum, primary olfactory cortex and endopiriform cortex. The germinal cell layer of the striatal eminence is the source of origin for these non-striatal cell groups as well as for cells destined to form the neostriatum. The present results suggest that CCK mRNA expression provides an unambiguous marker for many of the non-striatal cells in 'striatal' grafts.


Personality and personality disorders predict development and relapses of major depression.
The aim of this study was to investigate the role of personality deviations in the development and relapses of major depression. The study is based on an investigation of an initial sample of 298 psychiatric out-patients, who were re-evaluated after 6 years when the sample included 253 patients. SCID-R was used for assessment of possible relapses and new cases, and a logistic regression analysis was used to determine the best prediction of the recurrence of depression. Borderline personality disorders and dependency predicted relapses. In addition, borderline personality disorders, together with avoidant personality disorders, predicted the development of new cases. Comorbid clinical syndromes appear to be of no importance. These findings suggest that the comorbidity with personality deviations accounts for the chronicity and poor prognosis in major depression.


Investigations into the influence of posture on renal plasma flow and glomerular filtration rate during late pregnancy.
Renal plasma flow and glomerular filtration rate were investigated in three positions (supine, left lateral and sitting) in a group of eighteen healthy women during late pregnancy and again after the puerperium. No difference in renal function could be attributed to the position adopted. However, an unexplained decrease in both of the indices occurred during the course of prolonged infusion in any position.


Pancreatic β-cell glucose toxicity in type 2 diabetes mellitus.
Pancreatic β-cells secrete insulin when blood glucose levels become high. However, when β-cells are chronically exposed to hyperglycemia, their function gradually deteriorates. Although such phenomena are called as β-cell glucose toxicity, its molecular mechanism remained unclear. This manuscript describes the possible mechanism for such β-cell dysfunction. In the diabetic state, nuclear expression levels of pancreatic transcription factors PDX-1 and MafA are decreased. In addition, incretin receptor expression in β- cells is decreased, which is likely involved in the impairment of incretin effects in diabetes. Taken together, it is likely that down-regulation of pancreatic transcription factors and/or incretin receptors are involved in β-cell dysfunction observed in type 2 diabetes.


Morphological study and relations of the fascia vasto-adductoria.
The precise description of the fascia vasto-adductoria (FVA) has become an issue of great surgical and clinical importance. Neurovascular entrapment within the adductor canal (AC) may simulate many clinical conditions for cases presented with medial knee or leg pain and ischemic manifestations of the leg. The aim of the present work is to describe the morphological features of the FVA and to elucidate its neurovascular relations. Forty thigh specimens, pertaining to 15 embalmed and five fresh adult human cadavers, were dissected in pursuit of this aim. The FVA was a continuous subsartorial fascia, roofing the whole length of AC and extended between two points lying at a mean distance of 25.6 and 7 cm proximal to the base of patella. It was subdivided into two parts; proximal thin quadrangular (proximal part of FVA) and distal thick pentagonal (vastoadductor membrane; VAM) and the subsartorial space was observed superficial to it. The mean length of its proximal and distal parts was 7.8 and 7.9 cm, respectively. The proximal part of FVA, while stretched across the vastus medialis (VM) and the adductor longus (AL) muscles, became attached to the wall of the femoral artery and overlaid the femoral vessels, the saphenous nerve (SN), and an arterial pedicle for VM muscle. It was constantly pierced by two arterial pedicles arising from the femoral artery to the sartorius muscle and occasionally (50%) by a communicating nerve branch arising from the SN to join the medial femoral cutaneous nerve. The VAM stretched across the VM muscle and both the AL and adductor magnus (AM) muscles and overlaid the SN, its subsartorial and lower medial femoral cutaneous branches, femoral vessels, 1-3 arterial pedicles for the sartorius and descending genicular vessels. The VAM originated from the tendinous fibres of the AM tendon and constantly spread anterolaterally. It was constantly pierced by 1-3 arterial pedicles to sartorius muscle and both the lower medial femoral cutaneous branch and the subsartorial branches of the SN. An arterial pedicle to the VM muscle and perforating veins between the superficial veins and the femoral vein proved to pierce it in 8/40 specimens. Entrapment of the SN at the distal narrow aperture of the AC, or one of its cutaneous branches at the piercing sites of the FVA, should be remembered when diagnosing cases presented with medial knee or leg pain. The attachment of the proximal part of the FVA to the wall of the femoral artery could add to the mechanism of its potential compression. True AC block should be done deep to the FVA to ensure effective SN analgesia. Its site is recommended to be at the distal one cm of the proximal part of the AC which is at a distance of 16-17 cm proximal to the base of patella. The VAM, being an anatomical connection between the VM and AM muscles, is theorized to increase the mechanical efficiency of the VM oblique muscle to maintain the knee extensor mechanism.


Acid-base titration across the membrane system of rat-liver mitochondria. Catalysis by uncouplers.
1. Pulsed acid-base titrations of suspensions of rat-liver mitochondria under anaerobic equilibrium conditions show fast and slow titration processes. 2. The fast process is the titration of the outer aqueous phase of the mitochondria, which is continuous with the suspension medium, and the slow process can be identified with the titration of the inner aqueous phase of the mitochondria, which is separated from the outer aqueous phase by the non-aqueous osmotic barrier or M phase of the cristae membrane system. 3. The buffering power of the outer and inner phases have been separately measured over a range of pH values. 4. The rate of titration of the inner aqueous phase under a known protonmotive force across the M phase has been characterized by an effective proton conductance coefficient, which, near pH7 and at 25 degrees , is only 0.45mumho/cm.(2) of the M-phase membrane. 5. The low effective proton conductance of the M phase will account quantitatively for the observed respiratory control in state 4, assuming that oxidoreduction and phosphorylation are coupled by a circulating proton current as required by the chemi-osmotic hypothesis. 6. The addition of 2,4-dinitrophenol (or carbonyl cyanide p-trifluoromethoxyphenylhydrazone) at normal uncoupling concentrations causes a large increase in the effective proton conductance of the M phase of the cristae membrane. 7. The increase of the effective proton conductance of the M phase by 2,4-dinitrophenol (or carbonyl cyanide p-trifluoromethoxyphenylhydrazone) will account quantitatively for the short-circuiting effect of the uncoupling agent on the proton current and for the observed rise of the rate of respiration to that characteristic of state 3 or higher.


Effects of short term phosphorus deprivation on laying hens.
An experiment was conducted to determine the effects on laying hens of ingestion of a phosphorus deficient diet for 6, 9, or 21 days. Four experimental groups consisting of 3 replicates of 5 Leghorn pullets averaging 90 percent egg production were maintained in individual cages. A diet containing corn, soy, and meat and bone meal was formulated to contain 0.39 percent total P on a 90 percent dry matter basis (LP). A normal P diet (NP), 0.64 percent total P, was obtained by supplementation with an inorganic P source. Group 1 (Control) was fed the NP diet for 21 days. Groups 2, 3 and 4 were fed the LP diet for 6, 9, and 21 days respectively. Groups 2 and 3 resumed consumption of NP diet after 6 and 9 days. Individual egg production and egg weight were recorded daily. Individual hen determinations of serum P, g. shell/cm.2 surface area, and feed consumption by replicate were made at 3 or 4 day intervals. The serum P of Group 1 averaged 5.01 +/- 0.31 mg./100 ml. over the 21 days. Serum P was significantly reduced after 3 days of consuming the LP diet. Serum phosphorus of Groups 2,3, and 4 were 2.95 +/- 0.18, 3.03 +/- 0.24, 3.13 +/- 0.32 mg./100 ml. respectively after 6, 9, and 21 days of consuming the LP diet. Serum P returned to control levels within 4 days after resumption of the NP diet by Groups 2 and 3. There were no differences in feed consumption, egg production nor any detrimental effects on egg weight or shell calcification despite the low serum P. Body weight gain of the hens fed the phosphorus deficient diet for 21 days was significantly reduced. At the end of the experiment femur density was determined; the hens which had consumed the phosphorus deficient diet for 21 days had reduced femur density (osteoporous) compared to the control group or the hens fed the phosphorus deficient diet for only 9 days. It is concluded that pullets in 90 percent production can tolerate this low P diet for at least 9 days without apparent detrimental effects.


Identification of Novel Hemostatic Biomarkers of Adverse Clinical Events in Patients Implanted With a Continuous-Flow Left Ventricular Assist Device.
Heart failure affects over 5 million people in the United States. Its rising prevalence and the limited supply of donor hearts is increasing the use of mechanical cardiac support with the implantation of continuous-flow ventricular assist devices (CF-VAD). Patients with CF-VAD implants are at risk of complications, specifically adverse hemostatic events such as nonsurgical bleeding and thrombosis. Development of a pump thrombus requires clinical intervention and/or surgical replacement significantly increasing the risk of patient morbidity and mortality. Identification of biomarkers for these events could improve current risk assessment models, subsequent treatment, and quality of life prognoses for VAD-implanted patients. The standard means for identifying thrombus in VAD patients is currently limited to monitoring levels of lactate dehydrogenase (>2× upper limit of normal), which is incapable of predicting a future event, but describes the risk of a present thrombus. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry is a technique used to identify biomarkers. In this study, 3 groups of unique peaks were identified in plasma from patients with left ventricular assist devices: 8.1-kDa, 11.7-kDa, and a 15.2-/16.1-kDa pair. Unique correlations were found for each peak, respectively, with microparticles (MPs) and MP procoagulant activity, C-reactive protein, and MP-tissue factor. Furthermore, the use of 8.1-kDa peaks may be able to differentiate thrombotic events from other hemostatic events.


Serum cholesterol level and the risk of colorectal cancer.
The relation between cancer and serum cholesterol has been studied by many scientists. In the analyses of cancers of the colon and the rectum, both negative and positive relations to cholesterol have been described. The divergent results may, to some extent, be explained by the use of different statistical methods or non-comparable cohorts. A short review and discussion of some studies dealing with the question of the relationship between serum cholesterol and risk of cancer of the colon and the rectum is presented.


A new human species of aldolase A mRNA from fibroblasts.
A full-length cDNA aldolase A clone was isolated from a human fibroblast cDNA library and completely sequenced. Excluding the poly(A) tail, the clone covers 1095 base pairs (bp) of the coding region, plus 199 bp downstream for the termination codon and 146 bp upstream for the initiation codon, within a total of 1440 bp. Primer extension experiments performed with human cultured fibroblast mRNA indicate an elongated product of a further 40 bp. These results evaluated together with those obtained in a concurrent study concerning aldolase A mRNA isolated from human liver are direct evidence of aldolase A mRNA multiplicity in man. The data also suggest the existence in mammals of three different classes of aldolase A mRNA, which would account for tissue specificity and resurgence of foetal expression in tumors.


High-dose ropivacaine wound infiltration for pain relief after inguinal hernia repair: a clinical and pharmacokinetic evaluation.
Early data on ropivacaine, a recently introduced local anesthetic, indicate a longer duration of skin analgesia than with bupivacaine, along with lower toxicity. The objective of this study was to evaluate ropivacaine 7.5 mg/mL for wound infiltration pain relief after hernia surgery, in higher doses than used before, in an open, nonrandomized design. Twenty otherwise healthy men underwent elective unilateral open hernia repair by the same surgeon. General anesthesia was used during surgery, and infiltration of the operating field with 300 mg (n = 10) or 375 mg (n = 10) ropivacaine, 7.5 mg/mL, was employed for postoperative pain relief. Any sign of an adverse event was recorded. Plasma concentrations of ropivacaine were monitored. Pain at rest and on mobilization was regularly assessed over 24 hours by a visual analog scale. Patients' ability to walk and void and the need for supplementary analgesics were recorded. No serious adverse effects occurred. Plasma concentrations showed large variations but no toxic levels. No significant differences between the two groups were detected in pain scores which were low in both groups, at rest or on mobilization, or in the consumption of supplementary analgesics. At 4 hours, 19 patients were able to walk. Within 8 hours of surgery, all patients had passed urine without any problem. Wound healing was normal. Infiltration of ropivacaine 7.5 mg/mL during hernia surgery can be employed safely in doses of 300 mg and 375 mg to control pain after hernia surgery. The lower dose is recommended, since the higher one did not give any clinically relevant advantages.


In vitro-engineered non-antibody protein therapeutics.
Antibodies have proved to be a valuable mode of therapy for numerous diseases, mainly owing to their high target binding affinity and specificity. Unfortunately, antibodies are also limited in several respects, chief amongst those being the extremely high cost of manufacture. Therefore, non-antibody binding proteins have long been sought after as alternative therapies. New binding protein scaffolds are constantly being designed or discovered with some already approved for human use by the FDA. This review focuses on protein scaffolds that are either already being used in humans or are currently being evaluated in clinical trials. Although not all are expected to be approved, the significant benefits ensure that these molecules will continue to be investigated and developed as therapeutic alternatives to antibodies. Based on the location of the amino acids that mediate ligand binding, we place all the protein scaffolds under clinical development into two general categories: scaffolds with ligand-binding residues located in exposed flexible loops, and those with the binding residues located in protein secondary structures, such as α-helices. Scaffolds that fall under the first category include adnectins, anticalins, avimers, Fynomers, Kunitz domains, and knottins, while those belonging to the second category include affibodies, β-hairpin mimetics, and designed ankyrin repeat proteins (DARPins). Most of these scaffolds are thermostable and can be easily produced in microorganisms or completely synthesized chemically. In addition, many of these scaffolds derive from human proteins and thus possess very low immunogenic potential. Additional advantages and limitations of these protein scaffolds as therapeutics compared to antibodies will be discussed.


The role of pro- and anti-inflammatory responses in silica-induced lung fibrosis.
It has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged. Using biochemical, histological, immunohistochemistry, and cellular analyses, we compared the lung responses (inflammation and fibrosis) to fibrogenic silica particles (2.5 and 25 mg/g lung) in Sprague-Dawley rats and NMRI mice. Rats treated with silica particles developed chronic and progressive inflammation accompanied by an overproduction of TNF-alpha as well as an intense lung fibrosis. Dexamethasone or pioglitazone limited the amplitude of the lung fibrotic reaction to silica in rats, supporting the paradigm that inflammation drives lung fibrosis. In striking contrast, in mice, silica induced only a limited and transient inflammation without TNF-alpha overproduction. However, mice developed lung fibrosis of a similar intensity than rats. The fibrotic response in mice was accompanied by a high expression of the anti-inflammatory and fibrotic cytokine IL-10 by silica-activated lung macrophages. In mice, IL-10 was induced only by fibrotic particles and significantly expressed in the lung of silica-sensitive but not silica-resistant strains of mice. Anti-inflammatory treatments did not control lung fibrosis in mice. These results indicate that, beside chronic lung inflammation, a pronounced anti-inflammatory reaction may also contribute to the extension of silica-induced lung fibrosis and represents an alternative pathway leading to lung fibrosis.


Lifetime cost of everolimus vs axitinib in patients with advanced renal cell carcinoma who failed prior sunitinib therapy in the US.
Everolimus and axitinib are approved in the US to treat patients with advanced renal cell carcinoma (RCC) after failure on sunitinib or sorafenib, and one prior systemic therapy (e.g., sunitinib), respectively. Two indirect comparisons performed to evaluate progression-free survival in patients treated with everolimus vs axitinib suggested similar efficacy between the two treatments. Therefore, this analysis compares the lifetime costs of these two therapies among sunitinib-refractory advanced RCC patients from a US payer perspective. A Markov model was developed to simulate a cohort of sunitinib-refractory advanced RCC patients and estimate the cost of treating patients with everolimus vs axitinib. The following health states were included: stable disease without adverse events (AEs), stable disease with AEs, disease progression (PD), and death. The model included the following resources: active treatments, post-progression treatments, adverse events, physician and nurse visits, scans and tests, and palliative care. Resource utilization inputs were derived from a US claims database analysis. Additionally, a 3% annual discount rate was applied to costs, and the robustness of the model results was tested by conducting sensitivity analyses, including those on dosing scheme and post-progression treatment costs. Base case results demonstrated that patients treated with everolimus cost an average of $12,985 (11%) less over their lifetimes than patients treated with axitinib. The primary difference in costs was related to active treatment, which was largely driven by axitinib's higher dose intensity. RESULTS remained consistent across sensitivity analyses for AE and PD treatment costs, as well as dose intensity and discount rates. The results suggest that everolimus likely leads to lower lifetime costs than axitinib for sunitinib-refractory advanced RCC patients in the US.


Knowledge and beliefs about breast cancer and breast self-examination among athletic and nonathletic women.
Women' knowledge of breast cancer and their beliefs about susceptibility to breast cancer and benefits of breast self-examination were explored in relation to frequency of practice of breast self-examination. Previous findings indicated that knowledge and beliefs may affect the practice of preventive health behaviors. A self-report questionnaire was administered to 263 women contacted through sorority alumnae groups and Y.M.C.A. groups. Subjects were grouped according to levels of physical exercise (high, moderate, or none) and compared on knowledge and beliefs about breast cancer and breast self-examination (BSE) and practice of BSE. Data were analyzed using descriptive statistics and chi-square analysis. Results showed women overestimated the prevalence of breast cancer but were correctly aware that most lumps are not malignant. They generally were uninformed of the risk factors of breast cancer, except for a positive family history of breast cancer. The majority perceived themselves as strongly susceptible to breast cancer and almost all perceived BSE as beneficial in reducing the threat of death from breast cancer. Only 37 percent of the women practiced breast self-examination regularly. No significant relationship existed between knowledge or beliefs and frequency of performance of BSE. Nor were there any significant differences in frequency of practice between the exercisers and nonexercisers. It may be concluded from this study that knowledge of breast cancer, beliefs about breast cancer and breast self-examination or engaging in regular physical exercise as a preventive health behavior do not affect the practice of breast self-examination.


Study protocol: a survey exploring patients' and healthcare professionals' expectations, attitudes and ethical acceptability regarding the integration of socially assistive humanoid robots in nursing.
Population ageing, the rise of chronic diseases and the emergence of new viruses are some of the factors that contribute to an increasing share of gross domestic product dedicated to health spending. COVID-19 has shown that nursing staff represents the critical part of hospitalisation. Technological developments in robotics and artificial intelligence can significantly reduce costs and lead to improvements in many hospital processes. The proposed study aims to assess expectations, attitudes and ethical acceptability regarding the integration of socially assistive humanoid robots into hospitalised care workflow from patients' and healthcare professionals' perspectives and to compare them with the results of similar studies. The study is designed as a cross-sectional survey, which will include three previously validated questionnaires, the Technology-Specific Expectation Scale (TSES), the Ethical Acceptability Scale (EAS) and the Negative Attitudes towards Robots Scale (NARS). The employees of a regional clinical centre will be asked to participate via an electronic survey and respond to TSES and EAS questionaries. Patients will respond to TSES and NARS questionaries. The survey will be conducted online. Ethical approval for the study was obtained by the Medical Ethics Commission of the University Medical Center Maribor. Results will be published in a relevant scientific journal and communicated to participants and relevant institutions through dissemination activities and the ecosystem of the Horizon 2020 funded project HosmartAI (grant no. 101016834). 06 May 2021. December 2021.


[Preface for special issue on enzyme engineering].
Enzyme engineering is a combined technology of enzymology and engineering, which is becoming one of the major fields of modem biotechnology. In recent years, China has made some advances in enzyme engineering research. To promote enzyme engineering research in China, invited reviews and selected research articles were published in this special issue of "Enzyme Engineering". The reviews and research articles focus on the fields of enzymatic conversion, therapeutic enzymes, enzymes as additives to animal feedstuff, enzymes for degradation of organic pollutes, and enzymes for biofuel and biorefinery.


A Ligand-Based Virtual Screening Method Using Direct Quantification of Generalization Ability.
Machine learning plays an important role in ligand-based virtual screening. However, conventional machine learning approaches tend to be inefficient when dealing with such problems where the data are imbalanced and features describing the chemical characteristic of ligands are high-dimensional. We here describe a machine learning algorithm LBS (local beta screening) for ligand-based virtual screening. The unique characteristic of LBS is that it quantifies the generalization ability of screening directly by a refined loss function, and thus can assess the risk of over-fitting accurately and efficiently for imbalanced and high-dimensional data in ligand-based virtual screening without the help of resampling methods such as cross validation. The robustness of LBS was demonstrated by a simulation study and tests on real datasets, in which LBS outperformed conventional algorithms in terms of screening accuracy and model interpretation. LBS was then used for screening potential activators of HIV-1 integrase multimerization in an independent compound library, and the virtual screening result was experimentally validated. Of the 25 compounds tested, six were proved to be active. The most potent compound in experimental validation showed an EC50 value of 0.71 µM.


Unsupervised classification of brain-wide axons reveals neuronal projection blueprint.
Long-range axonal projections are quintessential determinants of network connectivity, linking cellular organization and circuit architecture. Here we introduce a quantitative strategy to identify, from a given source region, all "projection neuron types" with statistically different patterns of anatomical targeting. We first validate the proposed technique with well-characterized data from layer 6 of the mouse primary motor cortex. The results yield two clusters, consistent with previously discovered cortico-thalamic and intra-telencephalic neuron classes. We next analyze neurons from the presubiculum, a less-explored region. Extending sparse knowledge from earlier retrograde tracing studies, we identify five classes of presubicular projecting neurons, revealing unique patterns of divergence, convergence, and specificity. We thus report several findings: (1) individual classes target multiple subregions along defined functions, such as spatial representation vs. sensory integration and visual vs. auditory input; (2) all hypothalamic regions are exclusively targeted by the same class also invading midbrain, a sharp subset of thalamic nuclei, and agranular retrosplenial cortex; (3) Cornu Ammonis, in contrast, receives input from the same presubicular axons projecting to granular retrosplenial cortex, also the purview of a single class; (4) path distances from the presubiculum to the same targets differ significantly between classes, as do the path distances to distinct targets within most classes, suggesting fine temporal coordination in activating distant areas; (5) the identified classes have highly non-uniform abundances, with substantially more neurons projecting to midbrain and hypothalamus than to medial and lateral entorhinal cortex; (6) lastly, presubicular soma locations are segregated among classes, indicating topographic organization of projections. This study thus demonstrates that classifying neurons based on statistically distinct axonal projection patterns sheds light on the functional organizational of their circuit.


[Detection of HPV 58 and cloning of its E7 gene in cervical cancer].
To detect HPV 58, a common type of human papillomavirus (HPV), clone and express its E7 gene from biopsy specimens of cervical cancer. HPV 58 from 58 biopsy tissues of cervical cancer was detected by GP5+/GP6+ PCR followed by template-directed dye-terminator incorporation assay with fluorescence polarization detection (TDI-FP). HPV 58 E7 gene was amplified from one HPV 58-positive sample, and then cloned into pGEM-T Easy vector. The recombinant plasmid, HPV58E7-pGEM-T was confirmed by sequencing. Subsequently, E7 gene was cloned into prokaryotic expression vector pRSET-A. The constructed pRSET-58E7 plasmids were transfected into BL21(DE3) cells, and induced to express 58 E7 protein by IPTG. Among the 58 biopsy tissues of cervical cancer, 10 were HPV 58-positive, accounting for 19.2% of 52 HPV-positive cases. HPV 58 E7 gene was amplified from one HPV 58-positive sample. The constructed plasmids were identified containing HPV58 E7 gene by restriction enzyme analysis and sequencing. SDS-PAGE analysis showed that HPV58 E7 His6 fusion protein of M(r) 16 x 10(3) was expressed by pRSET-58E7 after induction by IPTG. The fusion protein accounted for 30% of total bacterial proteins. HPV 58 is not uncommon in Chinese women with cervical cancer in Shaanxi province. Constructed HPV58 E7 recombinant plasmids can be effectively expressed in E.coli, which may provide a tool in diagnosis and vaccine design for HPV of HPV58-associated tumors.


Automated external defibrillation versus manual defibrillation for prolonged ventricular fibrillation: lethal delays of chest compressions before and after countershocks.
We sought to determine whether the delays in chest compressions and defibrillation associated with an automated external defibrillator would adversely affect outcome compared with manual defibrillation in a swine model of out-of-hospital prolonged ventricular fibrillation. After 8 minutes of untreated ventricular fibrillation, 16 swine (33+/-4 kg) were randomly assigned to automated external defibrillator defibrillation or manual defibrillation with the same biphasic truncated exponential waveform 150-J shock through the same type of pads. Defibrillation with the automated external defibrillator was performed as recommended by the manufacturer, and manual defibrillation was provided per American Heart Association Guidelines. The primary outcome measure was 24-hour survival with good neurologic outcome. Data are described as means+/-SD. None of 8 animals in the automated external defibrillator group survived for 24 hours, whereas 5 of 8 animals in the manual defibrillation group survived 24 hours, all with good neurologic outcome (P=.027). The time interval from simulated defibrillator arrival to first compressions was 98+/-18 seconds in the automated external defibrillator group versus 68+/-15 seconds in the manual defibrillation group. In particular, the interval from first shock to first chest compressions was 46+/-18 seconds versus 22+/-16 seconds, respectively. The mean percentage of time that chest compressions were performed in the first minute after the first countershock was 15%+/-13% versus 40%+/-15%, respectively. As a result, return of spontaneous circulation within 5 minutes of simulated defibrillator arrival occurred in only 1 of 8 animals in the automated external defibrillator group versus 6 of 8 animals in the manual defibrillation group. The longer delays in chest compressions with automated external defibrillator defibrillation versus manual defibrillation can worsen the outcome from prolonged ventricular fibrillation.


LASS6, an additional member of the longevity assurance gene family.
Longevity assurance genes (LAGs) represent a subgroup of the homeobox gene family. Five mammalian homologs have been reported, and the corresponding proteins have previously been investigated with respect to their key role in ceramide synthesis. However, members of the LAG family have been shown to be involved in cell growth regulation and cancer differentiation. In an effort to characterize additional members of the LAG family, we have screened the latest releases of genomic databases and report on the bioinformatic characterization of yet another member, LAG1 longevity assurance homolog 6 (LASS6). Like other LAG family members, the LASS6 protein contained a homeodomain and LAG1 domain. In phylogenetic analyses, it displayed highest homology to LASS5. The corresponding gene was localized to human chromosome 2q24.3, spanning a rather large genomic region of 318 kb. Orthologous sequences in mouse and zebrafish suggested a conservation of LASS6 in vertebrates as the protein and corresponding genomic sequences were highly conserved. LASS6 expression was analyzed in silico, and the gene was shown to be broadly expressed in a wide range of tissues. Furthermore, available microarray data suggested a role in cancer differentiation and early embryonic development.


Metabolism of [75Se]selenite by rhesus monkeys.
The metabolism of [75Se]selenite was studied in rhesus monkeys. In blood samples taken various times after injection, Sephadex G-150 gel filtration revealed that the majority of the 75Se was associated with hemoglobin and low-molecular-weight compounds in erythrocytes up to 24 hours after selenium injection. Subsequently a gradual increase of 75Se occurred in glutathione peroxidase (GSH-Px) with a concurrent decrease of label with hemoglobin. In contrast to the erythrocytes, over 80% of the labeled selenium in plasma was associated with one peak 3 hours and later after injection. This major protein eluted at a position similar to GSH-Px on gel filtration, but subsequent chromatography on diethylaminoethyl (DEAE)-Sephacel separated the radiolabeled protein from GSH-Px. Gel filtration of heart, muscle, brain and pancreas cytosol revealed two major selenium-containing proteins, whereas one was predominant in liver and kidney. The major selenium peak was associated with GSH-Px in liver but not in the kidney. GSH-Px activity with either organic or inorganic peroxides as substrates and glutathione transferase activity were higher in liver than kidney.


[An observational study of the patterns of carbamazepine and oxcarbazepine utilisation in adult patients with partial epilepsy in Spain].
The health outcomes research methodology is especially important for evaluating therapeutic efficiency and effectiveness in the case of patients with epilepsy. To describe the patterns of utilisation of carbamazepine and the new antiepileptic drug oxcarbazepine, as well as their relation with the quality of life (patient's satisfaction and social and occupational repercussion) and therapeutic efficiency (utilisation of health care resources). We performed an observational study of 284 adult patients with partial epilepsy that was clinically controlled with carbamazepine or oxcarbazepine either in monotherapy or with the addition of some other pharmaceutical agent. The study was carried out using the Morisky-Green questionnaire (for therapeutic compliance), the Sheehan Disability Scale (SDS, social functioning) and direct questioning (patient satisfaction); therapeutic efficiency was assessed with the register of medical visits, complementary examinations and concomitant treatments. The study showed that 65.6% suffered from partial seizures of a single type (simple, complex or with secondary generalisation) and 34.4% had several types of seizures. Oxcarbazepine treatment was being administered to 52% (mean dose: 1134.4 mg/day) and 48% were receiving carbamazepine (mean dose: 876.3 mg/day). The SDS scores were: occupational: 2.1; social: 2.0; and familial: 1.4. Most of the patients admitted having skipped some doses under certain circumstances; for this reason, 98.9% of them presented a medium level of compliance. It was found that 8.5% of patients visited the emergency department and 3% used hospitalisation services. The doses of oxcarbazepine tended to be lower than those recommended on the patient information leaflet. Patients only consider themselves to be mildly affected in their social and occupational relations and are satisfied with the control of their seizures. Patients receiving combination therapy utilise more health care resources.


Catalyst: Fast and flexible modeling of reaction networks.
We introduce Catalyst.jl, a flexible and feature-filled Julia library for modeling and high-performance simulation of chemical reaction networks (CRNs). Catalyst supports simulating stochastic chemical kinetics (jump process), chemical Langevin equation (stochastic differential equation), and reaction rate equation (ordinary differential equation) representations for CRNs. Through comprehensive benchmarks, we demonstrate that Catalyst simulation runtimes are often one to two orders of magnitude faster than other popular tools. More broadly, Catalyst acts as both a domain-specific language and an intermediate representation for symbolically encoding CRN models as Julia-native objects. This enables a pipeline of symbolically specifying, analyzing, and modifying CRNs; converting Catalyst models to symbolic representations of concrete mathematical models; and generating compiled code for numerical solvers. Leveraging ModelingToolkit.jl and Symbolics.jl, Catalyst models can be analyzed, simplified, and compiled into optimized representations for use in numerical solvers. Finally, we demonstrate Catalyst's broad extensibility and composability by highlighting how it can compose with a variety of Julia libraries, and how existing open-source biological modeling projects have extended its intermediate representation.


Cerebrospinal fluid pressure studies in normal pressure hydrocephalus and cerebral atrophy.
The surgical results obtained with a cerebrospinal fluid (CSF) shunt operation in 13 patients considered to be suffering from normal pressure hydrocephalus have been correlated with the findings of the constant manometric infusion test (IT) and of prolonged intracranial pressure recordings. A positive IT, high amplitude CSF pulse pressure and large transitory increases of CSF pressure during sleep seem to be useful criteria for the surgical prognosis. Ten more patients affected by primary cerebral atrophy have also been studied. The data obtained in both groups of patients have been utilized for a possible pathogenetic interpretation of the syndrome.


The Thoc1 encoded ribonucleoprotein is a substrate for the NEDD4-1 E3 ubiquitin protein ligase.
Ribonucleoprotein (RNP) complexes form around nascent RNA during transcription to facilitate proper transcriptional elongation, RNA processing, and nuclear export. RNPs are highly heterogeneous, and different types of RNPs tend to package functionally related transcripts. These observations have inspired the hypothesis that RNP mediated mechanisms help specify coordinated gene expression. This hypothesis is supported by the observation that mutations in RNP components can cause defects in specific developmental pathways. How RNP biogenesis itself is regulated, however, is not well understood. The evolutionarily conserved THO RNP complex functions early during transcription to package nascent transcripts and facilitate subsequent RNP biogenesis. THO deficiency compromises transcriptional elongation as well as RNP mediated events like 3' end formation and nuclear export for some transcripts. Using molecularly manipulated cells and in vitro reconstituted biochemical reactions, we demonstrate that the essential THO protein component encoded by the Thoc1 gene is poly-ubiquitinated by the NEDD4-1 E3 ubiquitin ligase. Poly-ubiquitinated pThoc1 is degraded by the proteasome. These results indicate THO activity is regulated by the ubiquitin-proteasome pathway, and that this regulation is evolutionarily conserved between yeast and mammals. Manipulation of NEDD4-1 levels has modest effects on Thoc1 protein levels under steady state conditions, but destabilization of Thoc1 protein upon treatment with a transcriptional elongation inhibitor is dependent on NEDD4-1. This suggests NEDD4-1 functions in conjunction with other post-translational mechanisms to regulate Thoc1 protein and THO activity.


Mutualistic interactions shape global spatial congruence and climatic niche evolution in Neotropical mimetic butterflies.
Understanding the mechanisms underlying species distributions and coexistence is both a priority and a challenge for biodiversity hotspots such as the Neotropics. Here, we highlight that Müllerian mimicry, where defended prey species display similar warning signals, is key to the maintenance of biodiversity in the c. 400 species of the Neotropical butterfly tribe Ithomiini (Nymphalidae: Danainae). We show that mimicry drives large-scale spatial association among phenotypically similar species, providing new empirical evidence for the validity of Müller's model at a macroecological scale. Additionally, we show that mimetic interactions drive the evolutionary convergence of species climatic niche, thereby strengthening the co-occurrence of co-mimetic species. This study provides new insights into the importance of mutualistic interactions in shaping both niche evolution and species assemblages at large spatial scales. Critically, in the context of climate change, our results highlight the vulnerability to extinction cascades of such adaptively assembled communities tied by positive interactions.


Advancing the frontiers: Revolutionary control and prevention paradigms against Nipah virus.
Nipah Virus (NiV) is a highly virulent pathogen that poses a significant threat to human and animal populations. This review provides a comprehensive overview of the latest control and prevention strategies against NiV, focusing on vaccine development, antiviral drug discovery, early diagnosis, surveillance, and high-level biosecurity measures. Advancements in vaccine research, including live-attenuated vaccines, virus-like particles, and mRNA-based vaccines, hold promise for preventing NiV infections. In addition, antiviral drugs, such as remdesivir, ribavirin, and favipiravir, have the potential to inhibit NiV replication. Early diagnosis through molecular and serological assays, immunohistochemistry, and real-time reverse transcription polymerase chain reaction plays a crucial role in timely detection. Surveillance efforts encompassing cluster-based and case-based systems enhance outbreak identification and provide valuable insights into transmission dynamics. Furthermore, the implementation of high-level biosecurity measures in agriculture, livestock practices, and healthcare settings is essential to minimize transmission risks. Collaboration among researchers, public health agencies, and policymakers is pivotal in refining and implementing these strategies to effectively control and prevent NiV outbreaks and safeguard public health on a global scale.


What Is the Evidence for Use of a Supplemental Feeding Tube Device as an Alternative Supplemental Feeding Method for Breastfed Infants?
According to the Healthy People 2020 goals, the sustainability of breastfeeding duration rates within the United States has not been achieved. To increase these rates, it is important that women with breastfeeding difficulties receive the support needed to continue breastfeeding. When supplementation occurs, it is essential that the breastfeeding relationship be preserved. Various methods of supplementation are often recommended including use of the supplemental feeding tube device (SFTD). The question guiding this brief is "What evidence exists to support the use of an SFTD as a method of supplementation for breastfed infants?" The PubMed and CINAHL databases were queried for original research published in English from 1990 through July 2016. Search terms included "supplemental feeding tube," "breastfeeding," "term infants," "premature infants," "Supplemental Nursing System," "Lact-aid," and "supply line." Very limited research exists on the use of SFTDs as a method of supplementation for breastfed infants; however, existing research suggests that an SFTD may be useful as a supplementation method for breastfed infants. High-quality research is needed to evaluate the efficacy of using an SFTD for supporting exclusive and all breastfeeding rates. Nurses and providers need to be educated and trained in the use of SFTDs as well as all supplemental feeding methods. Information on efficacy and SFTD use should also be included in policies related to breastfeeding and human milk use. Further research should determine best methods of supplementation for breastfed infants and should examine differences in breastfeeding rates when using the SFTD for supplementation.


Light scan evaluation of nonpalpable breast lesions.
Transillumination light scanning of the breast was performed immediately before needle localization of 112 nonpalpable mammographic abnormalities detected in 103 patients. Twenty-four cancers were diagnosed in 23 patients. The positive predictive value for mammography was 21%. Ten (42%) of these nonpalpable cancers were not visible on transillumination light scanning. Eleven of 16 invasive ductal cancers and three of seven intraductal cancers were evident on transillumination light scans, but a single case of lobular carcinoma in situ was not evident. There were 12 false-positive light scan examinations. Transillumination light scanning had a 58% sensitivity, an 86% specificity, a 54% positive predictive value, and an 88% negative predictive value for small breast lesions. Therefore, the authors are unable to recommend delaying biopsy in patients with mammographic abnormalities on the basis of a negative light scan study.


Significant contribution of the 3'→5' exonuclease activity to the high fidelity of nucleotide incorporation catalyzed by human DNA polymerase ϵ.
Most eukaryotic DNA replication is performed by A- and B-family DNA polymerases which possess a faithful polymerase activity that preferentially incorporates correct over incorrect nucleotides. Additionally, many replicative polymerases have an efficient 3'→5' exonuclease activity that excises misincorporated nucleotides. Together, these activities contribute to overall low polymerase error frequency (one error per 10(6)-10(8) incorporations) and support faithful eukaryotic genome replication. Eukaryotic DNA polymerase ϵ (Polϵ) is one of three main replicative DNA polymerases for nuclear genomic replication and is responsible for leading strand synthesis. Here, we employed pre-steady-state kinetic methods and determined the overall fidelity of human Polϵ (hPolϵ) by measuring the individual contributions of its polymerase and 3'→5' exonuclease activities. The polymerase activity of hPolϵ has a high base substitution fidelity (10(-4)-10(-7)) resulting from large decreases in both nucleotide incorporation rate constants and ground-state binding affinities for incorrect relative to correct nucleotides. The 3'→5' exonuclease activity of hPolϵ further enhances polymerization fidelity by an unprecedented 3.5 × 10(2) to 1.2 × 10(4)-fold. The resulting overall fidelity of hPolϵ (10(-6)-10(-11)) justifies hPolϵ to be a primary enzyme to replicate human nuclear genome (0.1-1.0 error per round). Consistently, somatic mutations in hPolϵ, which decrease its exonuclease activity, are connected with mutator phenotypes and cancer formation.


Pituitary dysfunction after aneurysmal subarachnoidal hemorrhage.
Aneurysmal subarachnoid hemorrhage (aSAH) results from the rupture of an intracranial aneurysm and represents a highly debilitating and devastating disorder. The prevalence rate of neuroendocrine impairment in the acute phase is extremely variable, ranging from 3.8% to 92.3%, depending on the time point considered, the method/test utilized, the clinical severity at admission, and probably also ethnicity. Further studies are needed to clarify such a wide range in neuroendocrine dysfunction in patients with aSAH. The overall neuroendocrine impairment rate in chronic aSAH is in the range 47%-83.3% with specific neuroendocrine impairment varying from 2.5% to 83.3%. The overall pituitary deficiency rate tends to decrease over time after SAH, with recovery of most endocrine and some de novo dysfunctions being reported. Only one study has reported an increase of overall endocrine impairment in the chronic follow-up. Neuroendocrine dysfunction seems to have a high prevalence in aSAH patients, even though its exact impact is not precisely known and is based on contrasting findings. More high-quality studies and trials are necessary before informing guidelines and protocols recommending preventive endocrine screening and related treatment (hormone replacement therapy) on a routine basis. The usage of standardized testing and reporting procedures could significantly move the field forward.


The helpfulness and timing of transition program education.
The purpose of this study was to examine relationships between transition program education and new graduate nurse transition. Although new graduates preferred hands-on learning, the helpfulness of workshops was associated with better transition. New graduates, many of whom were from the Millennial Generation, liked a variety of educational modalities. Access to support was better for nurse graduates who received education delivered throughout the first year of transition.


Nausea and vomiting during spinal anaesthesia. Effect of metoclopramide and domperidone: a double-blind trial.
A randomised, double-blind investigation was undertaken into the value of metoclopramide and domperidone as anti-emetics in orthopaedic patients who received spinal anaesthesia. Seventy-seven patients were divided into three statistically comparable groups: Group I received 10 mg metoclopramide, Group II 10 mg domperidone, and Group III NaCl as placebo. These substances were given intravenously before the spinal puncture. There was a comparable decrease in mean arterial blood pressure (MAP), level of sensory block and dose of tetracaine in all three groups. The patients who were nauseated and/or vomited showed a greater decrease in MAP. The incidence of nausea and/or vomiting in the metoclopramide and the placebo group were similar, 20% and 15% respectively, whereas this complication was apparent in 35% of patients who received domperidone. We conclude that metoclopramide and domperidone in the dosages used are ineffective in alleviating nausea and vomiting after spinal anaesthesia.


Transcriptomic landscape of endothelial cells: Key tumor microenvironment components indicating variable clinical outcomes in pancreatic ductal adenocarcinoma.
Endothelial cells (ECs) present in the tumor microenvironment (TME) exhibit significant diversity that may impact the efficacy of anti-tumor treatments. Thus, our study sought to elucidate the various clusters of ECs present in pancreatic ductal adenocarcinoma (PDAC) and explore their possible interactions and influence on clinical outcomes. We obtained single-cell transcriptome data from 24 PDAC tumors and 11 normal pancreases, minimizing any batch effects between samples. Next, we compared the relative abundance of various ECs clusters across distinct sample types. Pseudo-time analysis was employed to investigate the differentiation origin of ECs. A variety of bioinformatics methods were used to investigate potential communication between ECs and malignant cells, as well as assess metabolic changes, pathway alterations, and immune-related markers expression within distinct EC clusters. Lastly, we investigated the impact of particular ECs clusters on patient prognosis in bulk transcriptome data. Our study identified seven distinct clusters of ECs, denoted as CA4+ ECs, MMP2+ ECs, SPP1+ ECs, MT1F+ ECs, CCL5+ ECs, RGS5+ ECs, and TYROBP+ ECs. Pseudo-time analysis suggested that the loss of CA4+ ECs and MT1F+ ECs may promote malignant progression. Cell communication elucidated that MT1F+ ECs exhibited the strongest outgoing interaction strength, whereas RGS5+ ECs displayed the strongest incoming interaction strength. Furthermore, TYROBP+ ECs exhibited greater metabolic activity, and notably, CCL5+ ECs displayed increased expression of immune-related molecules. Lastly, across cohorts of bulk transcriptome levels, CA4+ ECs, MT1F+ ECs, and RGS5+ ECs consistently demonstrated prognostic indicative effects. PDAC patients exhibit the presence of seven distinct EC clusters, each demonstrating significant metabolic and immunological heterogeneity. Targeted therapeutic approaches directed toward CA4+ ECs and MT1F+ ECs may prove advantageous in addressing challenges associated with PDAC treatment. Additionally, variations in the relative abundance of CA4+ ECs, MT1F+ ECs, and RGS5+ ECs were indicated as predictive of patient prognosis.


Antinociceptive activity of Tilia americana var. mexicana inflorescences and quercetin in the formalin test and in an arthritic pain model in rats.
Tilia species are well known around the world for their properties in traditional medicine. Antinociceptive activity of hexane, methanol and aqueous extracts from Tilia americana var. mexicana inflorescences was evaluated in the pain-induced functional impairment model in rats (PIFIR). A preliminar 300 mg/kg dosage of aqueous extracts i.p., but not the same dose of methanol or hexane extract, produced an antinociceptive response in rats similar to that of tramadol (17.8 mg/kg i.p.). A dose-response curve from aqueous extract allowed the determination of ED(50) = 364.97 mg/kg in comparison to ED(50) = 10.35 mg/kg for tramadol in this model. A previous HPLC-DAD analysis corroborated by an HPLC-MS technique in this study demonstrated the flavonoid composition in this Tilia aqueous extract revealing the presence of glycosides mainly derived from quercetin. Thus, Tilia aqueous extract and quercetin were tested at 30 and/or 100 mg/kg dosages i.p. in the PIFIR and formalin models producing a significant and dose-dependent antinociceptive response resembling that produced by a total and a partial agonist of 5-HT(1A) receptors like 8-OH-DPAT (0.1 mg/kg, s.c.) and buspirone (5 mg/kg, i.p.), respectively. In all the treatments, antinociceptive response was inhibited in the presence of WAY 100635 (0.12 mg/kg, i.p.). Our results support the analgesic activity of T. americana var. mexicana inflorescences attributed by folk medicine; they also indicate that quercetin is partly responsible for this pharmacological activity that is likely mediated by serotonin 5-HT(1A) receptors.


Incorporation of 3H-2,3-DL-valine into pancreatic proteins of adrenalectomized rats stimulated with pancreozymin-CCK and secretin.
Incorporation of labelled valine was investigated in bilaterally adrenalectomized rats stimulated with pancreozymin-CCK and secretin 14 days after operation. The growth of rats, the blood pressure, the amount of pancreatic juice and the amylase output was less in the adrenalectomized animals as compared with sham operated or adrenalectomized and corticosterone substituted controls. The amylase concentration in the pancreatic juice reveals no difference between the groups but the output of amylase remained below that of the controls. The incorporation of labelled valine was higher in the pancreatic tissue and proteins in the adrenalectomized animals than in the controls. It is assumed that the adrenalectomy causes primarily a depletion in the metabolic activity and systemic blood pressure; diminished pancreatic juice secretion and output of amylase are only secondary consequences which are not compensable by hormonal stimulation of pancreatic secretion.


Potential use of ivermectin for the treatment and prophylaxis of SARS-CoV-2 infection.
Currently no treatment has been proven to be efficacious for patients with early symptoms of COVID-19. Although most patients present mild or moderate symptoms, up to 5-10% may have a poor disease progression, so there is an urgent need for effective drugs, which can be administered even before the onset of severe symptoms, i.e. when the course of the disease is modifiable. Recently, promising results of several studies on oral ivermectin have been published, which has prompted us to conduct the present review of the scientific literature. A narrative review has been carried out, focusing on the following four main topics: a) short-term efficacy in the treatment of the disease, b) long-term efficacy in the treatment of patients with post-acute symptoms of COVID-19, c) efficacy in the prophylaxis of the disease, and c) safety of ivermectin. The reviewed literature suggests that there seems to be sufficient evidence about the safety of oral ivermectin, as well as the efficacy of the drug in the early-treatment and the prophylaxis of COVID-19. In the view of the available evidence, the Frontline COVID-19 Critical Care Alliance (FLCCC) recommends the use of oral ivermectin for both prophylaxis and early-treatment of COVID-19. Further well-designed studies should be conducted in order to explore the efficacy and safety of invermectin at low and high doses, following different dosing schedules, in both, the short and long-term treatment.


Magnetically Induced Rotating Rayleigh-Taylor Instability.
Classical techniques for investigating the Rayleigh-Taylor instability include using compressed gasses1, rocketry2 or linear electric motors3 to reverse the effective direction of gravity, and accelerate the lighter fluid toward the denser fluid. Other authorse.g.4,5,6 have separated a gravitationally unstable stratification with a barrier that is removed to initiate the flow. However, the parabolic initial interface in the case of a rotating stratification imposes significant technical difficulties experimentally. We wish to be able to spin-up the stratification into solid-body rotation and only then initiate the flow in order to investigate the effects of rotation upon the Rayleigh-Taylor instability. The approach we have adopted here is to use the magnetic field of a superconducting magnet to manipulate the effective weight of the two liquids to initiate the flow. We create a gravitationally stable two-layer stratification using standard flotation techniques. The upper layer is less dense than the lower layer and so the system is Rayleigh-Taylor stable. This stratification is then spun-up until both layers are in solid-body rotation and a parabolic interface is observed. These experiments use fluids with low magnetic susceptibility, |χ| ~ 10-6 - 10-5, compared to a ferrofluids. The dominant effect of the magnetic field applies a body-force to each layer changing the effective weight. The upper layer is weakly paramagnetic while the lower layer is weakly diamagnetic. When the magnetic field is applied, the lower layer is repelled from the magnet while the upper layer is attracted towards the magnet. A Rayleigh-Taylor instability is achieved with application of a high gradient magnetic field. We further observed that increasing the dynamic viscosity of the fluid in each layer, increases the length-scale of the instability.


Long-Term Results Comparing Xenogeneic Collagen Matrix and Autogenous Connective Tissue Grafts With Coronally Advanced Flaps for Treatment of Dehiscence-Type Recession Defects.
Although connective tissue grafts with coronally advanced flaps (CTG + CAF) have been deemed the gold standard for recession defect treatment, to provide adequate recession coverage, the periodontal profession continues to pursue lower-morbidity, patient-preferred substitutes that are more convenient and of unlimited supply. Using a randomized, controlled, and masked contralateral comparison of matched-pair, within-patient recession defects, collagen matrix (CMX) + CAF therapy was compared with CTG + CAF at 6 months and 5 years. The primary efficacy endpoint was percentage of root coverage (RC). Secondary efficacy parameters included width of keratinized tissue (KTw), probing depth (PD), clinical attachment level (CAL), clinician rating of color and texture compared with surrounding tissues, and patient esthetic satisfaction. Seventeen patients were available for the 5-year recall. Mean RC between 6 months and 5 years changed from 89.5% to 77.6% for CMX + CAF test sites and 97.5% to 95.5% for CTG + CAF control sites. KTw averaged >3 mm for both test and control sites at 5 years. PD was equivalent at all time points. The 6-month to 5-year changes for RC, KTw, and PD were not significantly different between therapies. CAL change from 6 months to 5 years was greater for CTG + CAF (0.26 mm) than CMX + CAF (-0.21 mm). Tissue color match to surrounding tissues remained similar for both therapies throughout the study. There was a difference in tissue texture at both 6 months and 5 years, with CMX + CAF sites tending to be "equally firm" and CTG + CAF sites "more firm." Patient satisfaction was high, with no statistical difference in satisfaction between therapies at any time point. When balanced with patient-reported satisfaction, clinical rankings of esthetics, and control and historical RC results reported by other investigators, CMX + CAF appears to present a viable and long-term alternative to traditional CTG + CAF therapy.


Optimizing Recovery After Knee Meniscal or Cartilage Injury: Guidelines Help Deliver Quality Care.
An injury to your knee meniscus or joint cartilage can happen when you move suddenly or repeatedly move the wrong way. If you have such an injury, you may feel knee pain and have limited motion. Physical therapists can ensure that you and others with these injuries receive quality care to optimize recovery. The goal of revised clinical practice guidelines published in the February 2018 issue of the JOSPT is to make recommendations based on best practices from recent published literature for the evaluation, diagnosis, treatment, and determination of patient readiness to return to activities following knee meniscus or joint cartilage injury. Based on scientific research, these guidelines summarize the treatment options currently available. J Orthop Sports Phys Ther 2018;48(2):125. doi:10.2519/jospt.2018.0504.


Correspondence of supervisor and subordinate perspectives during major organizational change.
Staff members (N = 2,605) and supervisors (N = 55) of 39 administrative units in 2 healthcare organizations completed a survey measuring confidence in the organization, engagement with their work, and occupational hazards. A correlational analysis determined correspondence between the perspectives of supervisors with those of staff reporting to them as their facilities adjusted to major organizational changes. Supervisors' scores were significantly and positively correlated with the corresponding scores of staff members on cynicism, meaningfulness, acceptance of change, goals, hospital reputation, and health risks. Regression analysis found that relationships were relatively domain specific: Supervisor engagement with work was positively related to that of their staff members, and supervisors evaluations of the organization were positively related to those of their staff members. Supervisor assessment of occupational hazards was related to all 3 areas of staff perception.


Isolation and characterization of an infectious replication-competent molecular clone of ecotropic porcine endogenous retrovirus class C.
Xenotransplantation of pig organs is complicated by the existence of polytropic replication-competent porcine endogenous retroviruses (PERV) capable of infecting human cells. The potential for recombination between ecotropic PERV-C and human-tropic PERV-A and PERV-B adds another level of infectious risk. Proviral PERV-C were characterized in MAX-T cells derived from d/d haplotype miniature swine. Three proviruses were cloned from a genomic library. Clone PERV-C(1312) generated infectious particles after transfection into porcine ST-IOWA cells. Electron microscopy revealed the same morphologies of virions in MAX-T cells and in ST-IOWA cells infected with cell-free PERV-C(1312) particles, indicating that MAX-T cells harbor one functional PERV-C provirus.


Importance of Streptococci Infections in Childhood Neuropsychiatric Disorders.
Paediatric autoimmune neuropsychiatric disorders associated with streptococci (PANDAS) are important neuropsychiatric disorders in childhood. Streptococcus pyogenes infection associated with tics, obsessive-compulsive disorders, and chorea co-occurrence is important. Swedo et al. have increased the awareness of this situation since 1998. How streptococcal infections give rise to this condition is not clear yet, but the severity of the symptoms is reduced by the treatment of streptococcal infections is important. Eight-year- nine-month-old girl presented with complaints of a 2-year history of upper respiratory tract infections and increased severity of blinking of eyes, throat cleaning, tic disorder and obsession with hand cleaning. In addition, choreiform movements were present and fluoxetine did not improve the symptoms. The patient was followed-up and treated with PANDAS pre-diagnosis. Streptococcus treatment and prophylaxis decreased the patient's complaints. A six-year-four months old boy, admitted with abnormal hand and body movements, which increased severity after the school period, and causing deteriorated fine motor skills during infectious periods for two years. There were also complaints with vocal tics and obsessive-compulsive disorder in the form of throat cleaning. Treatment of S. pyogenes was administered in throat culture. After the penicillin prophylaxis, the complaints decreased. In this study, two patients were presented with choreiform movements, obsessive-compulsive disorder and tic disorder due to follow-up PANDAS diagnosis. PANDAS should be considered in children with neuropsychiatric disorders, especially symptoms associated with infection periods.


Kibra and Merlin Activate the Hippo Pathway Spatially Distinct from and Independent of Expanded.
The Hippo pathway is emerging as a key evolutionarily conserved signaling mechanism that controls organ size. Three membrane-associated proteins, Kibra, Merlin, and Expanded, regulate pathway activity, but the precise molecular mechanism by which they function is still poorly understood. Here we provide evidence that Merlin and Kibra activate Hippo signaling in parallel to Expanded at a spatially distinct cellular domain, the medial apical cortex. Merlin and Kibra together recruit the adapter protein Salvador, which in turn recruits the core kinase Hippo. In addition, we show that Crumbs has a dual effect on Hippo signaling. Crumbs promotes the ability of Expanded to activate the pathway but also sequesters Kibra to downregulate Hippo signaling. Together, our findings elucidate the mechanism of Hippo pathway activation by Merlin and Kibra, identify a subcellular domain for Hippo pathway regulation, and demonstrate differential activity of upstream regulators in different subcellular domains.


The C9ORF72 expansion mutation is a common cause of ALS+/-FTD in Europe and has a single founder.
A massive hexanucleotide repeat expansion mutation (HREM) in C9ORF72 has recently been linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here we describe the frequency, origin and stability of this mutation in ALS+/-FTD from five European cohorts (total n=1347). Single-nucleotide polymorphisms defining the risk haplotype in linked kindreds were genotyped in cases (n=434) and controls (n=856). Haplotypes were analysed using PLINK and aged using DMLE+. In a London clinic cohort, the HREM was the most common mutation in familial ALS+/-FTD: C9ORF72 29/112 (26%), SOD1 27/112 (24%), TARDBP 1/112 (1%) and FUS 4/112 (4%) and detected in 13/216 (6%) of unselected sporadic ALS cases but was rare in controls (3/856, 0.3%). HREM prevalence was high for familial ALS+/-FTD throughout Europe: Belgium 19/22 (86%), Sweden 30/41 (73%), the Netherlands 10/27 (37%) and Italy 4/20 (20%). The HREM did not affect the age at onset or survival of ALS patients. Haplotype analysis identified a common founder in all 137 HREM carriers that arose around 6300 years ago. The haplotype from which the HREM arose is intrinsically unstable with an increased number of repeats (average 8, compared with 2 for controls, P<10(-8)). We conclude that the HREM has a single founder and is the most common mutation in familial and sporadic ALS in Europe.


Overexpression of the pseudoautosomal gene MIC2 in Ewing's sarcoma and peripheral primitive neuroectodermal tumor.
Ewing's Sarcoma (ES), the second most frequent bone tumor in childhood and adolescence, and the probably closely related peripheral primitive neuroectodermal tumor (pPNET) share a unique cytogenetic translocation between chromosomes 11 and 22. Both of them expose high amounts of a glycoprotein on their cell surface, which can be specifically detected by the mAb HBA-71. The cDNA coding for the HBA-71 antigen was isolated by screening a cDNA expression library constructed from a pPNET-derived cell line. Nucleotide sequencing revealed the HBA-71 antigen to be the product of the pseudoautosomal gene MIC2 previously identified by the mAb 12E7 in haematopoietic cells. This antigen is a glycoprotein with a molecular weight of about 29,000 and is expressed in low amounts in most human cell lines and probably normal tissues and tumors with only a few exceptions. In T-cells the antigen is involved in cell adhesion processes. In ES- and pPNET-derived cell lines MIC2 expression is significantly enhanced. No gross changes in posttranslational modification could be observed. The high expression results in easy and specific detection of the antigen in immunocytochemical analysis of paraffin embedded tissue sections making HBA-71 a useful tool in tumor diagnosis.


Evidence for involvement of lymphocyte function-associated antigen 1 in T cell migration to epidermis.
Although it is well known that in various T cell-mediated skin diseases T cells migrate preferentially to epidermis, no direct evidence has been presented in which molecules on T cells are important in directing T cell traffic to epidermis. We have previously established CD4+ autoreactive cloned T cells with a special tropism for epidermis in vitro as well as in vivo. Antibody inhibition studies demonstrated that only anti-lymphocyte function associated Ag 1 (anti-LFA-1) mAb completely inhibited the in vitro migration of the T cells toward the epidermis, whereas mAb against other T cell surface molecules had little or no effect. Monovalent F(ab) fragment of the anti-LFA-1 mAb, although less efficient, also inhibited the T cell migration. The apparent dependency of the inhibition on the anti-alpha-chain mAb suggested a major role for the alpha-chain of LFA-1 in T cell migration to epidermis. The relevance of an LFA-1-dependent mechanism to the epidermotropic migration of T cells was further strengthened by the findings that the T cell migration to epidermis was inhibited by divalent cation depletion, cytochalasin B, and low temperature. These findings indicate that the LFA-1 molecule, which is thought to be primarily involved in cell-to-cell adhesions, also plays an important role in directing T cell migration to epidermis.


Targeting the IGF-Axis for Cancer Therapy: Development and Validation of an IGF-Trap as a Potential Drug.
The insulin-like growth factor (IGF)-axis was implicated in cancer progression and identified as a clinically important therapeutic target. Several IGF-I receptor (IGF-IR) targeting drugs including humanized monoclonal antibodies have advanced to phase II/III clinical trials, but to date, have not progressed to clinical use, due, at least in part, to interference with insulin receptor signaling and compensatory signaling by the insulin receptor (IR) isoform A that can bind IGF-II and initiate mitogenic signaling. Here we briefly review the current state of IGF-targeting biologicals, discuss some factors that may be responsible for their poor performance in the clinic and outline the stepwise bioengineering and validation of an IGF-Trap-a novel anti-cancer therapeutic that could bypass these limitations. The IGF-Trap is a heterotetramer, consisting of the entire extracellular domain of the IGF-IR fused to the Fc portion of human IgG1. It binds human IGF-I and IGF-II with a three-log higher affinity than insulin and could inhibit IGF-IR driven cellular functions such as survival, proliferation and invasion in multiple carcinoma cell models in vitro. In vivo, the IGF-Trap has favorable pharmacokinetic properties and could markedly reduce metastatic outgrowth of colon and lung carcinoma cells in the liver, outperforming IGF-IR and ligand-binding monoclonal antibodies. Moreover, IGF-Trap dose-response profiles correlate with their bio-availability profiles, as measured by the IGF kinase receptor-activation (KIRA) assay, providing a novel, surrogate biomarker for drug efficacy. Our studies identify the IGF-Trap as a potent, safe, anti-cancer therapeutic that could overcome some of the obstacles encountered by IGF-targeting biologicals that have already been evaluated in clinical settings.


Genotype-phenotype associations in breast pathology: Achievements of the past quarter century.
The first genotype-phenotype relationship in breast pathology developed in 1994 with the discovery of the CDH1 gene. This finding eventually provided biological insight into the characteristic morphology of invasive lobular carcinoma. Subsequent investigative efforts have uncovered additional molecular alterations largely responsible for the histology of several breast neoplasms including secretory carcinoma, adenoid cystic carcinoma, tall cell carcinoma with reversed polarity, fibroepithelial lesions, and most recently, adenomyoepithelioma. Evaluation of the genomic landscape of other special types of breast cancer with distinctive growth patterns, such as invasive mucinous carcinoma, have yet to uncover recurring cytogenetic and/or molecular alterations. Despite the lack of a hallmark alteration in mucinous carcinoma, it is important to note the relative decrease in PIK3CA mutations compared with invasive carcinoma of no special type. In this review, we describe the clinical and pathologic features of breast tumors with recognized genotype-phenotype correlations and summarize the molecular alterations of mucinous carcinoma.


Comparative genomics and DNA methylation analysis of Pseudomonas aeruginosa clinical isolate PA3 by single-molecule real-time sequencing reveals new targets for antimicrobials.
Pseudomonas aeruginosa (P.aeruginosa) is an important opportunistic pathogen with broad environmental adaptability and complex drug resistance. Single-molecule real-time (SMRT) sequencing technique has longer read-length sequences, more accuracy, and the ability to identify epigenetic DNA alterations. This study applied SMRT technology to sequence a clinical strain P. aeruginosa PA3 to obtain its genome sequence and methylation modification information. Genomic, comparative, pan-genomic, and epigenetic analyses of PA3 were conducted. General genome annotations of PA3 were discovered, as well as information about virulence factors, regulatory proteins (RPs), secreted proteins, type II toxin-antitoxin (TA) pairs, and genomic islands. A genome-wide comparison revealed that PA3 was comparable to other P. aeruginosa strains in terms of identity, but varied in areas of horizontal gene transfer (HGT). Phylogenetic analysis showed that PA3 was closely related to P. aeruginosa 60503 and P. aeruginosa 8380. P. aeruginosa's pan-genome consists of a core genome of roughly 4,300 genes and an accessory genome of at least 5,500 genes. The results of the epigenetic analysis identified one main methylation sites, N6-methyladenosine (m6A) and 1 motif (CATNNNNNNNTCCT/AGGANNNNNNNATG). 16 meaningful methylated sites were picked. Among these, purH, phaZ, and lexA are of great significance playing an important role in the drug resistance and biological environment adaptability of PA3, and the targeting of these genes may benefit further antibacterial studies. This study provided a detailed visualization and DNA methylation information of the PA3 genome and set a foundation for subsequent research into the molecular mechanism of DNA methyltransferase-controlled P. aeruginosa pathogenicity.


Enhancement of endotoxin-induced isolated renal tubular cell injury by toxic shock syndrome toxin 1.
The pathogenesis of toxic shock syndrome (TSS) remains unknown. On the basis of experimental data, it has been hypothesized that staphylococcal TSS Toxin 1 (TSST-1) may interact synergistically with low levels of endotoxin and give rise to many of the clinical findings. We have demonstrated previously that lipid A, the biologically active component of lipopolysaccharide (LPS), or endotoxin, induces dose-dependent necrosis of isolated rat renal tubular cells (RTCs). In the present studies, the authors investigated whether this injury could be augmented by TSST-1. The viability of RTCs was assessed by vital dye exclusion. Incubation of freshly isolated rat RTCs with either 1 ng/ml of TSST-1 or 0.1 ng/ml LPS or lipid A had minimal cytotoxicity (less than 6%). Exposure of RTCs to 1 ng/ml TSST-1 for 20 minutes, followed by washing, resulted in a significant enhancement of cytotoxicity when RTCs were exposed to 0.1 ng/ml LPS or lipid A. The sensitization of RTCs by TSST-1 to LPS- or lipid-A-induced injury was prevented by methylamine and chloroquine, two inhibitors of receptor-mediated endocytosis (RME). Chelation of extracellular calcium by 2 mM EGTA also blocked the TSST-1-induced sensitization of RTCs to LPS or lipid A. Inhibition of RTC arachidonic acid metabolism by methylprednisolone, indomethacin, ibuprofen, and piriprost significantly inhibited RTC necrosis induced by TSST-1 and LPS or lipid A by 33-62%. Thiourea and deferoxamine, agents which ameliorate oxidant injury, also inhibited this synergistic injury by 34-67%. Thus, TSST-1 enhanced the cytotoxic effects of LPS/lipid A, and the sensitization of RTCs appeared to involve RME or TSST-1. Oxidative metabolism of arachidonic acid and generation of reactive oxygen species appeared to participate in LPS/lipid-A-mediated RTC death.


The response of chironomid taxonomy- and functional trait-based metrics to fish farm effluent pollution in lotic systems.
The lotic habitats affected by trout farm waste are colonized with a particular invertebrate community of which chironomids are the most abundant group. However, there is little information available regarding how chironomid community structures respond to this type of pollution at the highest taxonomic resolution. Eight fish farms, together with their lotic systems as recipients, were used to test the variability of the chironomid community and its surrogates (taxonomic and functional metrics) across spatially arranged sampling sites to form a gradual decrease in the trout farm influence. The self organizing map (SOM) classified six different types of chironomid communities which were characteristic for both the control and affected habitats. The species indicator analyses listed 32 taxa as positive indicators of water pollution. The SOM and Kruskal-Wallis test revealed that the pattern of chironomid community structure obtained was mainly driven by six environmental parameters (Altitude, conductivity, distance from the outlet, hardness, HN4-N, NO3-N). Categorical principal components analysis (CATPCA) derived three models for each type of biotic metric, in which for diversity-, taxonomy- and functional feeding group-based metrics, the first two dimensions explained 55.2%, 58.3% and 55.4%, of the total variance respectively for 315 sampling sites. According to this analysis, the total number of taxa (S), abundance and the Shannon-Wiener index (H') (as a diversity metric), as well as the proportion of Tanypodinae (as taxonomic group) and grazers/scraper (GRA) and gatherer collector (GAT)(as FFG metrics), were related to the outlet distance gradient, thus showing great potential to be used in the multimetric approach in bioassessment.


[Supraglottic horizontal partial laryngectomies in 163 cases].
To evaluate the clinical value of supraglottic horizontal partial laryngectomy. One hundred and sixty-three patients with supraglottic laryngeal carcinoma were treated surgically by supraglottic horizontal partial laryngectomy from 1978 to 1998. There were 64 males and 99 females. Five cases were staged I, 95 staged II, 48 staged III and 15 staged IV. The surgical techniques were improved: The hyoid was removed conventionally; The outer perichondrium of thyroid cartilage was turned into the laryngeal cavity and sutured with the mucosa of laryngeal ventricle and the base of tongue was sutured to the reserved thyroid cartilage. Survival was evaluated using the Kaplan-Meier method. The differences between stages were tested by Los-Rank method. The 5-year survival rate were 100.0%, 77.9%, 54.2% and 33.3% for patients staged I to IV respectively, and were statistically significant (P = 0.0006) between different clinical stages. The 5-year survival rate were 73.1% and 45.5% in patients with cN0 and cN + respectively, and were statistically significant (P = 0.0132). The speech and swallowing functions were good after operation. The decannulation rate was 91.4%. The main causes of death were cervical lymph node metastasis in 40% (20/50) and laryngeal recurrence in 18% (9/50). The occult metastasis rate was 23.1% (30/130) and cervical metastasis rates of patients with cN1-3 75.8% (25/33), with a total metastasis rate was 33.7 (55/163). Supraglottic horizontal partial laryngectomy is very effective in eradicating disease and in preserving laryngeal function on condition that the indications were selected correctly. The selective lateral neck dissection was recommended for supraglottic carcinoma.


Panaceas, uncertainty, and the robust control framework in sustainability science.
A critical challenge faced by sustainability science is to develop strategies to cope with highly uncertain social and ecological dynamics. This article explores the use of the robust control framework toward this end. After briefly outlining the robust control framework, we apply it to the traditional Gordon-Schaefer fishery model to explore fundamental performance-robustness and robustness-vulnerability trade-offs in natural resource management. We find that the classic optimal control policy can be very sensitive to parametric uncertainty. By exploring a large class of alternative strategies, we show that there are no panaceas: even mild robustness properties are difficult to achieve, and increasing robustness to some parameters (e.g., biological parameters) results in decreased robustness with respect to others (e.g., economic parameters). On the basis of this example, we extract some broader themes for better management of resources under uncertainty and for sustainability science in general. Specifically, we focus attention on the importance of a continual learning process and the use of robust control to inform this process.


Fibrosis and cardiac arrhythmias.
In this review article about fibrosis and arrhythmias, we show that the amount of collagen, a normal element of the heart muscle, increases with age and in heart disease. The relation between fibrosis and electrophysiological parameters such as conduction, fractionation of electrograms, abnormal impulse initiation as well as arrhythmogenicity is discussed. Next to the amount of fibrosis, we offer data suggesting that collagen texture too plays a role in conduction slowing and arrhythmia vulnerability. Data are shown revealing that fibrosis can also be induced by reduced sodium channel and connexin43 expression. Finally contrast-enhanced magnetic resonance to detect fibrosis and ventricular tachycardia vulnerability in a noninvasive way as well as a reduction of fibrosis and arrhythmogenicity by inhibition of the renin-angiotensin-aldosterone system is discussed.


Molecular diagnosis in dermatopathology: what makes sense, and what doesn't.
Molecular techniques have provided us with a wealth of information about biological events in healthy individual, and improved tremendously our understanding about the pathogenesis of a huge variety of cutaneous diseases. Those methods have originally been invented to support basic scientific investigations on a molecular level and are translated increasingly into sophisticated diagnostic tools changing the classic paradigm of diagnostic pathology; among them are immunohistochemistry (IHC), polymerase chain reaction (PCR), G-banding, loss of heterozygosity, fluorescence in situ hybridization (FISH), chromogen in situ hybridization (CISH), comparative genomic hybridization on chromosomes and microarray technology. Some of them such as IHC and PCR have already been standardized to a level that allows its utility in daily routine diagnostics for several dermatological diseases. For others like array-based technologies, their optimal indications await to be fully determined. These ancillary methods have the great potential to contribute important new information to challenging cases, and will help to improve diagnostic accuracy particularly in cases in which conventional histopathology is ambiguous. Thus, they will broaden our armamentarium for diagnostic pathology. Herein, some key techniques will be reviewed and their applicability towards the diagnosis of dermatological diseases critically discussed.


Mental and behavioural disorders in the ICD-11: concepts, methodologies, and current status.
This review provides an overview of the concepts, methods and current status of the development of the Eleventh Revision of the Mental and Behavioural Disorders chapter of the International Classification of Diseases and Related Health Problems (ICD-11) by the World Health Organization (WHO). Given the global use of the current version (ICD-10) for a wide range of applications in clinical practice and health statistics, a major aim of the development process for ICD-11 has been to increase the utility of the classification system. Expert working groups with responsibility for specific disorder groupings first suggested a set of revised diagnostic guidelines. Then surveys were performed to obtain suggestions for revisions from practicing health professionals. A completely revised structure for the classification of mental and behavioural disorders was developed and major revisions were suggested, for example, for schizophrenia and other primary psychotic disorders, substance use disorders, affective disorders and personality disorders. A new category of "gaming disorder" has been proposed and conditions related to sexual health and gender identity will be classified separately from mental disorders. An ICD-11 beta draft is freely available on the internet and public comments are invited. Field studies of the revised diagnostic guidelines are in process to obtain additional information about necessary improvements. A tabulated crosswalk from previous ICD-10 to then ICD-11 criteria will be necessary to ascertain the continuity of diagnoses for epidemiological and other statistical purposes. The final version of ICD-11 is currently scheduled for release by the World Health Assembly in 2018.


In vitro and in vivo antiplasmodial activity and cytotoxicity of extracts of Phyllanthus niruri L. herbs traditionally used to treat malaria in Indonesia.
In endemic areas where malaria is prevalent, medicinal plants are often used to treat malaria. This study was conducted to evaluate the in vitro and in vivo antiplasmodial activity and cytotoxicity of extracts of meniran (Phyllanthus niruri L.) herb traditionally used to treat malaria in Indonesia. Three extracts viz aqueous, methanolic and chloroformic extracts were obtained by maceration of the herbs. A radioactive method was used to evaluate the in vitro antiplasmodial activity of the extracts on chloroquine-resistant (FCR-3) and chloroquine-sensitive (D-10) strains of Plasmodium falciparum. In vitro antiplasmodial activity was expressed by the concentration inhibiting 50% of parasite growth (IC50). Cytotoxicity was estimated on Hela cells and the Cytotoxicity Index (CI = IC50 on HeLa cells/IC50 on FCR-3 strain) was calculated to evaluate the safety of tested extracts. A standard 4-day test on P berghei infected mice was used to evaluate the in vivo antiplasmodial activity of the extracts showing strong in vitro antiplasmodial activity, for both the methanolic and aqueous extracts. The in vivo antiplasmodial activity was expressed by the dose inhibiting 50% of parasite growth (ED50). The IC50 values obtained for these extracts against P. falciparum ranged from 2.3 to 202.4 microg/ml. The methanolic extract was the most active in vitro extract with an IC50 that ranged from 2.3 to 3.9 microg/ml and a CI that ranged from 41.3 to 57.5. This was also the most in vivo active extract with an ED50 of 9.1 mg/kg/d. Further study will be conducted to isolate and purify active compounds presented in the methanolic extract.


The training and generalization of social interaction skills with autistic youth.
Two experiments were conducted to increase the initiations and duration of social interactions between autistic and nonhandicapped youths. Experiment 1 taught two autistic youths to initiate and elaborate social interactions with three age-appropriate and commonly used leisure objects; a radio, a video game, and gum. The students were first taught to use the objects and subsequently instructed in the related social skills. The youths generalized these social responses to other non-handicapped peers in the same leisure setting. A second experiment trained a third autistic youth to emit similar social leisure skills. The use of the leisure objects and the related social skills were taught at the same time. The autistic youth learned these skills and generalized them to other handicapped peers in the same leisure setting. The importance of teaching generalized social responding in particular subenvironments was emphasized.


Interferon production by human-mouse hybrid cells: dominant mouse control of superinduction and priming.
We have examined the production of interferon by a number of human-mouse hybrid clones in response to polyriboinosinic acid:polyribocytidylic acid copolymer [poly(rI).poly(rC)] all of which produced both human and mouse interferons when stimulated with a virus. Their capacity to be superinduced and primed for interferon production in response to poly(rI).poly(rC) was compared to that of the parental human and mouse cells. It was found that the hybrids responded in a way similar to their mouse cell parents, indicating dominant mouse control of both the priming and superinduction phenomena.


A staff perspective of early warning signs intervention for individuals with psychosis: clinical and service implications.
Research has established the benefits of early warnings signs monitoring in the prevention of relapse for individuals with psychosis. This study explored staff views (n = 8) of the implementation of an early warning signs clinic within a day hospital of an adult mental health service. A qualitative methodology using focus groups was adopted and content analysis was used to discover themes arising from the data. Overall, the data indicated a positive view of the early warning signs clinic, with benefits for clients, staff and their relationship; and for service delivery and resources. The clinical and service implications are discussed.


Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor.
Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colony-stimulating factor (M-CSF), a primary cytokine for macrophages. Here, we show that the inhibitory effect of Nef is due to the Hck-dependent down-regulation of the cell surface expression of M-CSF receptor Fms. In the presence of Hck, Nef induced the accumulation of an immature under-N-glycosylated Fms at the Golgi, thereby down-regulating Fms. The activation of Hck by the direct interaction with Nef was indispensable for the down-regulation. Unexpectedly, the accumulation of the active Hck at the Golgi where Nef prelocalized was likely to be another critical determinant of the function of Nef, because the expression of the constitutive-active forms of Hck alone did not fully down-regulate Fms. These results suggest that Nef perturbs the intracellular maturation and the trafficking of nascent Fms, through a unique mechanism that required both the activation of Hck and the aberrant spatial regulation of the active Hck.