CAMcog as a screening tool for diagnosis of mild cognitive impairment and dementia in a Brazilian clinical sample of moderate to high education.
The CAMCOG is a brief neuropsychological battery designed to assess global cognitive function and ascertain the impairments that are required for the diagnosis of dementia. To date, the cut-off scores for mild cognitive impairment (MCI) have not been determined. Given the need for an earlier diagnosis of mild dementia, new cut-off values are also necessary, taking into account cultural and educational effects. One hundred and fifty-seven older adults (mean age: 69.6 +/- 7.4 years) with 8 or more years of formal education (mean years of schooling 14.2 +/- 3.8) attending a memory clinic at the Institute of Psychiatry University of Sao Paulo were included. Subjects were divided into three groups according to their cognitive status, established through clinical and neuropsychological assessment: normal controls, n = 62; MCI, n = 65; and mild or moderate dementia, n = 30. ROC curve analyses were performed for dementia vs controls, MCI vs controls and MCI vs dementia. The cut-off values were: 92/93 for dementia vs controls (AUC = 0.99: sensitivity: 100%, specificity: 95%); 95/96 for MCI vs controls (AUC = 0.83, sensitivity: 64%, specificity: 88%), and 85/86 for MCI vs dementia (AUC = 0.91, sensitivity: 81%, specificity: 88%). The total CAMCOG score was more accurate than its subtests Mini-mental State Examination, Verbal Fluency Test and Clock Drawing Test when used separately. The CAMCOG discriminated controls and MCI from demented patients, but was less accurate to discriminate MCI from controls. The best cut-off value to differentiate controls and demented was higher than suggested in the original publication, probably because only cases of mild to moderate dementia were included. This is important given the need for a diagnostic at earlier stages of Alzheimer's disease.


Respiratory symptoms and cotton dust exposure; results of a 15 year follow up observation.
To determine chronic effects of long term exposure to cotton dust and endotoxin on incidence of respiratory symptoms and the effect of cessation of exposure. Respiratory health in 429 Chinese cotton textile workers (study group) and 449 silk textile workers (control group) was followed prospectively from 1981 to 1996. Byssinosis, chest tightness, and non-specific respiratory symptoms were assessed by means of identical standardised questionnaires at four time points. Exposures to cotton dust and endotoxin were estimated using area samples collected at each survey. Incidence and persistence of symptoms were examined in relation to cumulative exposure and exposure cessation using generalised estimating equations (GEE). Among cotton workers, the cumulative incidence of byssinosis and chest tightness was 24% and 23%, respectively, and was significantly more common in smokers than in non-smokers. A high proportion of symptoms was found to be intermittent, rather than persistent. Among silk workers, no typical byssinosis was identified; the incidence of chest tightness was 10%. Chronic bronchitis, cough, and dyspnoea were more common and persistent in the cotton group than in the silk group. Significantly lower odds ratios for symptoms were observed in cotton workers who left the cotton mills; risk was also related to years since last worked. Multivariate analysis indicated a trend for higher cumulative exposure to endotoxin in relation to a higher risk for byssinosis. Chronic exposure to cotton dust is related to both work specific and non-specific respiratory symptoms. Byssinosis is more strongly associated with exposure to endotoxin than to dust. Cessation of exposure may improve the respiratory health of cotton textile workers; the improvement appears to increase with time since last exposure.


Basal arterial occlusive disease.
Seventeen patients with basal occlusive disease have been seen over the past 4 years. Nine of these had a classical moyamoya appearance on angiography. Of these nine, seven were adults and two were children. Eight had ischemic episodes, and one had a hemorrhage. One had neurofibromatosis with a chiasmal glioma and had received radiotherapy. Eight patients underwent superficial temporal-middle cerebral artery (STA-MCA) bypass, and one refused operation. Six patients improved, one had a stroke on the opposite side, and one died. Eight patients had unilateral basal arterial occlusive disease. Of these, three had ischemic episodes, four had hemorrhages, and one had only headaches. Four were adults, and four were children. Five underwent STA-MCA bypass with improvement, one with headaches had an aneurysm treated, and two were not operated upon. Considerations regarding the cause, therapeutic options, and disease course in these patients are discussed.


A review of the status of alternative approaches to animal testing and the development of integrated testing strategies for assessing the toxicity of chemicals under REACH--a summary of a DEFRA-funded project conducted by Liverpool John Moores University and FRAME.
Liverpool John Moores University and FRAME were recently awarded a DEFRA tender to conduct a review of the status of alternative approaches to animal testing, and to recommend further research with regard to the forthcoming European Union REACH (Registration, Evaluation and Authorisation of Chemicals) system for the safety testing and risk assessment of chemicals. The outcome of the project is summarised, including the prospects for in vitro and in silico testing, areas where reduction and refinement could be applied, and how decision-tree integrated testing strategies could be used to reduce the number of animals needed to fulfil the testing requirements of the REACH system. This paper is a prelude to a series of individual papers on detailed suggestions for applying non-animal methods to each of the major toxicity endpoints in REACH.


FOXO1 Inhibition Generates Potent Nonactivated CAR T Cells against Solid Tumors.
Chimeric antigen receptor (CAR) T cells have shown promising results in the treatment of B-cell malignancies. Despite the successes, challenges remain. One of them directly involves the CAR T-cell manufacturing process and especially the ex vivo activation phase. While this is required to allow infection and expansion, ex vivo activation dampens the antitumor potential of CAR T cells. Optimizing the nature of the T cells harboring the CAR is a strategy to address this obstacle and has the potential to improve CAR T-cell therapy, including for solid tumors. Here, we describe a protocol to create CAR T cells without ex vivo preactivation by inhibiting the transcription factor FOXO1 (CAR TAS cells). This approach made T cells directly permissive to lentiviral infection, allowing CAR expression, with enhanced antitumor functions. FOXO1 inhibition in primary T cells (TAS cells) correlated with acquisition of a stem cell memory phenotype, high levels of granzyme B, and increased production of TNFα. TAS cells displayed enhanced proliferative and cytotoxic capacities as well as improved migratory properties. In vivo experiments showed that CAR TAS cells were more efficient at controlling solid tumor growth than classical CAR T cells. The production of CAR TAS from patients' cells confirmed the feasibility of the protocol in clinic.


Relationship between Maternal Body Mass Index and Obstetric and Perinatal Complications.
Over the past few decades, overweight and obesity have become a growing health problem of particular concern for women of reproductive age as obesity in pregnancy has been associated with increased risk of obstetric and neonatal complications. The objective of this study is to describe the incidence of obstetric and perinatal complications in relation to maternal body mass index (BMI) at the time prior to delivery within the Spanish Health System. For this purpose, a cross-sectional observational study was conducted aimed at women who have been mothers between 2013 and 2018 in Spain. Data were collected through an online survey of 42 items that was distributed through lactation associations and postpartum support groups. A total of 5871 women answered the survey, with a mean age of 33.9 years (SD = 4.26 years). In the data analysis, crude odds ratios (OR) and adjusted odds ratios (AOR) were calculated through a multivariate analysis. A linear relationship was observed between the highest BMI figures and the highest risk of cephalopelvic disproportion (AOR of 1.79 for obesity type III (95% CI: 1.06-3.02)), preeclampsia (AOR of 6.86 for obesity type III (3.01-15.40)), labor induction (AOR of 1.78 for obesity type III (95% CI: 1.16-2.74)), emergency C-section (AOR of 2.92 for obesity type III (95% CI: 1.68-5.08)), morbidity composite in childbirth (AOR of 3.64 for obesity type III (95% CI: 2.13-6.24)), and macrosomia (AOR of 6.06 for obesity type III (95% CI: 3.17-11.60)), as compared with women with normoweight. Women with a higher BMI are more likely to develop complications during childbirth and macrosomia.


Functional and comparative evaluation of flexible monopolar endoscopic scissors.
The continued success of natural orifice translumenal endoscopic procedures requires reliable, accurate tissue dissection and suture cutting. This study aimed to evaluate a flexible endoscopic scissors prototype. An acute study of two domestic swine was conducted. Laparoscopic access provided an overview and allowed comparison of the flexible endoscopic scissors with laparoscopic shears. The endoscopic cautery-compatible scissors consists of cutting blades with a flexible wire catheter assembly (outer diameter, 3.1 mm) for use within a therapeutic endoscopic channel. A dual-channel colonoscope was advanced through a gastrotomy created for peritoneal access. With the aide of a grasping forceps, multiple peritoneal biopsies were obtained using the endoscopic scissors. Cautery (Monopolar 18-30 W) then was attached to the scissors, and gallbladder dissection proceeded. The device then was used to perform a small bowel enterotomy. A timed comparison of this function with laparoscopic enterotomy was made. Finally, 3-0 Polyglactin 910 suture was cut using the endoscopic scissors. Peritoneal biopsies 2 cm(2) in size were obtained from multiple abdominal locations and endoscopic positions, including the retroflexed position. The scissors cut effectively and accurately. Cutting performance was enhanced with parallel countertraction provided by grasping forceps passed through the second endoscopic channel. The use of cautery with the scissors controlled small vessels (2-3 mm) and permitted partial dissection of the gallbladder from the hepatic bed. Small bowel enterotomy sufficiently large for stapler passage was created in 4 min and 54 s. Laparoscopically, this was completed in 1 min and 22 s. Suture was successfully cut at the first attempt in a controlled, reproducible fashion. Controlled tissue biopsy, dissection, enterotomy creation, and suture cutting can be performed with this endoscopic scissors. Endoscopic tissue dissection and enterotomy creation was completed effectively but less efficiently than with laparoscopy primarily due to parallel device use imposed by the dual-channel endoscope.


Energy cost of physical activities in persons with spinal cord injury.
The objectives of this descriptive study were (a) to determine the energy expenditure of activities commonly performed by individuals with a spinal cord injury (SCI) and summarize this information and (b) to measure resting energy expenditure and establish the value of 1 MET for individuals with SCI. One-hundred seventy adults with SCI were partitioned by gender, anatomical level of SCI, and American Spinal Injury Association designations for motor function. Twenty-seven physical activities, 12 recreational/sport and 15 daily living, were performed, while energy expenditure was measured continuously via a COSMED K4b portable metabolic system. In addition, 66 adult males with SCI completed 30 min of supine resting energy testing in a quiet environment. Results for the 27 measured activities are reported in kilocalories per minute (kcal·min(-1)) and VO2 (mL·min(-1) and mL·kg(-1)·min(-1)). One MET for a person with SCI should be adjusted using 2.7 mL·kg(-1)·min(-1). Using 2.7 mL·kg(-1)·min(-1), the MET range for persons in the motor incomplete SCI group was 1.17 (supported standing) to 6.22 (wheeling on grass), and 2.26 (billiards) to 16.25 (hand cycling) for activities of daily living and fitness/recreation, respectively. The MET range for activities of daily living for persons in the group with motor complete SCI was 1.27 (dusting) to 4.96 (wheeling on grass) and 1.47 (bait casting) to 7.74 (basketball game) for fitness/recreation. The foundation for a compendium of energy expenditure for physical activities for persons with SCI has been created with the completion of this study. In the future, others will update and expand the content of this compendium as has been the case with the original compendium for the able-bodied.


Cardiomyocytes Derived from Induced Pluripotent Stem Cells as a Disease Model for Propionic Acidemia.
Propionic acidemia (PA), one of the most frequent life-threatening organic acidemias, is caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme. Cardiac alterations (hypertrophy, dilated cardiomyopathy, long QT) are one of the major causes of mortality in patients surviving the neonatal period. To overcome limitations of current cellular models of PA, we generated induced pluripotent stem cells (iPSCs) from a PA patient with defects in the PCCA gene, and successfully differentiated them into cardiomyocytes. PCCA iPSC-derived cardiomyocytes exhibited reduced oxygen consumption, an accumulation of residual bodies and lipid droplets, and increased ribosomal biogenesis. Furthermore, we found increased protein levels of HERP, GRP78, GRP75, SIG-1R and MFN2, suggesting endoplasmic reticulum stress and calcium perturbations in these cells. We also analyzed a series of heart-enriched miRNAs previously found deregulated in the heart tissue of a PA murine model and confirmed their altered expression. Our novel results show that PA iPSC-cardiomyocytes represent a promising model for investigating the pathological mechanisms underlying PA cardiomyopathies, also serving as an ex vivo platform for therapeutic evaluation.


Association of living alone with clinical outcomes in patients with heart failure: A systematic review and meta-analysis.
Living alone is an objective sign of social isolation. It is uncertain whether living alone worsens clinical outcomes in heart failure (HF) patients. We aimed to assess how living alone affected clinical outcomes in individuals with HF. We searched the electronic databases of PubMed, Embase, and Cochrane from 1990 to April 2022 for studies comparing living alone with HF. A random-effects model with inverse variance was used to pool adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Seven studies were deemed to meet the standards. In patients with HF, compared with living with others, living alone was associated with an elevated risk of any hospitalization at the 30-day (HR: 1.78, 95% CI: 1.09-2.89), 90-day (HR: 1.24, 95% CI: 1.02-1.51), or ≥1-year (HR: 1.14, 95% CI: 1.04-1.26) follow-up periods. HF patients living alone also had a greater risk of any hospitalization or death at the 30-day (HR: 1.56, 95% CI: 1.15-2.11), 90-day (HR: 1.26, 95% CI: 1.05-1.50), and ≥1-year (HR: 1.18, 95% CI: 1.09-1.28) follow-up periods. However, patients living alone had no increased risk of all-cause death at the 30-day (HR: 1.0, 95% CI: 0.19-5.36), 90-day (HR: 0.46, 95% CI: 0.03-7.42), or ≥ 1-year (HR: 1.10, 95% CI: 0.73-1.67) follow-up periods. In comparison to living with others, living alone was associated with an increased risk of any hospitalization but not all-cause death in HF patients.


Mitogen-stimulated TIS21 protein interacts with a protein-kinase-Calpha-binding protein rPICK1.
TIS21 is induced transiently by PMA and a number of extracellular stimuli. Yeast two-hybrid screening has identified three TIS21 interacting clones from a rat cDNA library [Lin, Gary, Yang, Clarke and Herschman (1996) J. Biol. Chem 271, 15034-15044]. The amino acid sequence deduced from clone 5A shows 96.9% identity with the murine PICK1, a protein kinase Calpha (PKCalpha)-binding protein postulated to act as an intracellular receptor for PKC. A fusion protein of glutathione S-transferase and rPICK1 associates with the TIS21 translated in vitro, suggesting a direct physical interaction between these two proteins. TIS21 and rPICK1 are co-immunoprecipitated from NIH 3T3 cells overexpressing these two proteins. This indicates that the interaction also occurs in mammalian cells. Deletion of the PDZ domain at the N-terminus of rPICK1 abolishes its interaction with TIS21. A putative carboxylate-binding loop required for PICK1 to bind PKCalpha [Staudinger, Lu and Olson (1997) J. Biol. Chem 272, 32019-32024] is within this deleted region. Our results suggest a potential competition between TIS21 and PKC for binding to PICK1. We show that recombinant TIS21 is phosphorylated by PKC in vitro. The catalytic activity of PKC towards TIS21 is significantly decreased in the presence of rPICK1, whereas phosphorylation of histone by PKC is not affected. rPICK1 seems to modulate the phosphorylation of TIS21 through specific interactions between these two proteins. TIS21 might have a role in PKC-mediated extracellular signal transduction through its interaction with rPICK1.


Effect of timing of umbilical cord clamping and other strategies to influence placental transfusion at preterm birth on maternal and infant outcomes.
Infants born preterm (before 37 weeks' gestation) have poorer outcomes than infants at term, particularly if born before 32 weeks. Early cord clamping has been standard practice over many years, and enables quick transfer of the infant to neonatal care. Delayed clamping allows blood flow between the placenta, umbilical cord and baby to continue, and may aid transition. Keeping baby at the mother's side enables neonatal care with the cord intact and this, along with delayed clamping, may improve outcomes. Umbilical cord milking (UCM) is proposed for increasing placental transfusion when immediate care for the preterm baby is needed. This Cochrane Review is a further update of a review first published in 2004 and updated in 2012. To assess the effects on infants born at less than 37 weeks' gestation, and their mothers of: 1) delayed cord clamping (DCC) compared with early cord clamping (ECC) both with immediate neonatal care after cord clamping; 2) DCC with immediate neonatal care with cord intact compared with ECC with immediate neonatal care after cord clamping; 3) DCC with immediate neonatal care after cord clamping compared with UCM; 4) UCM compared with ECC with immediate neonatal care after cord clamping. We searched the Cochrane Pregnancy and Childbirth Group Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (10 November 2017), and reference lists of retrieved studies. We updated the search in November 2018 and added nine new trial reports to the awaiting classification section to be assessed at the next update. Randomised controlled trials (RCTs) comparing delayed with early clamping of the umbilical cord (with immediate neonatal care after cord clamping or with cord intact) and UCM for births before 37 weeks' gestation. Quasi-RCTs were excluded. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Random-effects are used in all meta-analyses. Review authors assessed the certainty of the evidence using the GRADE approach. This update includes forty-eight studies, involving 5721 babies and their mothers, with data available from 40 studies involving 4884 babies and their mothers. Babies were between 24 and 36+6 weeks' gestation at birth and multiple births were included. The data are mostly from high-income countries. Delayed clamping ranged between 30 to 180 seconds, with most studies delaying for 30 to 60 seconds. Early clamping was less than 30 seconds and often immediate. UCM was mostly before cord clamping but some were milked after cord clamping. We undertook subgroup analysis by gestation and type of intervention, and sensitivity analyses by low risk of selection and attrition bias.All studies were high risk for performance bias and many were unclear for other aspects of risk of bias. Certainty of the evidence using GRADE was mostly low, mainly due to imprecision and unclear risk of bias.Delayed cord clamping (DCC) versus early cord clamping (ECC) both with immediate neonatal care after cord clamping (25 studies, 3100 babies and their mothers)DCC probably reduces the number of babies who die before discharge compared with ECC (average risk ratio (aRR) 0.73, 95% confidence interval (CI) 0.54 to 0.98, 20 studies, 2680 babies (moderate certainty)).No studies reported on 'Death or neurodevelopmental impairment' in the early years'.DCC may make little or no difference to the number of babies with severe intraventricular haemorrhage (IVH grades 3 and 4) (aRR 0.94, 95% CI 0.63 to 1.39, 10 studies, 2058 babies, low certainty) but slightly reduces the number of babies with any grade IVH (aRR 0.83, 95% CI 0.70 to 0.99, 15 studies, 2333 babies, high certainty).DCC has little or no effect on chronic lung disease (CLD) (aRR 1.04, 95% CI 0.94 to 1.14, 6 studies, 1644 babies, high certainty).Due to insufficient data, we were unable to form conclusions regarding periventricular leukomalacia (PVL) (aRR 0.58, 95% CI 0.26 to 1.30, 4 studies, 1544 babies, low certainty) or maternal blood loss of 500 mL or greater (aRR 1.14, 95% CI 0.07 to 17.63, 2 studies, 180 women, very low certainty).We identified no important heterogeneity in subgroup or sensitivity analyses.Delayed cord clamping (DCC) with immediate neonatal care with cord intact versus early cord clamping (ECC) (one study, 276 babies and their mothers)There are insufficient data to be confident in our findings, but DCC with immediate neonatal care with cord intact may reduce the number of babies who die before discharge, although the data are also compatible with a slight increase in mortality, compared with ECC (aRR 0.47, 95% CI 0.20 to 1.11, 1 study, 270 babies, low certainty). DCC may also reduce the number of babies who die or have neurodevelopmental impairment in early years (aRR 0.61, 95% CI 0.39 to 0.96, 1 study, 218 babies, low certainty). There may be little or no difference in: severe IVH; all grades IVH; PVL; CLD; maternal blood loss ≥ 500 mL, assessed as low certainty mainly due to serious imprecision.Delayed cord clamping (DCC) with immediate neonatal care after cord clamping versus umbilical cord milking (UCM) (three studies, 322 babies and their mothers) and UCM versus early cord clamping (ECC) (11 studies, 1183 babies and their mothers)There are insufficient data for reliable conclusions about the comparative effects of UCM compared with delayed or early clamping (mostly low or very low certainty). Delayed, rather than early, cord clamping may reduce the risk of death before discharge for babies born preterm. There is insufficient evidence to show what duration of delay is best, one or several minutes, and therefore the optimum time to clamp the umbilical cord remains unclear. Whilst the current evidence supports not clamping the cord before 30 seconds at preterm births, future trials could compare different lengths of delay. Immediate neonatal care with the cord intact requires further study, and there are insufficient data on UCM.The nine new reports awaiting further classification may alter the conclusions of the review once assessed.


Tunable electrical conductivity in metal-organic framework thin-film devices.
We report a strategy for realizing tunable electrical conductivity in metal-organic frameworks (MOFs) in which the nanopores are infiltrated with redox-active, conjugated guest molecules. This approach is demonstrated using thin-film devices of the MOF Cu3(BTC)2 (also known as HKUST-1; BTC, benzene-1,3,5-tricarboxylic acid) infiltrated with the molecule 7,7,8,8-tetracyanoquinododimethane (TCNQ). Tunable, air-stable electrical conductivity over six orders of magnitude is achieved, with values as high as 7 siemens per meter. Spectroscopic data and first-principles modeling suggest that the conductivity arises from TCNQ guest molecules bridging the binuclear copper paddlewheels in the framework, leading to strong electronic coupling between the dimeric Cu subunits. These ohmically conducting porous MOFs could have applications in conformal electronic devices, reconfigurable electronics, and sensors.


Estimation of dielectric function of biotin-capped gold nanoparticles via signal enhancement on surface plasmon resonance.
Biotin-capped gold nanoparticles assembled on flat gold with volume fraction f are studied by surface plasmon resonance (SPR) spectroscopy and atomic force microscopy (AFM) in order to estimate the dielectric function of the gold nanoparticles based on the Maxwell-Garnett (MG) theory. The complex dielectric function (epsilon',epsilon'') of the spherical nanoparticles at three representative wavelengths in the vis-near-IR region, i.e., lambda = 543, 632.8, and 1152 nm, is estimated for a surface homogeneously covered with nanoparticles in order to discuss the wavelength dependence of the dielectric function. The SPR response of a surface covered with particles in 2D aggregates is also analyzed. The experimental SPR curve of the particle aggregates deviates from the theoretical predictions, suggesting dipole interactions between particles.


BET 1: Prone positioning of awake patients with acute hypoxaemic respiratory failure.
A short-cut review of the literature was carried out to examine the potential utility of prone positioning in awake patients with hypoxaemic respiratory failure. Four papers were identified as suitable for inclusion using the reported search strategy. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of the best papers are tabulated. It is concluded that there is no evidence that regular prone positioning in the awake patient with hypoxaemic respiratory failure impacts on clinically relevant outcomes. Further research is required to evaluate the safety and effectiveness of this intervention, compared with routine mobilisation strategies.


Characterization of cross-links between cellulose microfibrils, and their occurrence during elongation growth in pea epicotyl.
The occurrence and chemical nature of the cross-links between cellulose microfibrils in outer epidermal cell walls in Pisum sativum cv. Alaska was investigated by rapid-freezing and deep-etching techniques coupled with chemical and enzymatic treatments. The cell wall in the elongating region of epidermal cells was characterized by the absence of the cross-links, while in the elongated region, the cell wall was characterized by the presence of cross-links. The cross-links remained in the cell wall of the elongated region after treatment with SDS electrophoresis sample buffer and treatment with 4% potassium hydroxide. After treatment with endo-1,4-beta-glucanase, which fragments xyloglucan, the cross-links were remarkably reduced from the cell wall of the elongated region. The endoglucanase treatment also reduced immunogold labeling of xyloglucan in the cell wall. The endoglucanase hydrolysate from the cell wall fraction of the elongated region gave spots of oligosaccharides in thin layer chromatography, which were identical to the spots of xyloglucan oligosaccharides produced by xyloglucanase from both the cell wall fraction and tamarind xyloglucan. These results indicate that the cross-links are made of xyloglucan. We discussed the possibility of cross-links involved in the control of mechanical properties of the cell wall.


Quantification of the importance of individual steps in the control of aromatic amino acid metabolism.
The quantitative importance of the individual steps of aromatic amino acid metabolism in rat liver was determined by calculation of the respective Control Coefficients (Strengths). The Control Coefficient of tryptophan 2,3-dioxygenase for tryptophan degradation was determined in a variety of physiological conditions and with a range of activities of tryptophan 2,3-dioxygenase. The Control Coefficient varied from 0.75 with basal enzyme activity to 0.25 after maximal induction of the enzyme by dexamethasone. The remainder of the control for tryptophan degradation was associated with the transport of the amino acid across the plasma membrane, with only very small contributions from kynureninase and kynurenine hydroxylase. The Control Coefficients of tyrosine aminotransferase for tyrosine degradation were approx. 0.70 and 0.20 with basal and dexamethasone-induced tyrosine aminotransferase activities respectively; the Control Coefficients of the transport of the amino acid into the cell were 0.22 and 0.58 respectively. Phenylalanine hydroxylase was found to have a Control Coefficient for the degradation of phenylalanine of approx. 0.50 under conditions of basal enzyme activity; after maximal activation by glucagon, the Control Coefficient decreased to 0.12. The transport of phenylalanine was responsible for the remaining control in the pathway. These results have important implications, directly for the regulation of aromatic amino acid metabolism in the liver, and indirectly for the regulation of neuroamine synthesis in the brain.


Self-assembled structures of hydrogen-bonded poly(vinyl chloride-g-4-vinyl pyridine) graft copolymers.
An amphiphilic graft copolymer of poly(vinyl chloride-graft-4-vinyl pyridine), i.e., PVC-g-P4VP was synthesized via atom transfer radical polymerization (ATRP) and modified by introducing 1,5-dihydroxynaphthalene (DHN) as a hydrogen bonding donor to form hydrogen-bonded macromolecules. The PVC-g-P4VP graft copolymer prepared from a selective solvent for PVC, i.e., tetrahydrofuran (THF) exhibited a well-organized micellar morphology consisting of a P4VP core and a PVC corona. However, the graft copolymer prepared from a good solvent for both domains, i.e., N, N-dimethylformamide (DMF) showed a less-organized, random microphase-separated morphology. Upon the introduction of DHN, a more spherical morphology and a more-organized 'bicontinuous-like' morphology was observed in THF and DMF, respectively. This results from strong segregation between the two domains due to the enhanced interfacial energy by DHN. When DHN was removed by methanol, nanoporous films with versatile pore sizes and shapes were generated.


Preliminary investigation and application of a novel deformable PRESAGE® dosimeter.
Deformable 3D dosimeters have potential applications in validating deformable dose mapping algorithms. This study evaluates a novel deformable PRESAGE® dosimeter and its application toward validating the deformable algorithm employed by VelocityAI. The deformable PRESAGE® dosimeter exhibited a linear dose response with a sensitivity of 0.0032 ΔOD/(Gy/cm). Comparison of an experimental dosimeter irradiated with an MLC pencilbeam checkerboard pattern under lateral compression up to 27% to a non-deformed control dosimeter irradiated with the same pattern verified dose tracking under deformation. CTs of the experimental dosimeter prior to and during compression were exported into VelocityAI and used to map an Eclipse dose distribution calculated on the compressed dosimeter to its original shape. A comparison between the VelocityAI dose distribution and the distribution from the dosimeter showed field displacements up to 7.3 mm and up to a 175% difference in field dimensions. These results highlight the need for validating deformable dose mapping algorithms to ensure patient safety and quality of care.


Research advances on microbial genetics in China in 2015.
In 2015, there are significant progresses in many aspects of the microbial genetics in China. To showcase the contribution of Chinese scientists in microbial genetics, this review surveys several notable progresses in microbial genetics made largely by Chinese scientists, and some key findings are highlighted. For the basic microbial genetics, the components, structures and functions of many macromolecule complexes involved in gene expression regulation have been elucidated. Moreover, the molecular basis underlying the recognition of foreign nucleic acids by microbial immune systems was unveiled. We also illustrated the biosynthetic pathways and regulators of multiple microbial compounds, novel enzyme reactions, and new mechanisms regulating microbial gene expression. And new findings were obtained in the microbial development, evolution and population genetics. For the industrial microbiology, more understanding on the molecular basis of the microbial factory has been gained. For the pathogenic microbiology, the genetic circuits of several pathogens were depicted, and significant progresses were achieved for understanding the pathogen-host interaction and revealing the genetic mechanisms underlying antimicrobial resistance, emerging pathogens and environmental microorganisms at the genomic level. In future, the genetic diversity of microbes can be used to obtain specific products, while gut microbiome is gathering momentum.


Long-term memory deficits are associated with elevated synaptic ERK1/2 activation and reversed by mGluR5 antagonism in an animal model of autism.
A significant proportion of patients with autism exhibit some degree of intellectual disability. The BTBR T(+) Itpr3(tf)/J mouse strain exhibits behaviors that align with the major diagnostic criteria of autism. To further evaluate the BTBR strain's cognitive impairments, we quantified hippocampus-dependent object location memory (OLM) and found that one-third of the BTBR mice exhibited robust memory, whereas the remainder did not. Fluorescence deconvolution tomography was used to test whether synaptic levels of activated extracellular signal-regulated kinase 1/2 (ERK1/2), a protein that contributes importantly to plasticity, correlate with OLM scores in individual mice. In hippocampal field CA1, the BTBRs had fewer post-synaptic densities associated with high levels of phosphorylated (p-) ERK1/2 as compared with C57BL/6 mice. Although counts of p-ERK1/2 immunoreactive synapses did not correlate with OLM performance, the intensity of synaptic p-ERK1/2 immunolabeling was negatively correlated with OLM scores across BTBRs. Metabotropic glutamate receptor (mGluR) 5 signaling activates ERK1/2. Therefore, we tested whether treatment with the mGluR5 antagonist MPEP normalizes synaptic and learning measures in BTBR mice: MPEP facilitated OLM and decreased synaptic p-ERK1/2 immunolabeling intensity without affecting numbers of p-ERK1/2+ synapses. In contrast, semi-chronic ampakine treatment, which facilitates memory in other models of cognitive impairment, had no effect on OLM in BTBRs. These results suggest that intellectual disabilities associated with different neurodevelopmental disorders on the autism spectrum require distinct therapeutic strategies based on underlying synaptic pathology.


Ancestral chytrid pathogen remains hypervirulent following its long coevolution with amphibian hosts.
Many amphibian species around the world, except in Asia, suffer morbidity and mortality when infected by the emerging infectious pathogen Batrachochytrium dendrobatidis (Bd). A lineage of the amphibian chytrid fungus isolated from South Korean amphibians (BdAsia-1) is evolutionarily basal to recombinant global pandemic lineages (BdGPL) associated with worldwide amphibian population declines. In Asia, the Bd pathogen and its amphibian hosts have coevolved over 100 years or more. Thus, resilience of Asian amphibian populations to infection might result from attenuated virulence of endemic Bd lineages, evolved immunity to the pathogen or both. We compared susceptibilities of an Australasian amphibian, Litoria caerulea, known to lack resistance to BdGPL, with those of three Korean species, Bufo gargarizans, Bombina orientalis and Hyla japonica, after inoculation with BdAsia-1, BdGPL or a blank solution. Subjects became infected in all experimental treatments but Korean species rapidly cleared themselves of infection, regardless of Bd lineage. They survived with no apparent secondary effects. By contrast, L. caerulea, after infection by either BdAsia-1 or BdGPL, suffered deteriorating body condition and carried progressively higher Bd loads over time. Subsequently, most subjects died. Comparing their effects on L. caerulea, BdAsia-1 induced more rapid disease progression than BdGPL. The results suggest that genomic recombination with other lineages was not necessary for the ancestral Bd lineage to evolve hypervirulence over its long period of coevolution with amphibian hosts. The pathogen's virulence may have driven strong selection for immune responses in endemic Asian amphibian host species.


Worker caste polymorphism has a genetic basis in Acromyrmex leaf-cutting ants.
Division of labor is fundamental to the success of all societies. The most striking examples are the physically polymorphic worker castes in social insects with clear morphological adaptations to different roles. These polymorphic worker castes have previously been thought to be a classic example of nongentically controlled polymorphism, being mediated entirely by environmental cues. Here we show that worker caste development in the leaf-cutting ant Acromyrmex echinatior has a significant genetic component. Individuals of different patrilines within the same colony differ in their propensities to develop into minor or major workers. The mechanism appears to be plastic, with caste destiny resulting from interplay between nurture and nature. Unlike the few other recently discovered examples of a genetic influence on caste determination, the present result does not relate to any rare or exceptional circumstances, such as interspecific hybridization. The results suggest that a significant role of genetics may have been overlooked in our understanding of other complex polymorphisms of social insects.


Effect of replacing uridine 33 in yeast tRNAPhe on the reaction with ribosomes.
We have determined several kinetic parameters for the reaction of poly(U)-programmed ribosomes with ternary complexes of elongation factor Tu, GTP, and yeast Phe-tRNA analogs with different bases substituted for uridine in position 33. These analogs test whether disruption of the hydrogen bonds normally formed by uridine 33 and steric crowding in the anticodon loop are detrimental to tRNA function on the ribosome. Single-turnover kinetic studies of the reaction of these ternary complexes with ribosomes show that these Phe-tRNA analogs decrease the apparent rate of GTP hydrolysis (kGTP) and the ratio of peptide formed to GTP hydrolyzed. Thus, the substitution of uridine 33 affects not only the selection of a ternary complex by the ribosome but also the selection of an aminoacyl-tRNA in the proofreading reaction. The effects become greater as first one, and then the other, H-bond is disrupted. Steric crowding in the anticodon loop is also important, but does not have as great an effect on the rate constants. An analysis of the elementary rate constants which comprise the rate constant, kGTP, demonstrates that the reduction in kGTP results from a decreased rate of ternary complex association with the ribosome (k1) and that there is little or no effect on the rate of GTP cleavage (k2). An analysis of the rate constants involved in proofreading shows that all the modified (tRNAs have increased rates of aminoacyl-tRNA rejection (k4) but that the rate of peptide bond formation (k3) is unaffected.


Immune Checkpoint Inhibitors for Patients With Advanced Non-Small-Cell Lung Cancer: A Systematic Review.
Second-line treatment options are limited for patients with advanced non-small-cell lung cancer (NSCLC). Standard therapy includes the cytotoxic agents docetaxel and pemetrexed, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib. Immune checkpoint inhibitors are a new class of treatment that have shown durable overall radiologic response rates and have been well tolerated. The objective of this systematic review was to investigate the efficacy of immune checkpoint inhibitors compared with other chemotherapies in patients with advanced NSCLC. Medline, Embase, and PubMed were searched for randomized controlled trials comparing treatment with immune checkpoint inhibitors against treatment with chemotherapy in patients with stage IIIB or IV NSCLC. Nine randomized controlled trials with 15 publications were included. A significant overall survival benefit of second-line nivolumab (nonsquamous: hazard ratio [HR] = 0.72, 95% confidence interval [CI], 0.60-0.77; P < .001; squamous: HR = 0.59, 95% CI, 0.44-0.79; P < .001) or second-line atezolizumab (HR = 0.73, 95% CI, 0.62-0.87; P = .0003) or second-line pembrolizumab (in patients with programmed cell death ligand 1 [PD-L1]-positive tumors) (pembrolizumab 2 mg/kg HR = 0.71, 95% CI, 0.58-0.88; P = .0008; pembrolizumab 10 mg/kg HR = 0.61, 95% CI, 0.49-0.75; P < .0001) or first-line pembrolizumab (HR = 0.60, 95% CI, 0.41-0.89; P = .005) compared with chemotherapy was found. The adverse effects were mainly higher in the chemotherapy arms. For patients with advanced stage IIIB/IV NSCLC, the improvement in overall survival outweighed the harms and supported the use of first-line pembrolizumab (in patients with ≥ 50% PD-L1-positive tumors) or second-line nivolumab, atezolizumab, or pembrolizumab (in patients with PD-L1-positive tumors).


Single-stage "Fix and Flap" gives Good Outcomes in Grade 3B/C Open Tibial Fractures: A Prospective Study.
Grade 3B/C open tibial fractures with grossly contaminated degloving injuries have poor outcomes, with or without vascular injuries. Treatment decision oscillates between limb salvage and amputation. The standard protocol of repeated debridement and delayed wound cover is a challenge in developing countries due to overcrowded emergencies and limited operating room availability. We present results of our modified protocol involving primary stabilisation with external fixation and immediate wound cover as an aggressive modality of treatment. Thirty-three patients with severe open tibial shaft fractures were managed using a standardised protocol of emergent debridement, external fixation and immediate wound cover with free distant/local rotational muscle flaps and fasciocutaneous flaps, and with vascular repair in Grade 3C fractures. Intra-articular fractures were excluded. Patients were followed for a minimum of three years, with an assessment of clinical, radiological and functional outcomes. Wound cover was achieved with 24 distant free muscle flaps, four local rotational muscle flaps and five fasciocutaneous flaps. All fractures united with an average time to union of 40.3 weeks (16-88). Fifteen patients (45.4%) underwent only a single major surgery using primary definitive external fixation. Deep infection was seen in four patients (12.1%). Nineteen patients had excellent to good outcomes, six were fair, and eight were poor. "Fix and Flap" in the same sitting, using immediate wound cover and external fixation, has given good results in our hands despite the delayed presentation, the neurovascular deficit and the degloving injury. This may be a better management strategy in overcrowded tertiary care centres of developing countries, with a single surgical procedure in almost half the cases.


Trace elements in sickle cell disease.
Trace elements in 84 adult patients (38 men and 46 women) with sickle cell disease (SCD) were reflected in clinical and biochemical data. Height was retarded in six men and five women. Eighty percent of the SCD patients in this sample were below the 50th percentile from the normal mean for weight. Twenty-eight men showed a lack of facial and body hair, and five additional subjects showed only scanty facial hair. Whereas zinc in plasma, red blood cells, and hair was decreased, the excretion of zinc in urine was increased in SCD patients as compared to the controls. We believe that one of the mechanisms accounting for zinc deficiency in SCD may be hyperzincuria and that growth retardation and hypogonadism in men so commonly seen in SCD may be related to zinc deficiency.


Safety and bactericidal efficacy of cold atmospheric plasma generated by a flexible surface Dielectric Barrier Discharge device against Pseudomonas aeruginosa in vitro and in vivo.
Cold atmospheric plasma (CAP), which is ionized gas produced at atmospheric pressure, could be a novel and potent antimicrobial therapy for the treatment of infected wounds. Previously we have shown that CAP generated with a flexible surface Dielectric Barrier Discharge (sDBD) is highly effective against bacteria in vitro and in ex vivo burn wound models. In the current paper, we determined the in vitro and in vivo safety and efficacy of CAP generated by this sDBD device. The effect of CAP on DNA mutations of V79 fibroblasts was measured using a hypoxanthine-guanine-phosphoribosyltransferase (HPRT) assay. Furthermore, effects on cell proliferation, apoptosis and DNA damage in ex vivo burn wound models (BWMs) were assessed using immunohistochemistry. Next, 105 colony forming units (CFU) P. aeruginosa strain PAO1 were exposed to CAP in a 3D collagen-elastin matrix environment to determine the number of surviving bacteria in vitro. Finally, rat excision wounds were inoculated with 107 CFU PAO1 for 24 h. The wounds received a single CAP treatment, repeated treatments on 4 consecutive days with CAP, 100 µL of 1% (wt/wt) silver sulfadiazine or no treatment. Wound swabs and punch biopsies were taken to determine the number of surviving bacteria. Exposure of V79 fibroblasts to CAP did not increase the numbers of mutated colonies. Additionally, the number of proliferative, apoptotic and DNA damaged cells in the BWMs was comparable to that of the unexposed control. Exposure of PAO1 to CAP for 2 min resulted in the complete elimination of bacteria in vitro. Contrarily, CAP treatment for 6 min of rat wounds colonized with PAO1 did not effectively reduce the in vivo bacterial count. CAP treatment was safe but showed limited efficacy against PAO1 in our rat wound infection model.


Phase selection during the crystallization of metal-organic frameworks; thermodynamic and kinetic factors in the lithium tartrate system.
We report the phase behaviour of chiral, racemic and meso-lithium tartrate frameworks, which was examined as a function of solvent system, temperature and ligand isomer. Through our comprehensive investigation of this system of 14 diverse phases, we have gained detailed insight into the effect of synthesis conditions on product structure, and elucidated the thermodynamic and kinetic factors involved in phase selection. Reactions in ethanol between lithium acetate and chiral, racemic and meso-tartaric acids give rise to anhydrous kinetic products; polymorphs with higher entropy tend to appear at high temperatures. Reactions at room temperature in water-ethanol mixtures give rise to hydrated kinetic products, including two new crystal structures, [Li2(D,L-tartrate)(H2O)2]n in P1 and [Li2(meso-tartrate)(H2O)(0.5)]n in C222(1), whose structures are contrasted with known anhydrous products. Reactions at elevated temperatures in water-ethanol mixtures result in the formation of low enthalpy, anhydrous products and, furthermore, the global minimum energy structure appears at high temperatures in all cases owing to in situ ligand isomerization.


DNA damage and repair: underlying mechanisms leading to microcephaly.
DNA-damaging agents and endogenous DNA damage constantly harm genome integrity. Under genotoxic stress conditions, the DNA damage response (DDR) machinery is crucial in repairing lesions and preventing mutations in the basic structure of the DNA. Different repair pathways are implicated in the resolution of such lesions. For instance, the non-homologous DNA end joining and homologous recombination pathways are central cellular mechanisms by which eukaryotic cells maintain genome integrity. However, defects in these pathways are often associated with neurological disorders, indicating the pivotal role of DDR in normal brain development. Moreover, the brain is the most sensitive organ affected by DNA-damaging agents compared to other tissues during the prenatal period. The accumulation of lesions is believed to induce cell death, reduce proliferation and premature differentiation of neural stem and progenitor cells, and reduce brain size (microcephaly). Microcephaly is mainly caused by genetic mutations, especially genes encoding proteins involved in centrosomes and DNA repair pathways. However, it can also be induced by exposure to ionizing radiation and intrauterine infections such as the Zika virus. This review explains mammalian cortical development and the major DNA repair pathways that may lead to microcephaly when impaired. Next, we discuss the mechanisms and possible exposures leading to DNA damage and p53 hyperactivation culminating in microcephaly.


A new practical classification of the mycobacteria.
A new classification is presented for mycobacteria cultured from clinical specimens. Five categories were defined on temperature requirement, and these were subdivided into 14 groups by pigmentation, oxygen preference and Tween hydrolysis. Support for some of the groups and for the recognition of certain important species within others was provided by drug-sensitivity tests. Less than 1-0% of the opportunist mycobacteria met in Britain eluded classification by these means.


[Cooperative therapy study of nontesticular germ cell tumors MAKEI 83 of the Society of Pediatric Oncology: analysis after 3 years].
The German Society of Pediatric Oncology has initiated in 1983 a cooperative trial for the treatment of extratesticular germ cell tumors. The treatment plan is stratified according to histology, tumor site and tumor extension. Patients with unfavourable histology received depending on prognostic factors 4 courses of either vinblastine, actinomycin D and cyclophosphamide, or the combination of vinblastine, bleomycin and cisplatinum (4 courses) completed by 4 additional courses of VP 16, ifosfamide and cisplatinum. Within 3 years, 115 patients from 37 different institutions were entered into the trial. 55 of 72 protocol patients are under observation for at least 10 months since diagnosis. The disease-free survival rate according to Kaplan-Meier is 80% (+/- 6%) at 36 months. From the interim results of this ongoing study, the following conclusions are drawn: The chemotherapeutic regimens as delivered are tolerable. Radiotherapy does not seem necessary with the exception of ovarian dysgerminomas stage I a. In coccygeal teratomas the resection of the coccygeal bone decreases the hazard of local recurrences. Using the risk adapted regimen, the prognosis for teratomas with Yolk sac origin appears as favourable as for patients with mature teratomas.


Angiotensin-converting enzyme gene insertion/deletion polymorphism in Saudi patients with rheumatic heart disease.
To investigate the association between angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphism and rheumatic heart disease (RHD) in Saudi patients. A case-control study was conducted in Saudi RHD patients. Genomic DNA was isolated from 99 RHD patients attending the Pediatric Cardiology Clinic at the Maternity and Children Hospital, Al-Madinah, Saudi Arabia from March 2013 to June 2014, and from 145 age- and gender-matched controls. Patient clinical records were reviewed to report major and minor modified Jones' criteria for diagnosis. The diagnosis was confirmed by echocardiography. The ACE I/D polymorphism was identified by polymerase chain reaction. A significant difference in ACE D allele carriage (DD+ID) distribution between RHD cases and controls was identified (p=0.02, odds ratio = 3.6, 95% confidence interval: 1.2-10.8). The D allele carriage was significantly associated with development of mitral valve lesions alone (p=0.03). The ACE I/D polymorphism is associated with an increased risk of RHD in the Saudi population. Further studies are needed to confirm our findings and to understand the molecular mechanisms underlying this association.


Association of Early vs Late Tracheostomy Placement With Pneumonia and Ventilator Days in Critically Ill Patients: A Meta-analysis.
The timing of tracheostomy placement in adult patients undergoing critical care remains unestablished. Previous meta-analyses have reported mixed findings regarding early vs late tracheostomy placement for ventilator-associated pneumonia (VAP), ventilator days, mortality, and length of intensive care unit (ICU) hospitalization. To compare the association of early (≤7 days) vs late tracheotomy with VAP and ventilator days in critically ill adults. A search of MEDLINE, CINAHL, Cochrane Central Register of Controlled Trials, references of relevant articles, previous meta-analyses, and gray literature from inception to March 31, 2020, was performed. Randomized clinical trials comparing early and late tracheotomy with any of our primary outcomes, VAP or ventilator days, were included. Two independent reviewers conducted all stages of the review. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was followed. Pooled odds ratios (ORs) or the mean difference (MD) with 95% CIs were calculated using a random-effects model. Primary outcomes included VAP and duration of mechanical ventilation. Intensive care unit days and mortality (within the first 30 days of hospitalization) constituted secondary outcomes. Seventeen unique trials with a cumulative 3145 patients (mean [SD] age range, 32.9 [12.7] to 67.9 [17.6] years) were included in this review. Individuals undergoing early tracheotomy had a decrease in the occurrence of VAP (OR, 0.59 [95% CI, 0.35-0.99]; 1894 patients) and experienced more ventilator-free days (MD, 1.74 [95% CI, 0.48-3.00] days; 1243 patients). Early tracheotomy also resulted in fewer ICU days (MD, -6.25 [95% CI, -11.22 to -1.28] days; 2042 patients). Mortality was reported for 2445 patients and was comparable between groups (OR, 0.66 [95% CI, 0.38-1.15]). Compared with late tracheotomy, early intervention was associated with lower VAP rates and shorter durations of mechanical ventilation and ICU stay, but not with reduced short-term, all-cause mortality. These findings have substantial clinical implications and may result in practice changes regarding the timing of tracheotomy in severely ill adults requiring mechanical ventilation.


Comparison of the prognostic values of inflammation markers in patients with acute pancreatitis: a retrospective cohort study.
Inflammation-based prognostic markers (neutrophil-lymphocyte ratio (NLR), prognostic nutritional index (PNI), red cell distribution width (RDW) and lymphocyte-monocyte ratio (LMR)) are associated with overall survival in some diseases. This study assessed their prognostic value in mortality and severity in acute pancreatitis (AP). A retrospective cohort study. Patients with AP were recruited from the emergency department at our hospital. A total of 359 patients with AP (31 non-survivors) were enrolled. Mortality and severity of AP were the primary and secondary outcome measures, respectively. Biochemistry and haematology results of the first test after admission were collected. Independent relationships between severe AP (SAP) and markers were assessed using multivariate logistic regression models. Mortality prediction ability was evaluated using receiver operating characteristic (ROC) curves. Overall survival was evaluated using the Kaplan-Meier method, with differences compared using the log-rank test. Independent relationships between mortality and each predictor were estimated using the Cox proportional hazard models. Compared with survivors of AP, non-survivors had higher RDW (p<0.001), higher NLR (p<0.001), lower LMR (p<0.001) and lower PNI (p<0.001) at baseline. C reactive protein (CRP; OR=8.251, p<0.001), RDW (OR=2.533, p=0.003) and PNI (OR=7.753, p<0.001) were independently associated with the occurrence of SAP. For predicting mortality, NLR had the largest area under the ROC curve (0.804, p<0.001), with a 16.64 cut-off value, 82.4% sensitivity and 75.6% specificity. RDW was a reliable marker for excluding death owing to its lowest negative likelihood ratio (0.11). NLR (HR=4.726, p=0.004), CRP (HR=3.503, p=0.003), RDW (HR=3.139, p=0.013) and PNI (HR=2.641, p=0.011) were independently associated with mortality of AP. NLR was the most powerful marker of overall survival in this patient series.


Diet Liberalisation in Older Australians Decreases Frailty without Increasing the Risk of Developing Chronic Disease.
Successful ageing relies on the prevention of frailty and chronic disease, many of which have a strong link with diet. Despite evidence suggesting diet is important in the management of frailty, there is little evidence investigating the impact of a liberal diet on the prevention of frailty and development of chronic diseases in the elderly. To determine the impact of a liberal diet on the development of frailty and whether this affects the incidence of obesity, diabetes, hypertension and hyperlipidaemia. Secondary data analysis of the Australian Longitudinal Study of Ageing, 1992 to 2000. Random selection of older adults from the South Australian electoral roll. 1298 older Australians (629 women, 669 men), mean age 77 years. A validated food frequency questionnaire was used to measure the dietary exposure; liberal diet defined as: energy >10% estimated requirements; sodium >1600mg; total fat >35% energy; saturated fat >10%; refined sugar >10%; fibre <38g males and <28g females. Frailty was determined using the Fried phenotype in combination with Cesari's biological definition of frailty. Chronic disease outcomes were measured by medication usage and obesity defined as BMI >30kg/m². Binary logistic regression was performed using participants free of chronic disease at baseline to determine the impact of each dietary exposure independently, and combined, on the development of frailty and the incidence of chronic disease over the subsequent eight years. Incidence of frailty after 8 years of follow up was 14%. The incidence of diabetes after 8 years of follow up was 5.3%, hypertension 39%, hyperlipidaemia 15% and obesity 6%. A liberal energy intake adjusted for age and sex, significantly reduced the risk of developing frailty eight years post baseline (OR 0.48, 95% CI 0.30, 0.77). After adjustment for age, sex and body weight, a liberal saturated fat intake (>10% of energy) increased the risk of hyperlipidaemia (OR 2.11, 95% CI 1.27, 3.54). A liberal intake of sodium, total fat, refined sugar and fibre did not increase the risk of diabetes, hypertension, hyperlipidaemia or obesity. This study suggests that a liberal intake of energy may decrease the risk of developing frailty in the elderly without increasing the risk of developing obesity, diabetes, hypertension or hyperlipidaemia. Caution should remain however in the prescription of diets high in saturated fat as the link established with hyperlipidaemia in young adults appears to be consistent in the elderly. Further research is required to explore the optimal sources of energy for a liberalised diet and the effect of a liberalised diet on other diet related health conditions.


Radiation-induced insufficiency fractures of the pelvis: evaluation with 99mTc-methylene diphosphonate scintigraphy.
99mTc-methylene diphosphonate (99mTc-MDP) bone scans in 80 patients, 30-80 years old (average, 62 years old) with uterine cancer who received high doses of radiation (10-60 Gy; average, 46 Gy) were reviewed retrospectively to evaluate the frequency of pelvic insufficiency fractures caused by radiotherapy and to study the appearance of the fractures on bone scans. Bone scans in 29 of 80 patients showed abnormalities in the pelvis: insufficiency fractures were identified in 27 patients (34%) and osseous metastases were found in two patients (3%). The fractures and metastases were diagnosed by CT and were confirmed by observing the patients' clinical courses. Fractures were identified in 27 (39%) of 69 postmenopausal women and in none of 11 premenopausal patients (p greater than .05). Fractures were found in 21 (84%) of 25 patients who had pelvic pain and in six (11%) of 55 patients who were asymptomatic (p greater than .001). Scintigrams in patients with fractures showed more than one fracture in most patients (85%), and fractures were often symmetric (67%). Scintigrams in two patients with osseous metastases showed increased activity in an iliac wing that was outside the radiation field. Our results suggest that a marked increase in insufficiency fractures occurs after radiation therapy, especially in postmenopausal patients. A symmetric area of increased uptake of radionuclide is a characteristic scintigraphic appearance of an insufficiency fracture.


Number of lymph nodes identified at axillary dissection: effect of neoadjuvant chemotherapy and other factors.
Several reports have shown a significantly lower number of axillary lymph nodes (AxLNs) found at axillary lymph node dissection (ALND) after neoadjuvant chemotherapy. The objective of the current study was to investigate the factors affecting the number of AxLNs identified at ALND. Medical records of patients seen at the study institution, a tertiary center, from 2004 to 2007 who underwent ALND for breast cancer were reviewed. Among the 698 patients who met study criteria, the mean number of AxLNs resected was 20.4. There were 649 (93%) patients with at least 10 AxLNs recovered. Seventy-one (10%) patients received neoadjuvant chemotherapy and 627 (90%) underwent surgical resection first. The mean number of AxLNs in the patients treated with neoadjuvant chemotherapy was 21.9 (range, 4-56 AxLNs) compared with 20.2 (range, 5-65 AxLNs) in the group treated with surgical resection first (P=.13). The number of patients with <10 AxLNs found at ALND was 44 of 627 (7.0%) in the surgical resection first group and 5 of 71 (7.0%) in the neoadjuvant chemotherapy group (P=1.0). The mean number of AxLNs was higher in the 599 (86%) ALNDs performed at the study center compared with the 99 cases from outside institutions (21.2 vs 15.2 AxLNs; P<.001). Among the cases performed at the study institution, 367 (61%) were performed by surgeons with oncologic training and 232 (39%) were not. Surgical oncologists recovered an average of 23 AxLNs, which was significantly higher than the 18.4 resected by the remaining surgeons (P<.001). The number of AxLNs recovered at ALND does not appear to be affected by neoadjuvant chemotherapy. Surgeons with oncologic training appear to retrieve more AxLNs.


Key somatic variables associated with, and differences between the 4 swimming strokes.
This study identified key somatic and demographic characteristics that benefit all swimmers and, at the same time, identified further characteristics that benefit only specific swimming strokes. Three hundred sixty-three competitive-level swimmers (male [n = 202]; female [n = 161]) participated in the study. We adopted a multiplicative, allometric regression model to identify the key characteristics associated with 100 m swimming speeds (controlling for age). The model was refined using backward elimination. Characteristics that benefited some but not all strokes were identified by introducing stroke-by-predictor variable interactions. The regression analysis revealed 7 "common" characteristics that benefited all swimmers suggesting that all swimmers benefit from having less body fat, broad shoulders and hips, a greater arm span (but shorter lower arms) and greater forearm girths with smaller relaxed arm girths. The 4 stroke-specific characteristics reveal that backstroke swimmers benefit from longer backs, a finding that can be likened to boats with longer hulls also travel faster through the water. Other stroke-by-predictor variable interactions (taken together) identified that butterfly swimmers are characterized by greater muscularity in the lower legs. These results highlight the importance of considering somatic and demographic characteristics of young swimmers for talent identification purposes (i.e., to ensure that swimmers realize their most appropriate strokes).


cml biology for the clinician in 2011: six impossible things to believe before breakfast on the way to cure.
Chronic myeloid leukemia (cml) is a model disease in oncology: it is the first human cancer linked to a distinct chromosomal abnormality, ultimately causing constitutive overactivity of a known oncogenic tyrosine kinase that represents a drug target. The introduction of the tyrosine kinase inhibitor imatinib into clinical practice has far exceeded expectations and resurrected hope that the fundamental insights from the "war on cancer" can lead to significant therapeutic advances. Nevertheless, the current perception among clinicians is that imatinib and its newer more potent cousins offer superb long-term disease control for most patients, but that cure without transplantation has remained elusive. However, several important laboratory-based observations over the last few years have changed those perceptions. Several of those developments are discussed here, including direct manipulation of the apoptosis pathway in cancer cells and prevention of disease progression with the use of antioxidants. Intriguing results from a French study indicate that, if disease progression is halted, a small but significant group of patients may be able to stop imatinib therapy without disease recurrence. And for patients whose disease, because of resistant stem cells, needs a more direct attack than tyrosine kinase inhibitors alone, several approaches investigated in laboratory and animal models seem promising, and some are ripe for clinical testing, including inhibitors of Smoothened and 5-lipoxygenase, and suppression of autophagy. Thus, there is realistic hope that true cure of cml, without transplantation, may be a feasible goal in the near future.


The role of temperature in the detection and diagnosis of neutropenic sepsis in adult solid tumour cancer patients receiving chemotherapy.
The primary aim of this study was to examine the value of temperature as a diagnostic and prognostic indicator of infection and sepsis in neutropenic patients. A secondary aim was to gain insight into the presenting symptoms reported by these patients at home or on their initial admission assessment. A cohort study was carried out using a case note review of 220 emergency admissions to a regional cancer centre. All participants were neutropenic and were diagnosed with infection on admission. The main outcome measures were relationships between Early Warning Scores and temperature values at home, on admission and during the hospital stay. 22% of patients who became acutely unwell did not have a fever. Pearson correlations showed only small associations between highest temperature value at any time point and highest early warning scores (r(202) = 0.176, P = .012). Temperature at home (B = 0.156, P = .336) and temperature on admission (B = 0.200, P = .052) did not predict highest Early Warning Scores. Body temperature is not a consistently reliable diagnostic or prognostic indicator for outcomes in patients with neutropenia and symptoms of infection. It can assist with early presentation and recognition of infection in many neutropenic patients. However, over-reliance on temperature risks missing the opportunity for early detection and treatment.


Solid lipid nanoparticles bearing flurbiprofen for transdermal delivery.
Topical application of the drugs at the pathological sites offer potential advantages of delivering the drug directly to the site of action and thus producing high tissue concentrations of the drug. The solid lipid nanoparticles (SLN) bearing flurbiprofen were prepared by microemulsion method by dispersing o/w microemulsion in a cold aqueous surfactant medium under mechanical stirring. The SLN gel was prepared by adding SLN dispersion to polyacrylamide gel prepared by using polyacrylamide (0.5%), glycerol (10%), and water (69.5%). Shape and surface morphology was determined by scanning electron microscopy that revealed fairly spherical shape of the formulation. Percent drug entrapment was higher in SLN dispersion in comparison to SLN gel formulations. In vitro drug release, determined using cellophane membrane, showed that SLN dispersion exhibited higher drug release compared with SLN gel formulations. Both the SLN dispersion and SLN-gel formulation possessed a sustained drug release over a 24-hr period, but this sustained effect was more pronounced with SLN-gel formulations. The percent inhibition of edema after 8 hr was 55.51 +/- 0.26% in case of SLN-T4-gel, whereas flurbiprofen and SLN-T4 dispersion exhibited 28.81 +/- 0.46 and 31.89 +/- 0.82 inhibition of edema. The SLN-T4-gel not only decreased the inflammation to larger magnitude, but also sustained its effect.


High-density lipoproteins during sepsis: from bench to bedside.
High-density lipoproteins (HDLs) represent a family of particle characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver conferring them a cardioprotective function. HDLs also display pleiotropic properties including antioxidant, anti-apoptotic, anti-thrombotic, anti-inflammatory, or anti-infectious functions. Clinical data demonstrate that HDL cholesterol levels decrease rapidly during sepsis and that these low levels are correlated with morbi-mortality. Experimental studies emphasized notable structural and functional modifications of HDL particles in inflammatory states, including sepsis. Finally, HDL infusion in animal models of sepsis improved survival and provided a global endothelial protective effect. These clinical and experimental studies reinforce the potential of HDL therapy in human sepsis. In this review, we will detail the different effects of HDLs that may be relevant under inflammatory conditions and the lipoprotein changes during sepsis and we will discuss the potentiality of HDL therapy in sepsis.


C-N bond forming cross-coupling reactions: an overview.
Nitrogen containing compounds are of great importance because of their interesting and diverse biological activities. The construction of the C-N bond is of significant importance as it opens avenues for the introduction of nitrogen in organic molecules. Despite significant advancements in this field, the construction of the C-N bond is still a major challenge for organic chemists, due to the involvement of harsh reaction conditions or the use of expensive catalysts in many cases. Thus, it is a challenge to develop alternative, milder and cheaper methodologies for the construction of C-N bonds. Herein, we have selected some prime literature reports that may serve this purpose.


Mitochondrial fatty-acid oxidation disorders.
Inherited defects in mitochondrial fatty-acid beta-oxidation comprise a group of at least 12 diseases characterized by distinct enzyme or transporter deficiencies. Most of these diseases have a variable age of onset and clinical severity. Symptoms are often episodic and associated with mild viral illness, physiologic stress, or prolonged exercise that overwhelms the ability of mitochondria to oxidize fatty acids. Depending on the specific genetic defect, patients develop fasting hypoketotic hypoglycemia, cardiomyopathy, rhabdomyolysis, liver dysfunction, or sudden death. Neuropathy and pigmentary retinopathy are seen in some of the diseases. The diagnosis is based on finding an accumulation of specific biochemical markers such as acylcarnitine metabolites in blood and urinary dicarboxylic acids and acylglycines. Confirmatory testing requires enzymatic studies and DNA analysis. Therapeutic approaches are generally effective in preventing severe symptomatic episodes, including sudden death. Newborn screening for fatty-acid oxidation disorders promises to identify many affected patients before the onset of symptoms.


Professional development in scientifically based reading instruction: teacher knowledge and reading outcomes.
This article reviews the literature and presents data from a study that examined the effects of professional development in scientifically based reading instruction on teacher knowledge and student reading outcomes. The experimental group consisted of four first- and second-grade teachers and their students (n = 33). Three control teachers and their students (n = 14), from a community of significantly higher socioeconomic demographics, were also followed. Experimental teachers participated in a 35-hour course on instruction of phonemic awareness, phonics, and fluency and were coached by professional mentors for a year. Although teacher knowledge in the experimental group was initially lower than that of the controls, their scores surpassed the controls on the posttest. First-grade experimental students' growth exceeded the controls in letter name fluency, phonemic segmentation, nonsense word fluency, and oral reading. Second-grade experimental students exceeded controls in phonemic segmentation. Although the teacher sample was small, findings suggest that teachers can improve their knowledge concerning explicit reading instruction and that this new knowledge may contribute to student growth in reading.


Overexpression of inducible heat shock protein 70 in Cos-1 cells fails to protect from cytotoxicity of oxidized ldls.
Oxidized low density lipoproteins (OxLDLs) are believed to play a central role in atherogenesis and to possess a wide variety of biological properties; among them, OxLDLs are cytotoxic to cultured vascular cells in that they induce necrosis and apoptosis. Moreover, OxLDLs are known to induce the expression of heat shock protein 70 (Hsp70), a protein that protects cells from several cytotoxic stimuli. To determine whether Hsp70 can protect cells against OxLDL-induced cytotoxicity, COS-1 cells were transfected with a construct containing human Hsp70. A number of cell lines permanently expressing Hsp70 were obtained, 1 of which (cos-Hsp70/10, with high Hsp70 expression) was selected for further studies. Hsp70 overexpression protected cells from toxic stimuli, such as H(2)O(2), UV irradiation, and heat shock, suggesting that the overexpressed protein was functional. When incubated with OxLDLs, however, the clone overexpressing Hsp70 showed a significant decrease in viability, as determined by the [(3)H]adenine release assay (319.8+/-3.16% of control for transfected cells versus 217.6+/-6.08% for control cells exposed to 100 microgram protein/mL of OxLDL), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay (12.5+/-0.9% versus 28.9+/-1.99% of control, respectively), and LDH release (48.4+/-0.04% versus 15.2+/-0.06% of control cells). The increased expression of BAX and the decreased expression of Bcl-2 (a proapoptotic and an antiapoptotic protein, respectively) in cos-Hsp70/10 cells and in control cells on incubation with OxLDLs suggested that overexpression of Hsp70 did not confer protection against apoptosis induced by OxLDLs. The analysis of nucleosome content and the nuclear staining with Hoechst 33258 confirmed this finding. These data suggest that overexpression of Hsp70 not only fails to protect COS-1 cells against OxLDL-induced apoptosis but rather confers a higher sensitivity to the cytotoxic action of these lipoproteins. Thus, the Hsp70 response, although induced by OxLDLs, cannot protect cells from lipoprotein toxicity.


Stereoselective Synthesis of Terminal Monofluoroalkenes from Trifluoromethylated Alkenes.
Herein we report the hydrodefluorination reaction of trifluoromethylated alkenes to access terminal monofluoroalkenes. The use of LiAlH4 allowed the stereoselective synthesis of the terminal monofluoroalkenes in good to excellent yields with good to excellent diastereoselectivities. Mechanistic studies suggested a hydroalumination reaction followed by a stereoselective fluoride elimination.


Comparative efficacy of ravulizumab and eculizumab in the treatment of atypical hemolytic uremic syndrome: An indirect comparison using clinical trial data.
Ravulizumab and eculizumab are approved terminal complement inhibitor treatments for atypical hemolytic uremic syndrome (aHUS). Ravulizumab was engineered from eculizumab to have an increased half-life allowing for reduced dosing frequency (8-weekly vs. 2-weekly). To account for differences in respective clinical trials, a validated balancing technique was used to enable an indirect comparison of ravulizumab and eculizumab treatment efficacy in aHUS. Patient-level data from four eculizumab clinical trials were available for pooling and comparison with data from two ravulizumab trials. In the primary analysis, adult native kidney data were compared. Propensity scores were calculated from baseline characteristics (dialysis status, estimated glomerular filtration rate, platelet count, serum lactate dehydrogenase). Stabilized inverse probability weighting was used to balance groups. Changes in outcomes from baseline to 26 weeks were compared between treatment groups. Sensitivity and subgroup analyses were conducted to assess the robustness of findings. Overall, 85 patients (46 ravulizumab, 39 eculizumab) were included in the primary analysis. Demographic and clinical characteristics were well balanced after weighting at baseline. At 26 weeks, clinical outcomes (including renal function, hematological markers, and dialysis prevalence), and fatigue and quality of life measures were improved with eculizumab and ravulizumab treatment. No differences between treatment groups reached statistical significance, although confidence intervals were wide. Sensitivity and subgroup analysis results were consistent with those of the primary analysis. Using appropriate methodology for indirect comparison of studies, no differences in outcomes were seen between ravulizumab and eculizumab, although, owing to small sample sizes, confidence intervals were wide.


Patient cooperation in treatment with removable appliances: a model of patient noncompliance with treatment implications.
The uncooperative or noncompliant patient presents a substantial problem during treatment with removable orthopedic/orthodontic appliances. Frequently, the uncooperative patient is labeled as having a poor or defiant attitude toward orthodontic treatment. In contrast to this attitude model of patient noncompliance, this article presents an analysis of uncooperative behavior in terms of behavior-environment relationships. The authors bring together backgrounds of expertise in both clinical psychology and orthodontics. The behavioral model presented is applied to clinical orthodontic patients undergoing treatment with removable functional appliances. Preliminary research findings suggest that the behavioral model described is a successful system for the introduction of a removable device to be worn by the patient. The techniques described also are useful for the previously uncooperative patient undergoing remedial treatment. Another major benefit of using this strategy is found in the response of the children's parents. The approach reduces the potential for and frequency of parent-child conflicts over dental health. Currently, a small sample of children are being treated by the behavioral method. Both parents and patients are involved. A specific schedule for wearing of a removable appliance is identified, along with parental observations and rewards based on patient compliance. Once the youngster is regularly meeting criteria, the program is altered to increase the desired response of appliance wear. The behavioral model has implications for various aspects of orthodontic care, including the use of such appliances as the Fränkel, Bionator, headgear, intraoral elastics, and proper lip posture. On the basis of this functional analysis of behavior, implications for treatment and prevention of noncompliance in orthodontic patients are discussed.


Improving family communications at the end of life: implications for length of stay in the intensive care unit and resource use.
Inadequate communication persists between healthcare professionals and patients and patients' families in intensive care units. Unwanted or ineffective treatments can occur when patients' goals of care are unknown or not honored, increasing costs and care. Having the primary physician provide medical information and then having a physician and clinical nurse specialist team improve opportunities for patients and their families to process that information could improve the situation. This model has not been tested for its effect on patients' outcomes and resource utilization. To evaluate the effect of a communication team that included a physician and a clinical nurse specialist on length of stay and costs for patients near the end of life in the intensive care unit. During a 1-year period, patients judged to be at high risk for death (N = 151) were divided into 2 groups: 43 patients who were cared for by the medical director teamed with a clinical nurse specialist and 108 patients who received standard care, provided by an attending physician. Compared with the control group, patients in the intervention group had significantly shorter stays in both the intensive care unit (6.1 vs 9.5 days) and the hospital (11.3 vs 16.4 days) and had lower fixed ($15,559 vs $24,080) and variable ($5087 vs $8035) costs. Use of a physician and a clinical nurse specialist focused on improving communication with patients and patients' families reduced lengths of stay and resource utilization.


Professional care workforce: a rapid review of evidence supporting methods of recruitment, retention, safety, and education.
Across the care economy there are major shortages in the health and care workforce, as well as high rates of attrition and ill-defined career pathways. The aim of this study was to evaluate current evidence regarding methods to improve care worker recruitment, retention, safety, and education, for the professional care workforce. A rapid review of comparative interventions designed to recruit, retain, educate and care for the professional workforce in the following sectors: disability, aged care, health, mental health, family and youth services, and early childhood education and care was conducted. Embase and MEDLINE databases were searched, and studies published between January 2015 and November 2022 were included. We used the Quality Assessment tool for Quantitative Studies and the PEDro tools to evaluate study quality. 5594 articles were initially screened and after applying the inclusion and exclusion criteria, 30 studies were included in the rapid review. Studies most frequently reported on the professional nursing, medical and allied health workforces. Some studies focused on the single domain of care worker education (n = 11) while most focused on multiple domains that combined education with recruitment strategies, retention strategies or a focus on worker safety. Study quality was comparatively low with a median PEDro score of 5/10, and 77% received a weak rating on the Quality Assessment tool for Quantitative Studies. Four new workforce strategies emerged; early career rural recruitment supports rural retention; workload management is essential for workforce well-being; learning must be contextually relevant; and there is a need to differentiate recruitment, retention, and education strategies for different professional health and care workforce categories as needs vary. Given the critical importance of recruiting and retaining a strong health and care workforce, there is an immediate need to develop a cohesive strategy to address workforce shortfalls. This paper presents initial evidence on different interventions to address this need, and to inform care workforce recruitment and retention. Rapid Review registration PROSPERO 2022 CRD42022371721 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022371721.


[Dynamics of terminal plaque structure during changes in the impulse activity of sensory endings in the process of their regeneration].
The dynamics of changes in terminal plates of frog's urinary bladder sensory free visceroceptors during their posttraumatic regeneration was studied. It was shown that during the time period from two months to one year the terminal plate number in receptor bush increased, while their average dimensions decreased and their shape changed. No correlations between the changes of afferent impulse activity and these morphological transformations were found. The data obtained suggest that terminal plates do not seem to participate in the generation of bioelectric activity, but rather appear to be the growth cones of non-myelinated terminal and thus are involved in repair processes.


Infection control and pneumonia prophylaxis strategies in the intensive care unit.
Conventional infection control approaches, such as dedicated surveillance and control programs and barrier isolation techniques, effectively interrupt acquisition of many pathogens and reduce infection rates in the intensive care unit (ICU). However, a substantial proportion of infections results from endogenous rather than acquired organisms and require that we also develop strategies to prevent the progression from colonization to infection. Studies of systemic antimicrobial prophylaxis for patients at risk for pneumonia have consistently failed to demonstrate benefit. Topical endotracheal prophylaxis succeeded in preventing pneumonia but was complicated by the emergence of intrinsically resistant gram-negative bacilli. More recently, a number of trails have evaluated selective decontamination of the oropharynx and gastrointestinal tract with nonabsorbable antibiotics. These regimens have demonstrated a substantial impact on pneumonia and overall infection rates in ICU patients. Further investigation will define the role of selective decontamination in selected patient populations as well as address concerns over selection of resistance. Other strategies, including immunoprophylaxis, colonization-resistant devices, and methods to decrease bacterial adherence may also prevent progression from colonization to infection and will be the subject of future investigation.


Differential habitat use by demographic groups of the redfinger rubble crab Eriphia gonagra (Fabricius, 1781).
The structurally diverse rocky shores along the northern coast of the state of São Paulo, Brazil, support a varied fauna and provide refuges for many organisms. Some of these environments allow for extensive microhabitats, among them the sand reefs formed by the polychaete Phragmatopoma lapidosa, which occupy much of this area. The beauty of the landscape attracts large numbers of tourists, who contribute to the damage to the sand reef colonies, causing an imbalance in the patterns of population distribution and of this ecosystem. We describe the structure and population biology of the redfinger rubble crab Eriphia gonagra, and investigated the differential occupation of the habitat by each demographic category of this species. Crabs were sampled monthly for two consecutive years on the rocky coast of Grande Beach, Ubatuba, São Paulo, during spring low tides. Sampling was carried out over an area of approximately 1200 m2, during two hours on the rock surface and another two hours on the sand reefs. A total of 1407 crabs were collected; 776 on the sand reef (SR) and 631 on the rocky shore (RO). The majority of juvenile crabs inhabited the SR, while adult crabs were equally distributed in both microhabitats. This study showed that the SR is a natural nursery ground for the establishment of the early juvenile stages of E. gonagra, which use the reefs as a refuge and food resource. Many other organisms (mollusks, echinoderms, polychaetes etc.) settle on the reefs, and these areas may be among the most important in maintaining benthic diversity in the region.


Enrichment, solubilization, and partial characterization of digitonin-solubilized muscarinic receptors derived from canine ventricular myocardium.
The subcellular distribution of cardiac muscarinic receptors was defined in canine ventricular myocardium, and receptors were solubilized from subcellular fractions enriched in muscarinic receptor content. The subcellular location of muscarinic receptors in cardiac tissue was determined by measurement of the distribution of [3H](+/-)quinuclidinyl benzilate-binding activity in particulate fractions isolated from canine ventricular myocardium. Based upon excellent correlation between [3H](+/-)quinuclidinyl benzilate binding and activity of the sarcolemmal Na+,K+-ATPase throughout the subcellular fractions, muscarinic receptors appeared to be localized to sarcolemma in canine ventricular myocardium. Therefore, membrane fractions enriched in sarcolemma were used as a source of cardiac muscarinic receptors for solubilization. Treatment of membrane vesicle fractions with digitonin (0.6%) resulted in solubilization of [3H](+/-)quinuclidinyl benzilate-binding activity with an extraction yield of 25-35%. Criteria of pharmacological specificity and stereospecificity established the identity of the solubilized binding activity of muscarinic receptors. Solubilization of muscarinic receptors was documented by demonstration of hydrodynamic behavior consistent with molecularly dispersed material. Upon glycerol gradient centrifugation, digitonin-solubilized muscarinic receptors from cardiac tissue sedimented with an apparent sedimentation coefficient of 9S. Pharmacological characterization of the digitonin-solubilized receptors revealed 8- to 39-fold reductions in affinities for muscarinic antagonists compared to the affinities exhibited by receptors in the membrane-bound state. Substantially greater reductions in agonist affinities (reduction of at least 700-fold for all agonists studied) suggested selective loss of ability of the digitonin-solubilized receptors to exhibit high affinity agonist interactions. In contrast to membrane-bound receptors, digitonin-solubilized receptors also demonstrated a loss of guanine nucleotide regulation, as well as steep agonist:radioligand competition curves with slope factors of 1.0, suggesting a homogeneous population of agonist-binding sites. Interpreted within the context of a model of state interconversion for membrane-bound receptors, the results suggested that either muscarinic receptors of a single state were selectively solubilized, or that solubilization induced conversion of all receptors to a single low affinity state, possibly by removal of constituents necessary for assumption of a high affinity agonist conformation.


Mitotic activity and bone marrow micrometastases have independent prognostic value in node positive breast cancer patients.
The purpose of this article is to investigate the prognostic value of the mitotic activity index (MAI) and the presence of disseminated tumor cells (DTCs) in bone marrow (BM), in clinically operable breast cancer patients. We compared routinely assessed MAI, classic prognosticators and BM DTCs, detected by a real-time RT-PCR multimarker assay including cytokeratin 19, mammaglobin A and TWIST1 mRNA, in 179 consecutive patients with operable breast cancer. Over a median follow-up of 96 months (range: 1-126 months), 31 (17.3%) patients experienced a systemic relapse and 26 (14.5%) died of breast cancer-related causes. MAI (≥ 10) was strongly associated with breast cancer-related death in lymph node (LN)-negative patients (hazard ratio (HR): 7.0, confidence interval (CI) 1.74-27.9), whereas both BM DTC-status (HR: 3.3, CI 1.25-8.52) and MAI (HR: 3.1, CI 1.08-8.8) were significant in LN-positive patients. With multivariate Cox regression, MAI was the only significant predictor of breast cancer-specific survival (HR 7.0, CI 1.7-27.9) in LN-negative patients. In LN-positive patients, both BM DTC-status and MAI were strong independent predictors of breast cancer-specific survival (HR 3.3, CI 1.25-8.49 and HR 3.1, CI 1.1-8.9), respectively. Where, however, MAI and BM DTC-status as single parameters were replaced by a combination of these, this showed to be the most significant prognostic marker in both LN-negative (HR 7.7, CI 1.2-50) and LN-positive (HR 6.0, CI 1.4 to 26.4) patients with regard to breast cancer-specific survival. A combination of MAI and BM DTC detection identified both LN-negative and LN-positive breast cancer patients with poor prognosis.


Simultaneous detection of ten psychedelic phenethylamines in urine by gas chromatography-mass spectrometry.
Psychedelic phenethylamines are an emerging class of designer drugs capable of producing a complex array of sought after adrenergic and hallucinogenic effects. Toxicological detection poses a number of challenges to laboratories. The purpose of this study was to develop a procedure for the detection of psychedelic amphetamines using techniques that are widely accepted in forensic toxicology laboratories. In all, 10 target analytes were selected: 2,5-dimethoxy-4-bromophenethylamine (2C-B), 2,5-dimethoxyphenethylamine (2C-H), 2,5-dimethoxy-4iodophenethylamine (2C-I), 2,5-dimethoxy-4ethylthiophenethylamine (2C-T-2), 2,5-dimethoxy-4-(n)propylthiophenethylamine (2C-T-7), 4-methylthioamphetamine (4-MTA), 2,5-dimethoxy-4-bromoamphetamine (DOB), 2,5-dimethoxy-4-ethylamphetamine (DOET), 2,5-dimethoxy4-iodoamphetamine (DOI), and 2,5-dimethoxy-4methylamphetamine (DOM). Target drugs in urine were analyzed by gas chromatography in selected ion monitoring mode after mixed-mode solid-phase extraction. Limits of detection for all analytes were 2-10 ng/mL, and limits of quantitation were 10 ng/mL or less. Precision evaluated at 50 and 500 ng/mL yielded CVs of 0.4-7.9% and accuracy in the range 91-116%. Calibration curves were linear to 1500 ng/mL using mescaline-d₉ as the internal standard. No carryover was evident at 5000 ng/mL (the highest concentration tested) and no interferences were observed from the presence of other structurally related compounds or endogenous bases.


A prospective study of PHACE syndrome in infantile hemangiomas: demographic features, clinical findings, and complications.
PHACE (OMIM no. 606519) is a neurocutaneous syndrome that refers to the association of large, plaque-like, "segmental" hemangiomas of the face, with one or more of the following anomalies: posterior fossa brain malformations, arterial cerebrovascular anomalies, cardiovascular anomalies, eye anomalies, and ventral developmental defects, specifically sternal defects and/or supraumbilical raphe. The etiology and pathogenesis of PHACE is unknown, and potential risk factors for the syndrome have not been systematically studied. The purpose of this study was thus to determine (1) the incidence of PHACE and associated anomalies among a large cohort of hemangioma patients, (2) whether certain demographic, prenatal or perinatal risk factors predispose infants to this syndrome, and (3) whether the cutaneous distribution of the hemangioma can be correlated to the types of anomalies present. We undertook a prospective, cohort study of 1,096 children with hemangiomas, 25 of whom met criteria for PHACE. These 25 patients represented 20% of infants with segmental facial hemangiomas. Compared to previous reports, our PHACE patients had a higher incidence of cerebrovascular and cardiovascular anomalies. Two developed acute arterial ischemic stroke during infancy, while two with cardiovascular anomalies showed documented evidence of normalization, suggesting that both progressive and regressive vascular phenomena may occur in this syndrome. Correlation to the anatomic location of the hemangioma appears to be helpful in determining which structural abnormalities might be present. A comparison of demographic and perinatal data between our PHACE cases and the hemangioma cohort overall showed no major differences, except a trend for PHACE infants to be of slighter higher gestational age and born to slightly older mothers. Eighty-eight percent were female, a finding which has been noted in multiple other reports. Further research is needed to determine possible etiologies, optimal evaluation, and outcomes.


A learning model for nursing students during clinical studies.
This paper presents a research project where the aim was to develop a new model for learning support in nursing education that makes it possible for the student to encounter both the theoretical caring science structure and the patient's lived experiences in his/her learning process. A reflective group supervision model was developed and tested. The supervision was lead by a teacher and a nurse and started in patient narratives that the students brought to the supervision sessions. The narratives were analyzed by using caring science concepts with the purpose of creating a unity of theory and lived experiences. Data has been collected and analyzed phenomenologically in order to develop knowledge of the students' reflection and learning when using the supervision model. The result shows that the students have had good use of the theoretical concepts in creating a deeper understanding for the patient. They have learned to reflect more systematically and the learning situation has become more realistic to them as it is now carried out in a patient near context. In order to reach these results, however, demands the necessity of recognizing the students' lifeworld in the supervision process.