AKT is indispensable for coordinating Par-4/JNK cross talk in p21 downmodulation during ER stress.
The double-edged role of p21 to command survival and apoptosis is emerging. The current investigation highlights ER stress-mediated JNK activation that plausibly triggers cell death by attenuating endogenous p21 level. Here, we demonstrated that ER stress activator 3-AWA diminishes the p21 levels in cancer cells by averting the senescent phenotype to commence G2/M arrest. In essence, the deceleration in p21 level occurs through ER stress/JNK/Caspase-3 axis via activation/induction of proapoptotic Par-4 and inhibition of AKT. The molecular dynamics studies identified important interactions, which may be responsible for the AKT inhibition and efficacy of 3-AWA towards AKT binding pocket. Interestingly, the p21 deceleration was rescued by incubating the cells with 3-AWA in the presence of an ER stress inhibitor, Salubrinal. Furthermore, we demonstrated that p21 expression decreases solitarily in Par-4+/+ MEFs; albeit, ER stress-induced JNK activation was observed in both Par-4+/+ and Par-4-/- MEFs. Par-4 knockdown or overexpression studies established that ectopic Par-4 along with ER stress are not sufficient to downregulate p21 in PC-3 cells but are adequate for DU-145 cells and that the ER stress inflicted activation of JNK, inhibition of AKT and Par-4 induction are all crucial to p21 downmodulation by 3-AWA. By using isogenic cell lines, such as HCT-116 p53+/+ and HCT-116 p53-/-, we found that deceleration in p21 expression due to ER stress is p53 independent. Moreover, in orthotopic carcinogen-induced rat colorectal carcinoma model, we found that 3-AWA inhibits colorectal tumor growth and formation of colorectal polyps at a tolerable dose, similar to the first-line drug for colorectal cancer-5-fluorouracil.


Expression of adrenomedullin in human epicardial adipose tissue: role of coronary status.
Epicardial white adipose tissue (eWAT) is in close contact with coronary vessels and therefore could alter coronary homeostasis. Adrenomedullin (AM) is a potent vasodilatator and antioxidative peptide which has been shown to play a cytoprotective role in experimental models of acute myocardial infarction. We studied, using immunohistochemistry and qRT-PCR, the expression of AM and its receptors calcitonin receptor-like receptor (CRLR), and receptor activity-modifying protein (RAMP)2 and -3 in paired biopsies of subcutaneous WAT (sWAT) and eWAT obtained from patients with coronary artery disease (CAD) or without CAD (NCAD). In eWAT obtained from NCAD or CAD patients, immunoreactivity for AM, CRLR, and RAMP2 and -3 was detected in blood vessel walls and isolated stromal cells close to adipocytes. Some of the AM positive stromal cells colocalized CD68 immunoreactivity. eWAT from CAD patients showed increased AM immunoreactivity and AM gene expression. CRLR mRNA levels were comparable in sWAT of both groups and decreased by 40-50% in eWAT, irrespectively of the coronary status. RAMP2 mRNA concentrations did not change while RAMP3 mRNA levels increased in sWAT from CAD patients. There was a positive linear relationship between eWAT 11beta-hydroxysteroid dehydrogenase type 1 mRNA (11beta-HSD-1, the enzyme that converts inactive to active glucocorticoids) and AM mRNA. In conclusion, we demonstrate that AM and its receptors are expressed in eWAT. Our data suggest that eWAT AM, which could originate from macrophages, is related to 11beta-HSD-1 expression. AM synthesis, which is increased in eWAT during chronic CAD in humans, can play a cardioprotective role.


Oral antibiotic treatment for methicillin-resistant Staphylococcus aureus skin and soft tissue infections: review of the literature.
The emergence of methicillin-resistant Staphylococcus aureus (MRSA) as a cause of hospital- and community-associated infection has been reported worldwide and has become an increasing health care problem. Treatment options for MRSA infection are limited, complicated and expensive. Oral antibiotics have been used in the outpatient setting for less severe MRSA infections such as skin and soft tissue infections (SSTIs), but their efficacy has not been well studied. We reviewed the literature and Internet information sources as well as recent abstracts for factors relevant to the in-vitro and in-vivo activity and adverse effects of oral antibiotics of possible value in treating MRSA SSTI. Most of MRSA isolates are still susceptible to linezolid, TMP-SMX, and the tetracyclines but less susceptible to the quinolones, clindamycin, and erythromycin. Only the quinolones have bactericidal activity, which may be a relevant factor if there is bacteremia. In-vivo studies indicate a high clinical cure rate with linezolid, TMP-SMX, doxycycline and minocycline. Adverse effects are different among the drugs and are a significant factor. Antibiotics with once-daily dosing such as the quinolones have advantage in regard to compliance. Linezolid has the highest daily cost of treatment whereas the cost of the tetracyclines, erythromycin, and TMP-SMX is much lower. The antibiotics available for MRSA SSTI vary widely in chances of resistance, activity, adverse effects, and cost. More clinical studies of clinical efficacy are needed, especially with comparative trials. Selection of the most appropriate antibiotic will depend upon local antibiotic resistance, type of infection, potential adverse effects, and cost for the individual.


Effects of added sodium caseinate on the formation of particles in heated milk.
The effects of heat at temperatures in the range of 80-90 degrees C on mixtures of reconstituted skim milk powder (RSMP) and sodium caseinate have been determined. In the absence of caseinate, the action of heat on RSMP produces soluble complexes of whey proteins and kappa-casein, as well as complexes of whey protein with the casein micelles. When sodium caseinate was added to RSMP at levels of 0.5 and 1.0%, the denaturation of the whey protein and the production of the soluble complexes in the serum were hardly affected, either in rate or in amount. However, during the heating, the caseinate disappeared from the serum. Further studies on model mixtures of the different components showed that it was probable that the bulk of the caseinate associated with the casein micelles during heating, probably by binding inside the surface layer of kappa-casein, because no increase in the diameters of the casein micelles could be observed.


Three-year clinical experience with a new endocardial screw-in lead with introduction protection for use in the atrium and ventricle.
There is still a high incidence of dislodgement, threshold rises, and loss of sensing with permanent transvenous endocardial leads. Atrial leads are an even greater problem and require particularly reliable methods of fixation. In March, 1976 we reported our preliminary results from animal experiments using a new transvenous screw-in lead with introduction protection. This lead differs from other screw-in models as its spiral tip is retracted in the insulating tube during insertion. For fixation purposes a torque is applied to the proximal end of the conductor coil, which is loosely positioned within the tube, and this moves the helical electrode forward. One hundred and fifty endocardial electrodes have been implanted; 127 of them in the dilated ventricle and 23 in the atrium. The technique of introducing the lead into the vein (cephalic or jugular) was the same as that for conventional leads. It was easy to manage and quite uncomplicated. The fixation features in the atrium or the ventricle were sufficiently reliable to allow some patients to go home several hours post-implant. The total working time of the leads used has been 900 months; the overall complication rate is 2%.


Expression of human mucin genes during normal and abnormal renal development.
Human mucin genes encode large O-glycoproteins, which are expressed in various epithelial tissues. The proteins are the main components of mucus, but also might be involved in morphogenesis of or carcinogenesis in many organs. We studied the expression of human mucin genes during fetal kidney development and in malformed cystic renal diseases in 10 normal fetal kidneys and 12 malformed kidneys by in situ hybridization and immunohistochemical analysis. MUC1, MUC3, and MUC6 were expressed in normal fetal kidney. MUC1 was expressed from 7.5 weeks of gestation in the metanephric blastema and throughout fetal life in the ureteric buds, distal convoluted tubules, and collecting ducts. MUC3 was expressed weakly in immature tubules from 8 weeks of gestation, after which it was expressed weakly and focally in the proximal convoluted tubules. MUC6 was expressed at 9.5 weeks of gestation in the tips of the ureteric buds and later in the collecting ducts. In malformative cystic diseases, only MUC1 expression was retained; no expression of MUC6 and MUC3 was observed. These results implicate human mucin genes (MUC1, MUC3, and MUC6) in renal morphogenesis processes.


Schizophrenia and weight management: a systematic review of interventions to control weight.
Weight gain is a frequent side effect of antipsychotic medication which has serious implications for a patient's health and well being. This study systematically reviews the literature on the effectiveness of interventions designed to control weight gain in schizophrenia. A systematic search strategy was conducted of major databases in addition to citation searches. Study quality was rated. Sixteen studies met the inclusion criteria. Five of eight pharmacological intervention studies reported small reductions in weight (<5% baseline body weight). All behavioural (including diet and/or exercise) interventions reported small reductions in, or maintenance of, weight. Weight loss may be difficult but it is not impossible. Given the inconsistent results, the widespread use of pharmacological interventions cannot be recommended. Both dietary and exercise counselling set within a behavioural modification programme is necessary for sustained weight control.


Using Intervention Mapping to Develop an Oral Health e-Curriculum for Secondary Prevention of Eating Disorders.
Preventing oral-systemic health issues relies on evidence-based interventions across various system-level target groups. Although the use of theory- and evidence-based approaches has been encouraged in developing oral health behavior change programs, the translation of theoretical constructs and principles to behavior change interventions has not been well described. Based on a series of six systematic steps, Intervention Mapping provides a framework for effective decision making with regard to developing, implementing, and evaluating theory- and evidence-informed, system-based behavior change programs. This article describes the application of the Intervention Mapping framework to develop the EAT (evaluating, assessing, and treating) evidence-based intervention with the goal of increasing the capacity of oral health providers to engage in secondary prevention of oral-systemic issues associated with disordered eating behaviors. Examples of data and deliverables for each step are described. In addition, results from evaluation of the intervention via randomized control trial are described, with statistically significant differences observed in behavioral outcomes in the intervention group with effect sizes ranging from r=0.62 to 0.83. These results suggest that intervention mapping, via the six systematic steps, can be useful as a framework for continued development of preventive interventions.


Steady dynamics of exothermic chemical wave fronts in van der Waals fluids.
We study the steady dynamics of an exothermic Fisher-Kolmogorov-Petrovsky-Piskunov chemical wave front traveling in a one-dimensional van der Waals fluid. The propagating wave is initiated by a nonuniformity in reactant concentration contrary to usual combustion ignition processes. The heat release and activation energy of the reaction play the role of control parameters. We recently proved that the propagation of an exothermic chemical wave front in a perfect gas displays a forbidden interval of stationary wave front speeds [G. Dumazer, M. Leda, B. Nowakowski, and A. Lemarchand, Phys. Rev. E 78, 016309 (2008)]. We examine how this result is modified for nonideal fluids and determine the effect of the van der Waals parameters and fluid density on the bifurcation between diffusion flames and Chapman-Jouguet detonation waves as heat release increases. Analytical predictions are confirmed by the numerical solution of the hydrodynamic equations including reaction kinetics.


The potential cholesterol-lowering and prebiotic effects of bamboo shoot dietary fibers and their structural characteristics.
The physicochemical and physiological properties of soluble dietary fiber (SDF) and insoluble dietary fiber (IDF) from bamboo shoots were investigated in present study. IDF showed better adsorption capacity than the corresponding SDF from the same species. Microstructure observation results indicated that the surface of IDF was porous, whereas the SDF was relatively flat and compact. The cholesterol-adsorption capacities of IDF and SDF from Fargesia spathacea were relatively higher than the other species. Both SDF and IDF from F. spathacea showed potential prebiotic effects, although the Lactobacillus and Bifidobacterium promotion effects of SDF were relatively stronger than IDF. Compared with control, the concentration of total short chain fatty acids in IDF and SDF supplement groups were increased by 1.28 and 0.71 folds, respectively. These results suggested that F. spathacea dietary fibers with strong cholesterol-adsorption activity and prebiotic potential, could be used as a bioactive ingredient in functional foods production.


[Effect of glycyrrhizic acid on growth of Streptococcus mutans under acid environment in vitro].
To investigate the antibacterial activity of glycyrrhizic acid (GA) against Streptococcus mutans (S. mutans) under acidic environment in vitro. Working culture were prepared by inoculation of S. mutans into TPY broth followed by static incubation under anaerobic condition at 37 degrees C for 24 h. TPY broth was supplemented with three kinds density of GA (0.78, 1.57, 3.13 mg x mL(-1)), whose acidity was regulated to pH7.0, pH 5.5 and pH4.0. And the group of pH 7.0 was used as negative control. The growth of S. mutans was measured by A600 of bacteria suspension and counting colony forming unit (CFU). In addition, the survival rate of S. mutans was calculated. In pH 5.5 groups, the survival rates of 0.78, 1.57 and 3.13 mg x mL(-1) GA groups were 60.96%, 60.27% and 45.58%, respectively, and in pH4.0 groups, the survival rates were 68.75%, 53.12% and 45.83%. In 0.78, 1.57 and 3.13 mg x mL(-1) GA groups, the survival rates of pH5.5 and pH4.0 were 52.25% and 39.05%, 74.39% and 43.11%, 86.38% and 55.30%, respectively. GA could inhibit the growth of S. mutans under acidic environment, which the effect is improved as the acidity increased.


Hyperbaric oxygenation for tumour sensitisation to radiotherapy.
Cancer is common and radiotherapy is one well-established treatment for some solid tumours. HBO may improve the ability of radiotherapy to kill hypoxic cancer cells, so the administration of radiotherapy while breathing HBO may result in a reduction in mortality and tumour recurrence. To assess the benefits and harms of radiotherapy while breathing HBO. In November 2004 we searched The Cochrane Central Register of Controlled Trials (CENTRAL), (The Cochrane Library Issue 3), MEDLINE, EMBASE , CINAHL, DORCTHIM and reference lists of articles. Relevant journals were handsearched. Randomised and quasi-randomised studies comparing the outcome of malignant tumours following radiation therapy while breathing HBO versus air (with or without sham therapy). Three reviewers independently evaluated the quality of the relevant trials using the method of Schulz (Schulz 1995) and extracted the data from the included trials. Nineteen trials contributed to this review (2286 patients: 1103 allocated to HBO and 1153 control). With HBO, there was a reduction in mortality for head and neck cancers at both one year and five years after therapy (Relative risk (RR) 0.83, P = 0.03, number needed to treat (NNT) = 11 and RR 0.82, P = 0.03, NNT = 5 respectively), as well as improved local tumour control at three months (RR with HBOT 0.58, P = 0.006, NNT = 7). The effect of HBO varied with different fractionation schemes. Local tumour recurrence was less likely with HBO at one year (head and neck, RR 0.66, P < 0.0001, NNT = 5), two years (uterine cervix RR 0.60, P = 0.04, NNT = 5) and five years (head and neck (RR 0.77, P = 0.01). Any advantage is achieved at the cost of some adverse effects. There was a significant increase in the rate of both severe radiation tissue injury (RR 2.35, P < 0.0001, (number needed to harm (NNH) = 8) and the chance of seizures during therapy (RR 6.76, P = 0.03, NNH 22) with HBO. There is some evidence that HBO improves local tumour control and mortality for cancers of the head and neck, and local tumour recurrence in cancers of the head and neck, and uterine cervix. These benefits may only occur with unusual fractionation schemes. HBO is associated with significant adverse effects including oxygen toxic seizures and severe tissue radiation injury. The methodological and reporting inadequacies of the primary studies included in this review demand a cautious interpretation. More research is needed for head and neck cancer, but is probably not justified for bladder cancer. There is little evidence available concerning malignancies at other anatomical sites on which to base a recommendation.


Kaiser-Bessel basis for particle-mesh interpolation.
In this work, we introduce the Kaiser-Bessel interpolation basis for the particle-mesh interpolation in the fast Ewald method. A reliable a priori error estimate is developed to measure the accuracy of the force computation in correlated charge systems, and is shown to be effective in optimizing the shape parameter of the Kaiser-Bessel basis in terms of accuracy. By comparing the optimized Kaiser-Bessel basis with the traditional B-spline basis, we demonstrate that the former is more accurate than the latter in part of the working parameter space, say, a relatively small real-space cutoff, a relatively small reciprocal space mesh, and a relatively large truncation of basis. In some cases, the Kaiser-Bessel basis is found to be more than one order of magnitude more accurate.


Laser Capture Microdissection of Single Neurons with Morphological Visualization Using Fluorescent Proteins Fused to Transmembrane Proteins.
Gene expression analysis in individual neuronal types helps in understanding brain function. Genetic methods expressing fluorescent proteins are widely used to label specific neuronal populations. However, because cell type specificity of genetic labeling is often limited, it is advantageous to combine genetic labeling with additional methods to select specific cell/neuronal types. Laser capture microdissection is one of such techniques with which one can select a specific cell/neuronal population based on morphological observation. However, a major issue is the disappearance of fluorescence signals during the tissue processing that is required for high-quality sample preparation. Here, we developed a simple, novel method in which fluorescence signals are preserved. We use genetic labeling with fluorescence proteins fused to transmembrane proteins, which shows highly stable fluorescence retention and allows for the selection of fluorescent neurons/cells based on morphology. Using this method in mice, we laser-captured neuronal somata and successfully isolated RNA. We determined that ∼100 cells are sufficient to obtain a sample required for downstream applications such as quantitative PCR. Capability to specifically microdissect targeted neurons was demonstrated by an ∼10-fold increase in mRNA for fluorescent proteins in visually identified neurons expressing the fluorescent proteins compared with neighboring cells not expressing it. We applied this method to validate virus-mediated single-cell knockout, which showed up to 92% reduction in knocked-out gene RNA compared with wild-type neurons. This method using fluorescent proteins fused to transmembrane proteins provides a new, simple solution to perform gene expression analysis in sparsely labeled neuronal/cellular populations, which is especially advantageous when genetic labeling has limited specificity.


Patients with alopecia areata are at risk of endothelial dysfunction: results of a case-control study.
Alopecia areata (AA) is an autoimmune form of hair loss, which may affect any hair-bearing area. It has been suggested that AA is associated with an increased risk of metabolic and cardiovascular comorbidities. To evaluate the early predictors of cardiovascular disease [endothelial function (EF) and arterial stiffness (AS)] in patients with AA without prior cardiovascular disease, and compare with healthy controls (HCs). In total, 52 patients with AA (38 women and 14 men; mean age 41 years, range 30-52 years) and 34 HCs, matched for age, sex and body mass index, were enrolled in the study. EF, expressed as reactive hyperaemia index (RHI), and AS, identified by augmentation index at 75 beats/min (AI@75) were assessed with the use of the Endo-PAT 2000 device. Endothelial dysfunction (ED) was defined as RHI value ≤1.67. ED was observed in 22 of 52 patients with AA (42%) and in 4 of 34 HCs (12%) (P < 0.01). Moreover, mean RHI was lower in patients with AA compared with HCs (1.90 ± 0.31 vs. 2.11 ± 0.45; P = 0.03). There was no significant difference in AI@75 between patients with AA and HCs. Patients with AA show abnormalities in early predictors of cardiovascular diseases. Regular cardiovascular screening might be appropriate for patients with AA.


Potassium supplements in patients receiving long-term diuretics for oedema.
Plasma, blood cell, and total body potassium levels were measured serially in 21 patients receiving long-term diuretics for the treatment of cardiac oedema and the results compared with similar measurements in 10 control subjects. Initially, all diuretic recipients received potassium chloride supplements. However, in 17 of the 21 subjects these were discontinued and measurements of potassium status were repeated regularly thereafter. No significant fall in the measured indicators of potassium status were observed in the patients in whom potassium was withdrawn; however, in one subject with persistent cardiac failure who presented with hypokalaemia this was not corrected even after intensive potassium supplementation. It is concluded that for those taking a normal diet who are free of any major gastro-intestinal disorder, routine potassium supplementation is unnecessary, and might indeed occasionally prove harmful.


Supporting the returning veteran: building linkages between clergy and health professionals.
Rather than seeking psychiatric services, veterans often turn to clergy members as first responders to cope with exposure to traumatic events. The goal of this study was to evaluate clergy preparedness to assist with these issues and to determine if an educational symposium geared toward this population would increase preparedness and collaboration with psychiatrists. A pre- and post-conference survey was administered to clergy members who attended an educational symposium on the benefits of collaboration between psychiatry and spirituality for service members. Analyses found that clergy frequently self-reported difficulties recognizing symptoms of posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) and identifying resources. After attending a symposium on the topic, follow-up data indicated significant increases in the clergy's preparedness to address traumatic events. Educational programs may assist clergy in filling knowledge gaps related to recognizing symptoms of PTSD and TBI and providing resources to veterans and their family members.


Faecal microbiota transplantation.
The use of faeces for the treatment of gastrointestinal diseases was described in 4th century Chinese medicine for the treatment of severe diarrhoea.1 More recently there has been renewed interest in this unconventional biological therapy, particularly for the treatment of recurrent Clostridium difficile infection (CDI) and to a lesser extent inflammatory bowel diseases (IBD). Faecal microbiota transplantation† (FMT) involves the introduction of enteric bacteria from the faeces of healthy donors in order to restore a healthy balance of bacteria in the gut.2 In March 2014, the National Institute for Health and Care Excellence (NICE) issued guidance on the use of FMT for the treatment of recurrent CDI that has failed to respond to antibiotics and other treatments.2 Here we review the use of FMT in CDI and IBD.


Twenty-four-hour gastric luminal pH in normal subjects: influence of probe position, food, posture, and duodenogastric reflux.
The aim of this study was to determine the gastric pH at different levels in the stomach under varying physiological circumstances. Simultaneous 24-hour ambulatory gastric pH monitoring was performed with multiple electrodes in 24 normal subjects, divided into groups of six, to study the influence of food, the supine posture, and physiological duodenogastric reflux on gastric pH in different parts of the stomach. In 18 subjects, simultaneous recordings were made from two electrodes positioned 5 and/or 10 cm below the manometrically-defined lower border of the lower esophageal sphincter and, in six subjects, from three electrodes, one positioned 5 cm below the lower esophageal sphincter and two others positioned 5 and 8 cm proximal to the pylorus. During the daytime fasting period, pH was homogenous across the stomach with most time being spent between pH 1 and 2. Marked similarities in recorded pH were noted when two probes were placed in the stomach at the same level, indicating regional consistency in the pH of the chyme. This finding was observed when probes were free from each other or tethered together. Food increased pH most in the fundus, less in the midstomach, and least in the antrum. At night, when supine, alkaline shifts occurred in the distal stomach, most likely because of physiological duodenogastric reflux. These were commonly recorded in the antrum but only occasionally in the proximal stomach. Measurement of the gastric pH environment requires standardization of the probe position, of feeding, and of posture, and global measurement of gastric pH requires simultaneous recording in both the proximal and distal stomach.


HSP90 and Akt modulate Ang-1-induced angiogenesis via NO in coronary artery endothelium.
This study examines the notion that heat shock protein (HSP) 90 binding to nitric oxide (NO), endothelial NO synthase (eNOS), and PI3K-Akt regulate angiopoietin (Ang)-1-induced angiogenesis in porcine coronary artery endothelial cells (PCAEC). Exposure to Ang-1 (250 ng/ml) for periods up to 2 h resulted in a time-dependent increase in eNOS phosphorylation at Ser 1177 that occurred by 5 min and peaked at 60 min. This was accompanied by a gradual increase in NO release. Ang-1 also led to stimulation of HSP90 binding to eNOS and a significant increase in Akt phosphorylation. Thirty minutes of pretreatment of cells with either 1 microg/ml geldanamycin (a specific inhibitor of HSP90) or 500 nM wortmannin [a specific phosphatidylinositol 3 (PI3)-kinase (PI3K) inhibitor] significantly attenuated Ang-1-stimulated eNOS phosphorylation and NO production. Exposure to Ang-1 caused an increase in endothelial cell migration, tube formation, and sprouting from PCAEC spheroids, and pharmacological blockage of HSP90 function or inhibition of PI3K-Akt pathway completely abolished these effects. Inhibition of nitric oxide synthase by NG-nitro-l-arginine methyl ester (2.5 mM) also resulted in a significant decrease in Ang-1-induced angiogenesis. We conclude that stimulated HSP90 binding to eNOS and activation of the PI3-Akt pathway contribute to Ang-1-induced eNOS phosphorylation, NO production, and angiogenesis in PCAEC.


The impact of multidisciplinary care on early morbidity and mortality after heart transplantation.
The impact of multidisciplinary care on outcome after heart transplantation (HTx) remains unclear. This retrospective study investigates the impact of multidisciplinary care on the primary end point 1-year all-cause mortality (ACM) and the secondary end point mean acute cellular rejection (ACR) grade within the first postoperative year. This study includes a total 140 HTx recipients (median age: 53.5 years; males: 80%; donor/recipient gender mismatch: 38.3%; mean length of in-hospital stay: 34 days; mean donor age: 41 years). Multidisciplinary care was implemented in 2008, 66 HTx recipients had operation in 2000-07 and 74 patients had HTx thereafter (2008-14). Non-ischaemic dilated cardiomyopathy was more prevalent in HTx recipients of 2000-07 (63.6 vs 43.2%; P = 0.024). Pre-transplant mechanical circulatory support was more frequent in 2008-14 (9.1 vs 24.3%; P = 0.030). Groups were not different for pre-transplant cardiovascular risk factors or other comorbidity, invasive haemodynamics or echocardiographic parameters. In-hospital and 1-year ACM were numerically lower in 2008-14 (16.2 vs 22.2%; 18.9% vs 25.8%; P = 0.47/0.47, respectively). In 2000-07, pre-transplant weight and diabetes mellitus predicted in-hospital ACM (odds ratio -0.14, P = 0.02; OR 5.24, P = 0.01, respectively) while post-transplant length of in-hospital stay was related with in-hospital ACM (odds ratio -0.10; P = 0.016) and 1-year ACM (odds ratio -0.07; P = 0.007). In 2000-07, the mean grade of ACR within the first postoperative year was higher (0.65 vs 0.20; P < 0.0001) and ≥moderate ACR was associated with in-hospital mortality (χ2 = 3.92; P = 0.048). Multidisciplinary care in HTx compensates post-transplant risk associated with pre-transplant disease and has beneficial impact on the incidence of ACR and ACR-associated early mortality.


Synthesis of Gemcitabine-Threonine Amide Prodrug Effective on Pancreatic Cancer Cells with Improved Pharmacokinetic Properties.
To investigate the amino acid transporter-based prodrug anticancer strategy further, several amino acid-conjugated amide gemcitabine prodrugs were synthesized to target amino acid transporters in pancreatic cancer cells. The structures of the synthesized amino acid-conjugated prodrugs were confirmed by ¹H-NMR and LC-MS. The pancreatic cancer cells, AsPC1, BxPC-3, PANC-1 and MIAPaCa-2, appeared to overexpress the amino acid transporter LAT-1 by conventional RT-PCR. Among the six amino acid derivatives of gemcitabine, threonine derivative of gemcitabine (Gem-Thr) was more effective than free gemcitabine in the pancreatic cancer cells, BxPC-3 and MIAPaCa-2, respectively, in terms of anti-cancer effects. Furthermore, Gem-Thr was metabolically stable in PBS (pH 7.4), rat plasma and liver microsomal fractions. When Gem-Thr was administered to rats at 4 mg/kg i.v., Gem-Thr was found to be successfully converted to gemcitabine via amide bond cleavage. Moreover, the Gem-Thr showed the increased systemic exposure of formed gemcitabine by 1.83-fold, compared to free gemcitabine treatment, due to the significantly decreased total clearance (0.60 vs. 4.23 mL/min/kg), indicating that the amide prodrug approach improves the metabolic stability of gemcitabine in vivo. Taken together, the amino acid transporter-targeting gemcitabine prodrug, Gem-Thr, was found to be effective on pancreatic cancer cells and to offer an efficient potential means of treating pancreatic cancer with significantly better pharmacokinetic characteristics than gemcitabine.


Berkson error adjustment and other exposure surrogates in occupational case-control studies, with application to the Canadian INTEROCC study.
Many epidemiological studies assessing the relationship between exposure and disease are carried out without data on individual exposures. When this barrier is encountered in occupational studies, the subject exposures are often evaluated with a job-exposure matrix (JEM), which consists of mean exposure for occupational categories measured on a comparable group of workers. One of the objectives of the seven-country case-control study of occupational exposure and brain cancer risk, INTEROCC, was to investigate the relationship of occupational exposure to electromagnetic fields (EMF) in different frequency ranges and brain cancer risk. In this paper, we use the Canadian data from INTEROCC to estimate the odds of developing brain tumours due to occupational exposure to EMF. The first step was to find the best EMF exposure surrogate among the arithmetic mean, the geometric mean, and the mean of log-normal exposure distribution for each occupation in the JEM, in comparison to Berkson error adjustments via numerical approximation of the likelihood function. Contrary to previous studies of Berkson errors in JEMs, we found that the geometric mean was the best exposure surrogate. This analysis provided no evidence that cumulative lifetime exposure to extremely low frequency magnetic fields increases brain cancer risk, a finding consistent with other recent epidemiological studies.


Interferon-α suppresses cAMP to disarm human regulatory T cells.
IFN-α is an antineoplastic agent in the treatment of several solid and hematologic malignancies that exerts strong immune- and autoimmune-stimulating activity. However, the mechanisms of immune activation by IFN-α remain incompletely understood, particularly with regard to CD4(+)CD25(high)Foxp(+) regulatory T cells (Treg). Here, we show that IFN-α deactivates the suppressive function of human Treg by downregulating their intracellular cAMP level. IFN-α-mediated Treg inactivation increased CD4(+) effector T-cell activation and natural killer cell tumor cytotoxicity. Mechanistically, repression of cAMP in Treg was caused by IFN-α-induced MAP-ERK kinase (MEK)/extracellular signal-regulated kinase (ERK)-mediated phosphodiesterase 4 (PDE4) activation and accompanied by downregulation of IFN receptor (IFNAR)-2 and negative regulation of T-cell receptor signaling. IFN-α did not affect the anergic state, cytokine production, Foxp3 expression, or methylation state of the Treg-specific demethylated region (TSDR) within the FOXP3 locus associated with a stable imprinted phenotype of human Treg. Abrogated protection by IFN-α-treated Treg in a humanized mouse model of xenogeneic graft-versus-host disease confirmed IFN-α-dependent regulation of Treg activity in vivo. Collectively, the present study unravels Treg inactivation as a novel IFN-α activity that provides a conceivable explanation for the immune-promoting effect and induction of autoimmunity by IFN-α treatment in patients with cancer and suggests IFN-α for concomitant Treg blockade in the context of therapeutic vaccination against tumor antigens.


Graves' ophthalmopathy: the role of diffusion-weighted imaging in detecting involvement of extraocular muscles in early period of disease.
To evaluate involvement of the extraocular muscle (EOM) using diffusion-weighted imaging (DWI), to determine whether there is correlation with conventional orbital MRI and apparent diffusion coefficient (ADC) values in patients with Graves' ophthalmopathy (GO). 35 patients known clinically with GO and 21 healthy controls were studied. Patients were assessed with clinical activity scores. All subjects underwent conventional MRI and DWI study. Involvement of the EOM was evaluated. The patients were classified as involved or uninvolved on orbital MRI and their ADC values in DWI compared. There was significant difference in the mean ADC value of all the EOMs in patients vs controls. The ADC values of all the EOMs were higher in patients. There were significant differences in ADC values between uninvolved muscles on conventional MRI and controls for the MR, SR and LR. There was no significant difference in ADC value between the two groups when considering the IR. ADC values of medial, lateral and superior rectus muscles were increased. Increased ADC values of the EOM in patients with GO suggest that EOM damage begins at a very early stage before being detected on routine orbital MRI. The routine MRI with DWI sequence will be a useful adjunct in the selection of a group of patients most likely to benefit from early treatment. This study can help to evaluate the involvement of GO in early period with MRI added DWI.


Laminar Profile and Physiology of the α Rhythm in Primary Visual, Auditory, and Somatosensory Regions of Neocortex.
The functional significance of the α rhythm is widely debated. It has been proposed that α reflects sensory inhibition and/or a temporal sampling or "parsing" mechanism. There is also continuing disagreement over the more fundamental questions of which cortical layers generate α rhythms and whether the generation of α is equivalent across sensory systems. To address these latter questions, we analyzed laminar profiles of local field potentials (LFPs) and concomitant multiunit activity (MUA) from macaque V1, S1, and A1 during both spontaneous activity and sensory stimulation. Current source density (CSD) analysis of laminar LFP profiles revealed α current generators in the supragranular, granular, and infragranular layers. MUA phase-locked to local current source/sink configurations confirmed that α rhythms index local neuronal excitability fluctuations. CSD-defined α generators were strongest in the supragranular layers, whereas LFP α power was greatest in the infragranular layers, consistent with some of the previous reports. The discrepancy between LFP and CSD findings appears to be attributable to contamination of the infragranular LFP signal by activity that is volume-conducted from the stronger supragranular α generators. The presence of α generators across cortical depth in V1, S1, and A1 suggests the involvement of α in feedforward as well as feedback processes and is consistent with the view that α rhythms, perhaps in addition to a role in sensory inhibition, may parse sensory input streams in a way that facilitates communication across cortical areas. The α rhythm is thought to reflect sensory inhibition and/or a temporal parsing mechanism. Here, we address two outstanding issues: (1) whether α is a general mechanism across sensory systems and (2) which cortical layers generate α oscillations. Using intracranial recordings from macaque V1, S1, and A1, we show α band activity with a similar spectral and laminar profile in each of these sensory areas. Furthermore, α generators were present in each of the cortical layers, with a strong source in superficial layers. We argue that previous findings, locating α generators exclusively in the deeper layers, were biased because of use of less locally specific local field potential measurements. The laminar distribution of α band activity appears more complex than generally assumed.


Computationally effective algorithm for robust weighted averaging.
One of the greatest disadvantages of the weighted signal averaging method is its sensitivity to the presence of noise and outliers in data and the need to estimate the noise variance in all signal cycles. The robust weighted averaging method based on the epsilon-insensitive loss function is free of these disadvantages, but has a very high computational burden and requires a choice of the insensitivity parameter epsilon. In this study, a new computationally effective algorithm for robust weighted averaging with automatic adjustment of the insensitivity parameter is introduced.


Exploring single cells in space and time during tissue development, homeostasis and regeneration.
Complex 3D tissues arise during development following tightly organized events in space and time. In particular, gene regulatory networks and local interactions between single cells lead to emergent properties at the tissue and organism levels. To understand the design principles of tissue organization, we need to characterize individual cells at given times, but we also need to consider the collective behavior of multiple cells across different spatial and temporal scales. In recent years, powerful single cell methods have been developed to characterize cells in tissues and to address the challenging questions of how different tissues are formed throughout development, maintained in homeostasis, and repaired after injury and disease. These approaches have led to a massive increase in data pertaining to both mRNA and protein abundances in single cells. As we review here, these new technologies, in combination with in toto live imaging, now allow us to bridge spatial and temporal information quantitatively at the single cell level and generate a mechanistic understanding of tissue development.


Technical Note: Impact of cell repopulation and radionuclide uptake phase on cell survival.
To study theoretically the impact on cell survival of the radionuclide uptake rate inside tumor cells for a single administration of a radiopharmaceutical. The instantaneous-uptake model of O'Donoghue ["The impact of tumor cell proliferation in radioimmunotherapy," Cancer 73, 974-980 (1994)] for a proliferating cell population irradiated by an exponentially decreasing dose-rate is here extended to allow for the monoexponential uptake of the radiopharmaceutical by the targeted cells. The time derivative of the survival curve is studied in detail deducing an expression for the minimum of the surviving fraction and the biologically effective dose (BED). Surviving fractions are calculated over a parameter range that is clinically relevant and broad enough to establish general trends. Specifically, results are presented for the therapy radionuclides Y-90, I-131, and P-32, assuming uptake half-times 1-24 h, extrapolated initial dose-rates 0.5-1 Gy h(-1), and a biological clearance half-life of seven days. Representative radiobiological parameters for radiosensitive and rapidly proliferating tumor cells are used, with cell doubling time equal to 2 days and α-coefficient equal to 0.3 and 0.5 Gy(-1). It is shown that neglecting the uptake phase of the radiopharmaceutical (i.e., assuming instantaneous-uptake) results in a sizeable over-estimation of cell-kill (i.e., under-estimation of cell survival) even for uptake half-times of only a few hours. The differences between the exponential-uptake model and the instantaneous-uptake model become larger for high peak dose-rates, slow uptakes, and (slightly) for long-lived radionuclides. Moreover, the sensitivity of the survival curve on the uptake model was found to be higher for the tumor cells with the larger α-coefficient. The exponential-uptake rate of the radiopharmaceutical inside targeted cells appears to have a considerable effect on the survival of a proliferating cell population and might need to be considered in radiobiological models of tumor cell-kill in radionuclide therapy.


Racial variations in tests of fetoplacental function.
Fetoplacental function tests discriminated well between poorly grown and well grown fetuses in European mothers. In contrast, apart from human placental lactogen, the individual values of poorly grown Asian fetuses fell within the well grown range. Haemoglobin values rose in the second trimester in European pregnancies associated with poor growth, whereas the values fell in the Asian pregnancies both with well grown and poorly grown fetuses. These observations imply fundamental differences in the aetiology of intrauterine growth retardation in the two races.


Brief family therapy for childhood tic syndrome.
This paper reports the success of brief analytically oriented outpatient family therapy exclusively in treating an eight-year old girl presenting with a short history of multiple tics involving facial, thoracic, and upper limb musculature, with associated hoarse coughing and grunting. Diagnostic features are reviewed. No medicines were used, and the patient remained asymptomatic nine months after ceasing family therapy. Tentative indications for family therapy for tiqueurs are proposed.


Short-time UVA exposure to human keratinocytes instigated polyunsaturated fatty acid without inducing lipid peroxidation.
Short-term exposure to ultraviolet A (UVA) radiation can directly injure our skin through inflammatory response and indirectly through oxidative stress, triggering polyunsaturated fatty acid (PUFA) peroxidation in skin cell membrane and formation of DNA adduct, 8-hydroxy-2'-deoxyguanosine (8-OHdG). It is known that UVA exposure leads to photoaging, immunosuppression and skin cancer. However, the changes in PUFA and its oxidized metabolites, and cell cycle after short UVA exposure, are debatable. In this study, human keratinocytes (HaCaT) were exposed to low dose (5 J/cm2) and high dose (20 J/cm2) of UVA and assessed immediately, 8 h, 12 h, and 24 h post-treatment. Both doses showed a transient suppression in S-phase after 8 h of UVA exposure, and G2/M phase arrest after 12-h UVA exposure in the cell cycle but subsequently returned to normal cycle. Also, no observable DNA damage took place, where 8-OHdG levels were below par after 24-h UVA exposure. A dose of 20 J/cm2 UVA stimulated significant amount of arachidonic acid, n-3 docosapentaenoic acid, and docosahexaenoic acid (DHA) but lowered adrenic acid and eicospentaenoic acid after 24-h exposure. Among the 43 oxidized PUFA products determined, enzyme-dependent oxidized PUFAs, namely, 14-hydroxy-DHA (HDoHE) level reduced, and 8- and 13-HDoHE levels elevated significantly in a linear trend with post-treatment time. Out of the nonenzymatic oxidized PUFAs, a significant linear trend with post-treatment time was shown on the reduction of 5-F2t-Isoprostane (IsoP), 15-F2t-IsoP, Isofurans, 5-F3t-IsoP, Neurofurans, and 20-HDoHE. Our observations indicate oxidative stress through short UVA exposure on human keratinocytes did not have detrimental consequences.


Evaluating the impact of synthetic herbicides on soil dwelling macrobes and the physical state of soil in an agro-ecosystem.
This study evaluated three herbicides active ingredients: Paraquat, Glyphosate and 2,4-D Amine in commercial formulations as Frankoquat, Roundup and Agriherb respectively under field conditions to determine their influence on soil dwelling macrobes and the physical state of soil. Herbicides were serially diluted to three treatment concentrations for each plus three controls. Herbicide concentrations were applied to the demarcated field on three consecutive occasions in splits. Macrobes extraction from soil was done under a stereo microscope at 20 × magnification. The Simpson's diversity index was used to calculate the soil macrobes diversity. Soil water content, bulk density and total porosity of sampled soils were determined. The study revealed that both herbicides and non-herbicides treatment had no statistical significance (p > 0.05) on the soil dwelling macrobes. Also, a Simpson's index of diversity, estimated as 53.46%, showed how the experimental area is lowly diverse in the specific soil dwelling macrobes identified. Significant correlations existed between the soil water content, bulk density, total porosity and number of soil macrobes at p < 0.05. This level of significance showed in most instances for Frankoquat herbicide concentration treatments as well as Roundup. For Agriherb and control treatments the correlations were present but majority was not significant. In most situations, the soil dwelling macrobes decreased with increasing soil physical conditions. Thus, the dynamics in soil physical properties affected macrobes abundance in soil, with the slightest influence coming from the herbicides concentrations used in the experiment. The study recommended that Frankoquat and Roundup herbicides could be used to control weeds on farmer's field because, their influence were slightly felt on the soil macrobes and also, quite a number soil dwelling macrobes recovered after application.


Networking possibilities for waste recycling in Miyagi prefecture, Japan.
Successful case studies for waste recycling in Japan have not been evaluated. The evaluation of economic efficiency and environmental effects were lacking at the time the actual network was established. A waste/resource input/output (I/O) coincidence retrieval system called ZENESYS was developed to examine the usefulness of a waste-exchange network in a nonmanufacturing district. We analyzed data from the Miyagi prefecture, a region without heavy industry. The data were collected from 77 companies using a questionnaire and interviews. A total of 33 possible waste exchange links arose after analysis using ZENESYS. However, these were frail networks that relied heavily on the construction industry. Two waste recycling technologies were selected from the ZENESYS database: reclaiming fuel from waste plastic and making construction materials from bottom ash. Evaluation of the environmental effects and economics of these two technologies showed they were both suitable for the environment, but no profit was made from reclaiming fuel from waste plastics. We concluded that in an area with no heavy industry, it may be difficult to adopt recycling technologies that have high environmental and economic performance. Materials are difficult to circulate among manufacturing industries even if a waste-exchange network exists, and resources are consumed during transportation and recycling.


Laser therapy as an effective method for implant surface decontamination: a histomorphometric study in rats.
To the best of the authors' knowledge, a standard protocol for treating peri-implantitis is not yet established. A total of 150 titanium disks with smooth or rough surfaces contaminated with microbial biofilm were implanted subcutaneously in rats after undergoing one of three treatments: 1) low-intensity laser (LIL); 2) antimicrobial photodynamic therapy (aPDT); or 3) toluidine blue O (TBO). Sterile and contaminated disks served as negative (NC) and positive (C) control groups, respectively. After days 7, 28, and 84, tissue inflammation was evaluated microscopically by measuring the density of collagen fibers (degree of fibrosis) and concentration of polymorphonuclear neutrophils. Surface texture did not affect the degree of inflammation, but the area of reactive tissue was significantly greater for rough implants (2.6 ± 3.7 × 10(6) µm(2)) than for smooth ones (1.9 ± 2.6 × 10(6) µm(2); P = 0.0377). Group C presented the lowest and group NC presented the highest degree of fibrosis with significance only after day 7; these groups had the highest and lowest scores, respectively, for degree of inflammation. Group C showed the largest area of reactive tissue (9.11 ± 2.10 × 10(6) µm(2)), but it was not significantly larger than group LIL (P = 0.3031) and group TBO (P = 0.1333). Group aPDT showed the smallest area (4.34 ± 1.49 × 10(6) µm(2)) of reactive tissue among the treatment groups. After day 28, groups LIL, aPDT, TBO, and C resembled group NC in all the studied parameters. Group aPDT showed more favorable results in parameter area of reactive tissue than the other methods after day 7, but over longer time periods all methods produced outcomes equivalent to sterile implants.


Microbial volatiles as plant growth inducers.
Agricultural practices require novel products that allow sustainable development and commercial production according to the needs of farmers and consumers. Therefore, in the last decade, eco-friendly alternatives have been studied, so volatile organic compounds (VOCs) emitted by microorganisms have emerged as a cheaper, effective, efficient, and an eco-friendly alternative. VOCs are lipophilic compounds derived from microbial metabolic pathways with low molecular weight (<300 g mol-1), low boiling point, and high vapor pressure that allow them to act as signal molecules over short and long distances. Main case studies provide evidence that VOCs released from diverse microorganisms (i.e. Bacillus, Pseudomonas, Arthrobacter, Fusarium, and Alternaria) can stimulate growth on a specific "target" seedling, such as Arabidopsis and tobacco. Some identified compounds, such as 3-hydroxy-2-butanone (acetoin), 2,3-butanediol, 2-pentylfuran, or dimethylhexadecylmine have shown their ability to elicit growth at root or leaf level. Few studies indicate that VOCs act in the regulation at phytohormone, metabolic pathways and nutrition levels according to genetic, proteomic, and metabolic analyses; but action mechanisms associated with growth-inducing activity are poorly understood. In this work, we reviewed case studies regarding identified compounds and action mechanisms for a better understanding of the information collected so far. Additionally, a brief description about the effects of VOCs for induction of resistance and tolerance in plants are presented, where compounds such as acetoin, dimethyl disulfide, 3-pentanol and 6-pentyl-α-pyrone have been reported. Furthermore, we summarized the knowledge to direct future studies that propose microbial VOCs as a technological innovation in agriculture and horticulture.


Injury-induced 92-kilodalton gelatinase and urokinase expression in rat brain.
Proteolytic disruption of the extracellular matrix is important in pathologic processes. We have shown that activated 72-kilodalton (kd) type IV collagenase injected intracerebrally attacks brain extracellular matrix and opens the blood-brain barrier. Therefore, we tested the hypothesis that endogenous production of matrix-degrading proteases may be a factor in secondary brain injury. Adult rats had a hemorrhagic injury produced by injection of 0.4 units of bacterial collagenase into the caudate/putamen. Endogenous production of matrix metalloproteinases and plasminogen activators (PA) was measured by substrate-gel sodium dodecyl sulfate-polyacrylamide gel electrophoresis (zymography) at 1, 4, 8, 16, 24, and 48 hours, and 7 and 14 days after the injury. Gelatin-containing zymograms had bands of the expected molecular weights from the injected bacterial collagenase at 1 hour. By 8 hours a new 92-kd gelatinase was seen in zymograms. EDTA eliminated the 92-kd band, indicating that it was a metalloproteinase. The 92-kd type IV collagenase/gelatinase was maximally increased by 24 hours (p < 0.0001). Plasminogen-casein zymography showed 40- and 60-kd bands from PA. The 40-kd PA reached a maximum at 24 hours (p < 0.05) and remained elevated for 7 days. Amiloride completely eliminated the 40-kd band and reduced the 60-kd band, suggesting that they were a urokinase-type PA. Hemorrhagic injury induces both 92-kd type IV collagenase/gelatinase and 40-kd urokinase-plasminogen activator expression in brain. We propose that metalloproteinases and serine proteases take part in a proteolytic cascade that breaks down extracellular matrix, opening the blood-brain barrier with secondary brain edema and cell death.


Protective Effects of Oleic Acid Against Palmitic Acid-Induced Apoptosis in Pancreatic AR42J Cells and Its Mechanisms.
Palmitic acid (PAM), one of the most common saturated fatty acid (SFA) in animals and plants, has been shown to induce apoptosis in exocrine pancreatic AR42J cells. In this study, we investigated cellular mechanisms underlying protective effects of oleic acid (OLA) against the lipotoxic actions of PAM in AR42J cells. Exposure of cells to long-chain SFA induced apoptotic cell death determined by MTT cell viability assay and Hoechst staining. Co-treatment of OLA with PAM markedly protected cells against PAM-induced apoptosis. OLA significantly attenuated the PAM-induced increase in the levels of pro-apoptotic Bak protein, cleaved forms of apoptotic proteins (caspase-3, PARP). On the contrary, OLA restored the decreased levels of anti-apoptotic Bcl-2 family proteins (Bcl-2, Bcl-xL, and Mcl-1) in PAM-treated cells. OLA also induced up-regulation of the mRNA expression of Dgat2 and Cpt1 genes which are involved in triacylglycerol (TAG) synthesis and mitochondrial β-oxidation, respectively. Intracellular TAG accumulation was increased by OLA supplementation in accordance with enhanced expression of Dgat2 gene. These results indicate that restoration of anti-apoptotic/pro-apoptotic protein balance from apoptosis toward cell survival is involved in the cytoprotective effects of OLA against PAM-induced apoptosis in pancreatic AR42J cells. In addition, OLA-induced increase in TAG accumulation and up-regulation of Dgat2 and Cpt1 gene expressions may be possibly associated in part with the ability of OLA to protect cells from deleterious actions of PAM.


Correcting for sparsity and interdependence in glycomics by accounting for glycan biosynthesis.
Glycans are fundamental cellular building blocks, involved in many organismal functions. Advances in glycomics are elucidating the essential roles of glycans. Still, it remains challenging to properly analyze large glycomics datasets, since the abundance of each glycan is dependent on many other glycans that share many intermediate biosynthetic steps. Furthermore, the overlap of measured glycans can be low across samples. We address these challenges with GlyCompare, a glycomic data analysis approach that accounts for shared biosynthetic steps for all measured glycans to correct for sparsity and non-independence in glycomics, which enables direct comparison of different glycoprofiles and increases statistical power. Using GlyCompare, we study diverse N-glycan profiles from glycoengineered erythropoietin. We obtain biologically meaningful clustering of mutant cell glycoprofiles and identify knockout-specific effects of fucosyltransferase mutants on tetra-antennary structures. We further analyze human milk oligosaccharide profiles and find mother's fucosyltransferase-dependent secretor-status indirectly impact the sialylation. Finally, we apply our method on mucin-type O-glycans, gangliosides, and site-specific compositional glycosylation data to reveal tissues and disease-specific glycan presentations. Our substructure-oriented approach will enable researchers to take full advantage of the growing power and size of glycomics data.


Characterisation by RNAi of pioneer genes expressed in the dorsal pharyngeal gland cell of Heterodera glycines and the effects of combinatorial RNAi.
Changes in transcript abundance of 24 genes expressed in the dorsal pharyngeal gland cell of Heterodera glycines encoding for putative secretions of unknown function were monitored by quantitative PCR (qPCR) at 0, 2, 7, 14 and 21 days post-invasion (pi) of soybean plantlets. Five groups of temporal patterns (A, B1, B2, C and D) were defined for the 24 genes plus data for two previously studied genes expressed in the same cell. Group D (two genes) showed no significant increase between 0 and 2 days pi and were the least abundantly expressed at 7-21 days pi. Transcripts of group C (nine genes including one studied previously) increased in abundance from 0 to 2 days pi but were the second least expressed for 7-21 days pi. Groups A (three genes), B1 (seven genes) and B2 (five genes including one studied previously) were all abundant at 7-21 days pi. B1 and B2 were discriminated by their relative abundance at 0 and 2 days pi. RNA interference (RNAi) targeting two genes of group A and one each of B1 and B2 in nematodes prior to invasion resulted in phenotypic effects on total parasites per plant and sexual fate at 10 days pi. Phenotype penetrance was reduced for three genes showing such effects and one with a strong effect in earlier work when two genes rather than one were concurrently targeted for RNAi. One gene (dg13) was more abundantly expressed after combinatorial RNAi than for either control nematodes or when targeting singly by RNAi. This work reports the unexpected elevation in mRNA expression after combinatorial RNAi that requires understanding before combinatorial RNAi can be advanced for highly effective cyst nematode control via plant biotechnology.


Useful lower limits to polarization contributions to intermolecular interactions using a minimal basis of localized orthogonal orbitals: theory and analysis of the water dimer.
The problem of describing the energy-lowering associated with polarization of interacting molecules is considered in the overlapping regime for self-consistent field wavefunctions. The existing approach of solving for absolutely localized molecular orbital (ALMO) coefficients that are block-diagonal in the fragments is shown based on formal grounds and practical calculations to often overestimate the strength of polarization effects. A new approach using a minimal basis of polarized orthogonal local MOs (polMOs) is developed as an alternative. The polMO basis is minimal in the sense that one polarization function is provided for each unpolarized orbital that is occupied; such an approach is exact in second-order perturbation theory. Based on formal grounds and practical calculations, the polMO approach is shown to underestimate the strength of polarization effects. In contrast to the ALMO method, however, the polMO approach yields results that are very stable to improvements in the underlying AO basis expansion. Combining the ALMO and polMO approaches allows an estimate of the range of energy-lowering due to polarization. Extensive numerical calculations on the water dimer using a large range of basis sets with Hartree-Fock theory and a variety of different density functionals illustrate the key considerations. Results are also presented for the polarization-dominated Na(+)CH4 complex. Implications for energy decomposition analysis of intermolecular interactions are discussed.


Optimizing long chain-polyunsaturated fatty acid synthesis in salmonids by balancing dietary inputs.
The increasing use of terrestrial plant lipids to replace of fish oil in commercial aquafeeds requires understanding synthesis and storage of long chain-polyunsaturated fatty acids (LC-PUFA) in farmed fish. Manipulation of dietary fatty acids may maximize tissue storage of LC-PUFA, through increased production and selective utilization. A data synthesis study was conducted to estimate optimal levels of fatty acids that may maximize the production and storage of LC-PUFA in the edible portion of salmonids. Data were compiled from four studies with Atlantic salmon, rainbow trout, and steelhead trout (total n = 180) which were fed diets containing different terrestrial-based oils to replace fish oil. LC-PUFA (%) were linearly correlated between diet and muscle tissue (p < 0.001; r2 > 44%), indicating proportional storage after consumption. The slope, or retention rate, was highest for docosahexaenoic acid (DHA) at 1.23, indicating that an additional 23% of DHA was stored in the muscle. Dietary saturated fatty acids were positively related to DHA stored in the muscle (p < 0.001; r2 = 22%), which may involve membrane structural requirements, as well as selective catabolism. DHA was found to be optimally stored with a dietary n-3: n-6 ratio of 1.03: 1. These new results provide a baseline of optimal dietary ratios that can be tested experimentally to determine the efficacy of balancing dietary fatty acids for maximum LC-PUFA storage.


[Effects of transforming growth factor-beta1 on rat cardiocyte hypertrophy].
To investigate the effects of transforming growth factor-beta1 (TGF-beta1) and signal protein Smad3 on rat myocardial hypertrophy. The total protein was analysed by flow cytometer assay to judge the hypertrophy of myocardial cell incubated with different level of TGF-beta1 in cultured myocardial cells of neonatal rats. The models of rat cardiac hypertrophy were produced with constriction of the abdominal aorta. At the different time after the operation, the rats were killed, and the left ventricular mass indexes (LVMl) were investigated. The mRNA expressions of TGF-beta1 and Smad3 of cultured cells and hypertrophic left ventricles were assessed by RT-PCR, the protein expressions of Smad3 were assessed by Western blot. In cultured neonatal myocardial cells, different level TGF-beta1 could significantly increase the total protein, and TGF-beta1 (3 ng/ml) could increase the expression of mRNA and protein of Smad3 and continued for 8 h of cultured cardiomyocytes. The LVMI and the expression of TGF-beta1 mRNA and Smad3 mRNA/protein of hypertrophic left ventricle were increased at the 3rd day after the operation and continued for 4 weeks. The peak expression of them was in 2 weeks after operation. TGF-beta1 has the effects on rat myocardial hypertrophy, signal protein Smad3 is included in the pathologic progress of rat myocardial hypertrophy.


Do teeth want to be straight? A nonsurgical approach to unerupted teeth.
Although some orthodontists believe that ectopic labially positioned canines may erupt without surgical exposure, many articles emphasize the surgical management of the nonpalatally impacted canine. In this article, the author discusses the treatment and results of 3 cases, with a total of 4 impacted maxillary canines. All cases were treated with a conservative approach and without surgical intervention. This nontraumatic, nonsurgical approach demonstrates the viability of conservative options for the management of unerupted teeth in carefully selected cases.


Chiral separation of flurbiprofen enantiomers by preparative and simulated moving bed chromatography.
This study presents the chiral resolution of flurbiprofen enantiomers by preparative liquid chromatography using the simulated moving bed (SMB) technology. Flurbiprofen enantiomers are widely used as nonsteroidal anti-inflammatory drugs, and although demonstrate different therapeutic actions, they are still marketed as a racemic mixture. The results presented here clearly show the importance of the selection of the proper solvent composition for the preparative separation of flurbiprofen enantiomers. Chiral SMB separation is carried out using a laboratory-scale unit (the FlexSMB-LSRE®) with six columns, packed with the Chiralpak AD® stationary phase (20 μm). Results presented include the experimental measurement of equilibrium and kinetic data for two very different solvent compositions, a traditional high hydrocarbon content [10%ethanol/90%n-hexane/0.01% trifluoroacetic acid (TFA)] and a strong polar organic composition (100%ethanol/0.01%TFA). Experimental data, obtained using the two mobile phase compositions, are used to predict and optimize the SMB operation. After selecting 10%ethanol/90%n-hexane/0.01%TFA as the most appropriate solvent composition, three feed concentrations of racemic flurbiprofen were considered. Using 40 g/l of racemic flurbiprofen feed solution, the purities for both outlet streams were above 99.4%, the productivity was 13.1 g(feed) /(L(bed) h), and a solvent consumption of 0.41 L(solvent) /g(feed) was achieved.


Solution-phase library synthesis of furanoses.
The solution-phase synthesis of amido-, urea-, and aminofuranoses was achieved. Alkylated furanose aldehydes were treated with primary amines in the presence of sodium triacetoxyborohydride to give secondary amines. Subsequent acylation with acid chlorides and isocyanates afforded amidofuranoses and ureafuranoses, respectively. Second, reductive amination of furanose aldehydes with secondary amines yielded tertiary amines. The resulting acetonides were treated with alcohols in the presence of acid to yield mixed acetals. In the library syntheses, functionalized scavenger resins were used in the purification of intermediates and products.


Surface Modification Determines the Distribution and Toxicity of Quantum Dots during the Development of Early Staged Zebrafish.
Surface modifications are generally used to functionalize QDots to improve their properties for practical applications, but the relationship between QDot modification and biological activity is not well understood. Using an early staged zebrafish model, we investigated the biodistribution and toxicity of CdSe/ZnS QDots with four types of modifications, including anionic poly(ethylene glycol)-carboxyl ((PEG)n-COOH), anionic mercaptopropionic acid (MPA), zwitterionic glutathione (GSH), and cationic cysteamine (CA). None of the QDots showed obvious toxicity to zebrafish embryos prior to hatching because the zebrafish chorion is an effective barrier that protects against QDot exposure. The QDots were mainly absorbed on the epidermis of the target organs after hatching and were primarily deposited in the mouth and gastrointestinal tract when the zebrafish started feeding. CA-QDots possessed the highest adsorption capacity; however, (PEG)n-COOH-QDots showed the most severe toxicity to zebrafish, as determined by mortality, hatching rate, heartbeat, and malformation assessments. It shows that the toxicity of the QDots is mainly attributed to ROS generation rather than Cd2+ release. This study provides a comprehensive understanding of the environmental and ecological risks of nanoparticles in relation to their surface modification.


Isolation and chemical analysis of nanoparticles from English ivy (Hedera helix L.).
Bio-inspiration for novel adhesive development has drawn increasing interest in recent years with the discovery of the nanoscale morphology of the gecko footpad and mussel adhesive proteins. Similar to these animal systems, it was discovered that English ivy (Hedera helix L.) secretes a high strength adhesive containing uniform nanoparticles. Recent studies have demonstrated that the ivy nanoparticles not only contribute to the high strength of this adhesive, but also have ultraviolet (UV) protective abilities, making them ideal for sunscreen and cosmetic fillers, and may be used as nanocarriers for drug delivery. To make these applications a reality, the chemical nature of the ivy nanoparticles must be elucidated. In the current work, a method was developed to harvest bulk ivy nanoparticles from an adventitious root culture system, and the chemical composition of the nanoparticles was analysed. UV/visible spectroscopy, inductively coupled plasma mass spectrometry, Fourier transform infrared spectroscopy and electrophoresis were used in this study to identify the chemical nature of the ivy nanoparticles. Based on this analysis, we conclude that the ivy nanoparticles are proteinaceous.


Cyclic changes in sensations to painful stimuli in migraine patients.
Migraine is characterized by cycling phases (interictal, preictal, ictal and postictal) with differing symptoms, while in chronic tension type headache pain phases are fluctuating. The question we asked is whether these phases are associated with changes in parameters of somatosensation and axon-reflex erythema. Patients with episodic migraine and chronic tension type headache were examined psychophysically in the interictal, preictal and ictal phase and healthy subjects on five different test days. Thresholds and suprathreshold ratings of pressure and electrical pain were assessed on three different regions of the head. In migraine patients and in healthy controls, electrically induced axon-reflex erythema was measured in the area of the first trigeminal branch. All migraine patients filled out questionnaires about prodromal symptoms at every visit. The axon-reflex erythema was always larger in patients with migraine in contrast to healthy subjects. The pressure pain threshold was lower in migraine patients and chronic tension type headache in comparison to healthy subjects. Electrical pain thresholds did not differ between headache patients and healthy subjects and showed no changes between the phases. However, suprathreshold pain ratings showed less habituation solely in the preictal phase of migraine. The number of prodromal symptoms in migraine patients was increased in the preictal and ictal phase. Reduced habituation was the unique sign of the preictal phase in migraine patients, independently of prodromal symptoms, whereas a larger axon-reflex erythema and higher pressure pain sensitivity are constitutional and non-phase dependent properties of migraine. Reduced inhibitory mechanisms in the preictal phase may contribute to trigger headache attacks in migraine.


Intestinal anti-inflammatory activity of coumarin and 4-hydroxycoumarin in the trinitrobenzenesulphonic acid model of rat colitis.
Coumarins represent an important class of phenolic compounds with multiple biological activities, including inhibition of lipidic peroxidation and neutrophil-dependent anion superoxide generation, anti-inflammatory and immunosuppressor actions. All of these proprieties are essential for that a drug may be used in the treatment of inflammatory bowel disease. The present study examined intestinal anti-inflammatory activity of coumarin and its derivative, the 4-hydroxycoumarin on experimental ulcerative colitis in rats. This was performed in two different experimental settings, i.e. when the colonic mucosa is intact or when the mucosa is in process of recovery after an initial insult. The results obtained revealed that the coumarin and 4-hydroxycoumarin, at doses of 5 and 25 mg/kg, significantly attenuated the colonic damage induced by trinitrobenzenesulphonic acid (TNBS) in both situations, as evidenced macroscopically, microscopically and biochemically. This effect was related to an improvement in the colonic oxidative status, since coumarin and 4-hydroxycoumarin prevented the glutathione depletion that occurred as a consequence of the colonic inflammation.


Clinical use of a tissue expander--enhanced transposition flap for face and neck reconstruction.
Tissue expanders have been used in reconstructive surgery with increasing frequency, primarily to construct local advancement flaps of tissue immediately adjacent to a tissue defect or deformity. These flaps often lack adequate mobility to allow coverage of large areas. This report describes the use of tissue expanders to enhance the area and vascularity of shoulder skin to provide suitable, ample tissue that can then be used as large pedicled transposition flaps for reconstruction of the face and neck. It is a clinical study based on previous laboratory studies cited that demonstrates that large flaps with very narrow pedicles remain well vascularized and can be transposed to cover very large defects. The tissue expander appears to enhance the vascularity of the flap. The thinning of the dermis and subcutaneous tissue seems to make the donor skin more similar in quality to face and neck skin. These studies suggest that even larger flaps may be developed to supply tissue to resurface the entire face or very large portions of it.


Epidemiology and aetiology of malocclusion among Syrian paediatric patients.
The knowledge of the distribution and causes of malocclusion in early childhood can prevent such malocclusions and their consequences and possibly to reduce complex orthodontic treatment. All children (n = 234; 116 male, 118 female, age 2-16) who presented with occlusal or functional problems at the Department of Paediatric Dentistry at Damascus University (1995-1999) were classified according to the type and causes of malocclusion and the subsequent orthodontic treatment. 57.3% of the malocclusions affected the anterior-posterior plane, 12.4% the vertical, and 35.9% the transverse. Most of the malocclusions had causes which could be modified by preventive or interceptive efforts: thumb sucking (5.12%), infantile swallowing (3.84%), mouth breathing (0.85%), tongue thrusting (1.7%), delayed exfoliation of a primary tooth (3.41%), premature loss of a primary tooth (9.82%), delayed eruption of a permanent tooth (2.13%), or an impacted tooth (6.41%). The subsequent early orthodontic treatment consisted of space maintainers (26%), removable (40.9%), functional (11.9%), or fixed appliances (21.2%). These data stress the importance of early orthodontic diagnosis in paediatric practice. Malocclusion in this Syrian sample could be treated to a great extent with preventive or interceptive orthodontics, which required only simple appliances and techniques.


Significance of Hypophosphatemia in Patients with Pneumonia.
Objective Phosphate is a fundamental element involved in a number of physiological pathways. A previous study showed abnormal laboratory findings and a higher mortality in hypophosphatemic patients than in normophosphatemic patients with pneumonia. Sporadic cases of pneumonia due to Legionella spp., Streptococcus pneumoniae, and viruses have been reported; however, the significance of hypophosphatemia in patients with pneumonia has not been adequately studied. We determined whether or not hypophosphatemia in patients with community-acquired pneumonia (CAP) was associated with specific pathogens, patient factors, disease severity, and mortality. Method We retrospectively analyzed 600 patients with CAP who were admitted to our hospital between January 1, 2010, and December 31, 2019. Results Hypophosphatemia was found in 72 (12.0%) of the 600 patients. The most frequent causative microbial agents of CAP in patients with hypophosphatemia were S. pneumoniae, Legionella spp., and influenza virus, whereas in severely ill patients with hypophosphatemia, influenza virus was the most common. Legionella spp., diabetes mellitus, and severe pneumonia were the independent factors for hypophosphatemia in the multivariable analysis. An impaired performance status, severe status on admission, interstitial pneumonia, bacteremia, and guideline-discordant therapy were the independent factors associated with mortality in the multivariable analysis. Hypophosphatemia was not significantly associated with mortality but showed a trend towards higher mortality in the multivariable analysis. Conclusion Hypophosphatemia was not associated with the prognosis in patients with CAP. However, the significance of hypophosphatemia for clinicians lies in the laboratory findings that predict abnormal glucose metabolism, Legionella infection, and severe disease.


Prescribing pattern of clozapine and other antipsychotics for patients with first-episode psychosis: a cross-sectional survey of early intervention teams.
To describe the pattern of antipsychotic drug prescribing in patients with first episode psychosis, with more emphasis in the use of clozapine in this group of patients. A cross-sectional survey involving six early intervention service (EIS) teams in the West Midlands was conducted. Data was extracted from case notes and electronic records by clinicians working in each participating team. The pattern of antipsychotic prescribing and the changes that took place after being accepted in EIS, including the use of clozapine, was established. Clinicians involved in the treatment of patients in each team rated the overall clinical response to treatment based on the presence or absence of positive psychotic symptoms. 431 patients with FEP were included in the final analysis. Low antipsychotic discontinuation rate was observed, with the majority (88.2%) still being prescribed antipsychotics. Most (77.3%) were prescribed second-generation antipsychotic drugs, with olanzapine (21.8%) and aripiprazole (19.7%) being the most frequently prescribed antipsychotics. There was low rate use of antipsychotic combinations (7.4%), high dose antipsychotic regime (3.9%), low depot antipsychotic prescribing (9.3%), and clozapine use was low (9.7%). On average, three antipsychotics were tried before clozapine was initiated and it took on average 19.5 months from being accepted into EIS to clozapine being initiated. The majority of patients were prescribed antipsychotics within the guidelines. EIS was associated with an overall low antipsychotic discontinuation. There was also a short waiting time before clozapine was initiated following patients being accepted into EIS.


Evaluating polygenic risk scores in assessing risk of nine solid and hematologic cancers in European descendants.
Genome-wide association studies (GWAS) have identified many genetic risk variants for cancers. The utility of these variants in assessing risk of esophageal, gastric and endometrial cancers, as well as melanoma, glioma, diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphoid leukemia and multiple myeloma, has not been adequately investigated. We constructed a site-specific polygenic risk score (PRS) for each of these nine cancers using their GWAS-identified risk variants. Using data from 400 807 participants of European descent in the UK Biobank, a population-based cohort study, we estimated the hazard ratios of each cancer associated with its PRS using Cox proportional hazard models. During a median follow-up of 5.8 years, 3905 incident cases of these nine cancers were identified in the cohort. The area under the receiver operating characteristic curve ranged from 0.53 to 0.69 for these cancers. Except for esophageal cancer, significant dose-response associations were observed between PRS and cancer risk. Compared to individuals in the middle quintile (40%-60%) at an average risk, those among the highest 5% of the PRS had a twofold elevated risk of melanoma, glioma, follicular lymphoma or multiple myeloma, and a fourfold elevated risk of chronic lymphoid leukemia. Using PRS, 63.0% of the participants could be classified as having an over twofold elevated risk for at least one cancer. The PRS derived using risk variants identified to date by GWAS showed the potential in identifying individuals at a significantly elevated risk of cancer for prevention.


Redescription of Mastigias papua (Scyphozoa, Rhizostomeae) with designation of a neotype and recognition of two additional species.
Mastigias, the 'golden' or 'spotted' jellyfish, is distributed throughout the Indo-Pacific. Specimens are identified routinely as Mastigias papua, although eight species were described historically, and molecular analyses evince at least three phylogenetic species. Understanding species diversity in Mastigias has become a priority because of its growing relevance in studies of boom-bust dynamics related to environmental change, cryptic species, local adaptation, parallel evolution, and peripatric speciation. However, species delimitation and identification are inhibited by a dearth of type specimens for most species, including M. papua. We address these issues by resampling Mastigias from the type locality in Waigeo, West Papua, as well as in the Philippines, and by comparing cytochrome c oxidase subunit I and up to 34 morphological characters of 268 Mastigias specimens from surrounding regions in the Indo-Pacific. We also gathered data from the historical descriptions of the eight species of Mastigias to estimate the identity of the two other currently revealed clades. Using this integrative taxonomic approach, we re-describe Mastigias papua as endemic to the tropical western Pacific islands (including Papua, Palau, Enewetak) and designate a neotype for the species. Additionally, based on morphological similarity and geographic overlap, we identified a second clade most probably as M. albipunctatus (from Japan, Komodo, Berau and Philippines) and a third clade tentatively as either M. andersoni or M. ocellatus. This study highlights the benefits of combining molecular analyses, samples from type locations, traditional descriptions and statistical analyses of morphological variation in systematic studies, and the concomitant potential of such studies to increase understanding of evolutionary patterns and processes in Scyphozoa.


Higher levels of hair ethyl glucuronide in patients with decreased kidney function.
Hair levels of ethyl glucuronide (EtG) are often used to differentiate social drinking from heavy drinking. Patients with decreased kidney function have delayed excretion of EtG, and increased incorporation into hair could be suspected. The aim of this study was to compare hair EtG levels in patients with decreased kidney function to those seen in healthy volunteers. Twelve patients with renal disease were included. The levels of EtG in hair were adjusted to estimated daily intake of ethanol (EDI) and compared to 21 previously published healthy individuals. The levels of hair EtG in the 12 patients ranged between < limit of detection and 134 pg/mg, and the EDI ranged between 0.1 and 12 g. The levels of EtG in hair were significantly higher in the patients compared to healthy volunteers (p = 0.009). These preliminary results indicate that hair levels of EtG in a population of patients with decreased kidney function should be interpreted with caution.


Excellent local control and tolerance profile after stereotactic body radiotherapy of advanced hepatocellular carcinoma.
To evaluate the efficacy and toxicity of stereotactic body radiotherapy (SBRT) in the treatment of advanced hepatocellular carcinoma (HCC). Patients with large HCCs (median diameter 7 cm, IQR 5-10 cm) with a Child-Turcotte-Pugh (CTP) score A (60%) or B (40%) and Barcelona-Clinic Liver Cancer (BCLC) classification stage B or C were treated with 3 to 12 fractions to allow personalized treatment according to the size of the lesions and the proximity of the lesions to the organs at risk aiming to give high biologically equivalent doses assuming an α/β ratio of 10 Gy for HCC. Primary end points were in-field local control and toxicity assessment. Forty seven patients with 64 lesions were treated with SBRT (median 45 Gy in 3-12 fractions) with a median follow up for patients alive of 19 months. The median biological effective dose was 76 Gy (IQR 62-86 Gy). Tumor vascular thrombosis was present in 28% and an underlying liver disease in 87% (hepatitis B or C in 21%, alcohol related in 51%, nonalcoholic steatohepatitis in 13% of the patients, primary biliary cirrhosis 2%). Eighty three percent received prior and in most cases multiple therapies. Local control at 1 year was 77%. The median overall survival from the start of SBRT was 9 months (95% CI 7.7-10.3). Gastrointestinal toxicities grade ≥ 2 were observed in 3 (6.4%) patients. An increase in CTP score without disease progression was observed in 5 patients, of whom one patient developed a radiation induced liver disease. One patient died due to liver failure 4 months after treatment. SBRT is an effective local ablative therapy which leads to high local control rates with moderate toxicity for selected patients with large tumors.


Mechanistic Insights and Synthetic Explorations of the Photoredox-Catalyzed Activation of Halophosphines.
The light-driven activation of halophosphines R2PX (R = alkyl- or aryl, X = Cl, Br) by an IrIII-based photocatalyst is described. It is shown that initially formed secondary phosphines R2PH react readily with the remaining R2PX in a parent-child reaction to form diphosphines R2P-PR2. Aryl-containing diphosphines can be further reduced to secondary phosphines RAr2PH under identical photoredox conditions. Dihalophosphines RPX2 are also activated by the photoredox protocol, giving rise to unusual 3-, 4-, and 5-membered cyclophosphines. Transient absorption studies show that the excited state of the Ir photocatalyst is reductively quenched by the DIPEA (N,N-di-iso-propylethylamine) electron donor. Electron transfer to R2PX is however unexpectedly slow and cannot compete with recombination with the oxidized donor DIPEA•+. As DIPEA is not a perfectly reversible donor, a small proportion of the total IrII population escapes recombination, providing the reductant for the observed transformations.


Atomistic modeling of the low-frequency mechanical modes and Raman spectra of icosahedral virus capsids.
We describe a technique for calculating the low-frequency mechanical modes and frequencies of a large symmetric biological molecule where the eigenvectors of the Hessian matrix are determined with full atomic detail. The method, which follows order N methods used in electronic structure theory, determines the subset of lowest-frequency modes while using group theory to reduce the complexity of the problem. We apply the method to three icosahedral viruses of various T numbers and sizes; the human viruses polio and hepatitis B, and the cowpea chlorotic mottle virus, a plant virus. From the normal-mode eigenvectors, we use a bond polarizability model to predict a low-frequency Raman scattering profile for the viruses. The full atomic detail in the displacement patterns combined with an empirical potential-energy model allows a comparison of the fully atomic normal modes with elastic network models and normal-mode analysis with only dihedral degrees of freedom. We find that coarse-graining normal-mode analysis (particularly the elastic network model) can predict the displacement patterns for the first few (approximately 10) low-frequency modes that are global and cooperative.


Cardiac Findings in the Fetus with Cerebral Arteriovenous Malformation Are Associated with Adverse Outcome.
To assess cardiac sequelae of fetal cerebral arteriovenous malformations (CAVMs) and evaluate any association with outcomes. We retrospectively analyzed cardiac structure and function in fetuses with CAVMs who underwent fetal echocardiography (October 1999 to August 2015, n = 11), and compared them with normal controls. The median gestational age was 36 weeks (range 18-38). Common abnormal findings included dilated superior vena cava (100%) and right atrium (82%), reduced middle cerebral artery pulsatility index (86%), tricuspid regurgitation (82%), and right ventricular (RV) dysfunction (64%). Hydrops was present in 1 fetus, who did not survive. The median cardiothoracic ratio (CTR) was 0.36 (0.29-0.45, n = 10); the median combined cardiac output indexed to estimated fetal weight (iCCO) was 565 ml/kg/min (379-1,565, n = 7). Of the 11 fetuses, 1 patient elected for termination, and 5 suffered neonatal demise. Comparing survivors (n = 5) and nonsurvivors (n = 6), a larger tricuspid valve (TV) z-score (p = 0.009) and RV dysfunction (p = 0.015) were associated with nonsurvival, and nonsurvivors had a higher iCCO than controls (990 vs. 550 ml/kg/min, p = 0.035). A larger difference between the TV and mitral valve z-scores (surrogate for RV dilation, p = 0.052), and CTR >0.38 (p = 0.0762) tended towards nonsurvival. CAVMs impose volume load on the fetal circulation, mainly affecting right heart structures. Increased right heart dilation and dysfunction are associated with nonsurvival.


Clinical Identification of Hypovitaminosis D among Elderly Attending Primary Care Centre in Saudi Arabia.
A large proportion of elderly people suffer from hypovitaminosis D, and depending on the severity of the condition, they develop complications that are detrimental to their health. To determine the consistency between the results of the vitamin D level in the blood compared to the result with the score of a simple questionnaire (Physician Vitamin D Status Predictor - VDSP) for elderly patients. Subjects and methods. This is a cross-sectional study conducted during the period between October 2018 and November 2019 in 3 primary health care centres (PHCCs) in Jeddah, Saudi Arabia. The subjects for this study were patients aged 60 or older. Data were collected in two phases: a questionnaire approach as the first phase, while the second phase involved blood testing for vitamin D levels. The validated questionnaire used in this study was the Physician`s Vitamin D Status Predictor (VDSP). The study included 335 participants who ranged between 60 and 107 years old with a mean age of 68.2 years and standard deviation (SD) of 7.3 years. Females represented 66.9% of the total participants. The prevalence of vitamin D deficiency was 60.8%; among them, 7.2% were categorized as severe deficiency, whereas the prevalence of vitamin D insufficiency was 29.9%. The outcomes of VDSP survey were not directly associated with serum 25(OH)D levels in elderly people, except for the number of medications. In addition, vitamin D supplementation was associated with serum 25(OH)D levels among those patients. Vitamin D supplementation was significantly associated with serum 25(OH)D levels. Moreover, this study showed a significant association between serum 25(OH)D levels and the number of medications taken by the participants.


Physical Activity Participation and Nutrition and Physical Activity Knowledge in University Dance Students.
To assess participation in physical activity and knowledge of general nutrition and current public health messages about the health benefits of physical activity in university dance students, and to investigate differences between first-year and later-year students and between students in dance and dance performance course groups. This cross-sectional study recruited 67 participants from dance undergraduate degrees in a university in Australia. Nutrition knowledge was assessed using the General Nutrition Knowledge Questionnaire. Physical activity participation and awareness of its benefits were assessed using the Active Australia Survey. Results indicate low nutrition knowledge among dance students, with 47% and 52% of responses correct in dance and dance performance students, respectively. Nutrition knowledge did not vary between students in first or later years. Self-reported participation in moderate and vigorous physical activity varied substantially and met or exceeded recommendations based upon duration and frequency for 98% of participants. However, awareness of physical activity messages varied, with dance students more likely to disagree about the level of activity needed for health benefits. Dance students report varying levels of physical activity that usually met or exceeded recommendations; however, knowledge of general nutrition and physical activity benefits was low. Improved knowledge could contribute to changes in behavior that improve health status in this population.


Utricular hypofunction in patients with type 2 diabetes mellitus.
The aim of this study was to assess the function of the utricle and horizontal semicircular canals in patients with type 2 diabetes mellitus receiving primary health care, with/without a history of falls. 101 patients with type 2 diabetes mellitus, 34 to 84 years old (26 with and 75 without a history of falls) and 51 healthy volunteers (40-83 years old) accepted to participate. They denied having a history of dizziness, vertigo, unsteadiness, hearing loss, or neurological disorders. None of them were seeking care due to sensory or balance decline. After a clinical evaluation and report of symptoms related to balance using a standardised questionnaire, lateral canal function was assessed by sinusoidal rotation at 0.16 Hz and 1.28 Hz (60°/sec peak velocity), otolith function was assessed by static visual vertical (average of 10 trials) and dynamic visual vertical during unilateral centrifugation (300°/sec at 3.5 cm) and static posturography was performed on hard/ soft surface with eyes open/closed. Compared to healthy volunteers, patients showed decreased responses to unilateral centrifugation, but similar responses to horizontal canal stimuli (independently of age, peripheral neuropathy or a history of falls) (ANCoVA p < 0.05) and a larger sway area with a lengthier sway path. Compared to patients with no falls, patients with falls had a higher female/male ratio and a higher frequency of score ≥ 4 on the questionnaire of symptoms related to balance, but similar age, body mass index and frequency of peripheral neuropathy. In patients with type 2 diabetes mellitus, receiving primary healthcare who are not seeking care due to sensory or balance decline, utricular function may be impaired even in the absence of horizontal canal dysfunction or a history of falls.


Is the aminoterminal propeptide of type III procollagen degraded in the liver? A study of type III procollagen peptide in serum during liver transplantation in pigs.
The aminoterminal propeptide of type III collagen was monitored in serum during liver transplantation in nine pigs. The aim was to investigate whether removal of the liver causes any changes in the serum concentration of the propeptide. Another connective tissue component, hyaluronan, a glycosaminoglycan known to be degraded in the liver endothelial cells, was also measured. Removal of the liver caused a significant increase in the concentration of the intact propeptide as well as of hyaluronan. Gel filtration confirmed the increase in the amount of intact propeptide. However, another large propeptide-related antigen, eluted near the void volume, appeared in the antigen profile during the anhepatic phase. This peak probably represents the propeptide still attached to the collagen molecule (pN collagen). The findings indicate that the liver is involved in the degradation of the propeptide and of larger propeptide-holding proteins.


Case study of a survivor of suicide who lost all family members through parent-child collective suicide.
South Korea is characterized by a high percentage of parent-child collective suicide. This case study explores one individual's personal experience as an adult survivor of suicide who lost his wife and his only son through parent-child collective suicide in South Korea. The study reports data from a semistructured interview, which were analyzed using interpretive phenomenological analysis (IPA). Two themes were identified through the analysis of the narratives of the survivor. The first theme provides a detailed picture of the survivor's explanation of why the parent-child collective suicide occurred. The second theme examines how the participant experienced complicated bereavement after his heart-breaking loss of both wife and son. We discuss the importance of support from other people or grief experts for the survivors of suicide who lose family to collective suicide.