Calibrated FMRI.
Functional magnetic resonance imaging with blood oxygenation level-dependent (BOLD) contrast has had a tremendous influence on human neuroscience in the last twenty years, providing a non-invasive means of mapping human brain function with often exquisite sensitivity and detail. However the BOLD method remains a largely qualitative approach. While the same can be said of anatomic MRI techniques, whose clinical and research impact has not been diminished in the slightest by the lack of a quantitative interpretation of their image intensity, the quantitative expression of BOLD responses as a percent of the baseline T2*- weighted signal has been viewed as necessary since the earliest days of fMRI. Calibrated MRI attempts to dissociate changes in oxygen metabolism from changes in blood flow and volume, the latter three quantities contributing jointly to determine the physiologically ambiguous percent BOLD change. This dissociation is typically performed using a "calibration" procedure in which subjects inhale a gas mixture containing small amounts of carbon dioxide or enriched oxygen to produce changes in blood flow and BOLD signal which can be measured under well-defined hemodynamic conditions. The outcome is a calibration parameter M which can then be substituted into an expression providing the fractional change in oxygen metabolism given changes in blood flow and BOLD signal during a task. The latest generation of calibrated MRI methods goes beyond fractional changes to provide absolute quantification of resting-state oxygen consumption in micromolar units, in addition to absolute measures of evoked metabolic response. This review discusses the history, challenges, and advances in calibrated MRI, from the personal perspective of the author.


Binding of thrombin to functionally defective platelets: a hypothesis on the nature of the thrombin receptor.
The initial step in the interaction of thrombin with human platelets is binding of thrombin to specific structures on the platelet surface. Data are presented which show that platelets from thrombasthenic patients bind thrombin similar to controls. In contrast, platelets from a patient with Bernard-Soulier syndrome had lower thrombin binding capacity. It is suggested that glycoprotein one (GP-I) on the platelet surface might be the receptor for thrombin.


Automated pattern analysis of corneal endothelium.
A proper understanding of the endothelial cell morphology of the cornea is of great significance to the corneal surgeon. Specular microscopy allows direct visualization of endothelial cell morphology and a proper analysis of these data needs automated computerized type of systems. Automated pattern analysis seems to offer a good option in this direction. From our experience it appears that such systems can be used with great advantage in the analysis of endothelial cell morphology. The data obtained from such analysis help to develop some indices for various facets of endothelial cell morphology.


Assessment on infection prevention and control knowledge among medical professionals in south Indian population.
Healthcare workers are always at higher risk of biological exposure as the healthcare setting is hazardous, and it is impracticable to exclude infection. Poor compliance with standard precautions among healthcare workers is one of the leading causes of healthcare-associated infections. This study analyzed the gaps in knowledge, attitude, and practice of infection control among healthcare workers and the influence of the COVID-19 pandemic, internet, and social media usage on infection control. A cross-sectional study was conducted from 1st to 31st March 2022 among various healthcare professionals using a self-administered structured questionnaire to evaluate knowledge, attitude, and practice on infection control. The impact of COVID-19, Internet, and social media usage on infection control practices was also analyzed. Among 382 healthcare workers who participated in the study, 89.4% of the participants had good knowledge, 55.26% had a neutral attitude, and all showed good practice levels on infection control. Similarly, the result showed that internet and social media usage during COVID-19 had significantly enhanced the knowledge, attitude, and practice on infection control. Healthcare professionals must be frequently updated on infection control guidelines and routine training programs. The hospital's adherence to the Joint Commission International (JCI) guidelines reduces the risk of healthcare-associated infections. As observed in this study, due to the prominent influence of social media and the internet, these platforms can be exploited to provide training and awareness to healthcare professionals and the public.


National targets for breastfeeding at hospital discharge have been achieved in Perth.
To report updated rates of breastfeeding in Perth through 2002/3 and to compare them to those from 1992/3. A 12-mo longitudinal study. Two public maternity hospitals in Perth, Australia. Eligible mothers of healthy newborn infants delivered between mid-September 2002 and mid-July 2003. All eligible mothers were asked to participate in a 12-mo longitudinal study of infant feeding. While in hospital, participating mothers completed a questionnaire that included questions on how they were feeding their newborn. Prevalence of ever breastfeeding, and breastfeeding at discharge. A total of 587 mothers, or 55% of those eligible, participated in the study. At hospital discharge, 93.8% of mothers in 2002/3 were breastfeeding compared with 83.8% in 1992/3. Significant increases were observed across all socio-demographic groups, with the biggest increase seen amongst younger mothers and those born outside of Australia. The national target of having in excess of 90% of mothers breastfeeding at discharge from hospital has been achieved in Perth. The challenge for health professionals and the community is to help maintain and further improve these breastfeeding practices.


Differential immunocytochemical staining for fetuin and transferrin in the developing cortical plate.
The distribution of the plasma proteins fetuin and transferrin in fetal sheep neocortex has been studied using the indirect immunoperoxidase method. Most of the cells (presumed to be neurons) in the early cortical plate (35 days gestation) were positive for fetuin. In contrast the fibre systems on either side of the cortical plate were positive for transferrin; some fibres were weakly positive for fetuin. It is proposed that these fibres may originate from brainstem and perhaps from some thalamic nuclei and that the plasma proteins are probably transferred from the neuronal cell bodies to their peripheral processes. It is further suggested that plasma proteins such as fetuin and transferrin may have a role in neuronal differentiation and synaptogenesis.


Quantitative assessment of bacterial growth phase utilizing flow cytometry.
Flow cytometry is currently underutilized for bacterial phenotyping and standard microbiological techniques do not provide phenotypic information about the state of the bacterial disease. Pseudomonas aeruginosa is a human pathogen of increased importance in public health due to both the ability to cause chronic diseases and the prevalence of functionally different subsets that can be difficult to treat and diagnose. In the present study, we used flow cytometry to analyze the growth phase of P. aeruginosa. A simple method for single cell quantitative detection of bacterial biofilm and planktonic cells was established with a combination of membrane permeable (SYTO 60) and impermeable (TOTO-1) dyes plus the addition of polystyrene counting beads. The specificity of the dye combination for biofilm detection was determined by comparison with impaired biofilm forming strains of P. aeruginosa LasI/RhlI-/- and ∆PfPhage. Results suggest that flow cytometric bacterial phenotyping serves as an expandable platform that may be useful for enumeration of population level variation in P. aeruginosa studies.


Validation of the food insulin index in lean, young, healthy individuals, and type 2 diabetes in the context of mixed meals: an acute randomized crossover trial.
The Food Insulin Index (FII) is a novel classification of single foods based on insulin responses in healthy subjects relative to an isoenergetic reference food. Our aim was to compare day-long responses to 2 nutrient-matched diets predicted to have either high or low insulin demand in healthy controls and individuals with type 2 diabetes (T2DM). Twenty adults (10 healthy adults and 10 adults with T2DM) were recruited. On separate mornings, subjects consumed either a high- or low-FII diet in random order. Diets consisted of 3 consecutive meals (breakfast, morning tea, and lunch), matched for macronutrients, fiber, and glycemic index (GI), but with 2-fold difference in insulin demand as predicted by the FII of the component foods. Postprandial glycemia and insulinemia were measured in capillary plasma at regular intervals over 8 h. As predicted by their GI, there were no differences in glycemic responses between the 2 diets in either group (mean ± SEM; healthy: 6.2 ± 0.2 compared with 6.1 ± 0.1 mmol/L · min, P = 0.429; T2DM: 9.9 ± 1.3 compared with 10.3 ± 1.6 mmol/L · min, P = 0.485). Compared with the high-FII diet, mean postprandial insulin response over 8 h was 53% lower with the low-FII diet in healthy subjects (mean ± SEM; incremental AUCinsulin 31,900 ± 4100 pmol/L · min compared with 68,100 ± 11,400 pmol/L · min, P = 0.003) and 41% lower in subjects with T2DM (mean ± SEM; incremental AUCinsulin 11,000 ± 1800 pmol/L · min compared with 18,700 ± 3100 pmol/L · min, P = 0.018). Incremental AUCinsulin was statistically significantly different between diets when groups were combined (P = 0.001). The FII algorithm may be a useful tool for reducing postprandial hyperinsulinemia in T2DM, thereby potentially improving insulin resistance and β-cell function. This trial was registered at the Australian New Zealand Clinical Trials Registry as ACTRN12611000654954.


Regulation of the multiple molecular forms of rat liver glucose 6-phosphate dehydrogenase by insulin and dietary restriction.
Insulin treatment of virgin female rats increased the hepatic activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase to levels 3.4 and 1.5 fold higher than controls. The increase in glucose 6-phosphate dehydrogenase activity was attributed to increased activity of all three dimer species. Thus dimer bands, 1, 2 and 3 of insulin-treated animals were 5, 3 and 2-fold higher respectively than controls. The activity of glucose 6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase decreased with fasting to 55% and 72% respectively of controls. The decrease in glucose 6-phosphate dehydrogenase activity reflected a lower activity of dimer bands 2 and 3 only, which were 62% and 39% of control activity respectively after three days fasting. A shift towards band 1 was observed under both conditions of starvation as well as under conditions of insulin treatment.


Preventing translational inhibition from ribosomal protein insufficiency by a herpes simplex virus-encoded ribosome-associated protein.
In addition to being required for protein synthesis, ribosomes and ribosomal proteins (RPs) also regulate messenger RNA translation in uninfected and virus-infected cells. By individually depleting 85 RPs using RNA interference, we found that overall protein synthesis in uninfected primary fibroblasts was more sensitive to RP depletion than those infected with herpes simplex virus-1 (HSV-1). Although representative RP depletion (uL3, uS4, uL5) inhibited protein synthesis in cells infected with two different DNA viruses (human cytomegalovirus, vaccinia virus), HSV-1-infected cell protein synthesis unexpectedly endured and required a single virus-encoded gene product, VP22. During individual RP insufficiency, VP22-expressing HSV-1 replicated better than a VP22-deficient variant. Furthermore, VP22 promotes polysome accumulation in virus-infected cells when uL3 or ribosome availability is limiting and cosediments with initiating and elongating ribosomes in infected and uninfected cells. This identifies VP22 as a virus-encoded, ribosome-associated protein that compensates for RP insufficiency to support viral protein synthesis and replication. Moreover, it reveals an unanticipated class of virus-encoded, ribosome-associated effectors that reduce the dependence of protein synthesis upon host RPs and broadly support translation during physiological stress such as infection.


Biodegradation of rhamnolipids in liquid cultures: effect of biosurfactant dissipation on diesel fuel/B20 blend biodegradation efficiency and bacterial community composition.
Bacterial utilization of rhamnolipids during biosurfactant-supplemented biodegradation of diesel and B20 (20% biodiesel and 80% diesel v/v) fuels was evaluated under conditions with full aeration or with nitrate and nitrite as electron acceptors. Rhamnolipid-induced changes in community dynamics were assessed by employing real-time PCR and the ddCt method for relative quantification. The experiments with rhamnolipids at 150 mg/l, approx. double critical micelle concentration (CMC) and diesel oil confirmed that rhamnolipids were readily degraded by a soil-isolated consortium of hydrocarbon degraders in all samples, under both aerobic and nitrate-reducing conditions. The presence of rhamnolipids increased the dissipation rates for B20 constituents under aerobic conditions, but did not influence the biodegradation rate of pure diesel. No effect was observed under nitrate-reducing conditions. The biodegradation of rhamnolipids did not favor the growth of any specific consortium member, which proved that the employed biosurfactant did not interfere with the microbial equilibrium during diesel/biodiesel biodegradation.


On the preparative use of recombinant beta(1-3)galactosyl-transferase.
A number of non-natural N-acyl derivatives of glucosamine is incubated with a recombinant beta(1-3)galactosyl-transferase and UDP-galactose. Surprisingly, the enzyme recognizes the non-natural acceptors as substrates and transfers galactose onto the 3-OH group in a beta-mode to give a series of Lewis(c)-(type 1) disaccharides.


Extraction and isolation of phenolic compounds.
Phenolic compounds constitute a major class of plant secondary metabolites that are widely distributed in the plant kingdom and show a large structural diversity. These compounds occur as aglycones or glycosides, as monomers or constituting highly polymerized structures, or as free or matrix-bound compounds. Furthermore, they are not uniformly distributed in the plant and their stability varies significantly. This greatly complicates their extraction and isolation processes, which means that a single standardized procedure cannot be recommended for all phenolics and/or plant materials; procedures have to be optimized depending on the nature of the sample and the target analytes, and also on the object of the study. In this chapter, the main techniques for sample preparation, and extraction and isolation of phenolic compounds have been reviewed-from classical solvent extraction procedures to more modern approaches, such as the use of molecularly imprinted polymers or counter-current chromatography.


Inflammation and disability as risk factors for mortality in elderly acute care patients.
Although the role of inflammation has been studied in specific diseases or in community living elderly, data in hospitalized acute care elderly patients are scarce. The present study was designed to determine the predictive value of sociodemographic, clinical and biological factors for mortality in acute care geriatric wards. Retrospective study was conducted in two acute care wards in a university-based geriatric hospital with elderly patients (n=224) consecutively admitted to acute care wards with available medical files. Sociodemographic variables, primary medical diagnosis and number of associated conditions, dementia, depression, pressure sores, functional status (measure by the activities of daily living=ADL scale), weight, and plasma levels of albumin, transthyretin, C-reactive protein (CRP) and orosomucoid were recorded at admission. Patients who died in the acute care wards were compared to those who survived. The mean length of stay was 16+/-13 days; mortality was 12%. Univariate analysis revealed that disability, no anti-depressant drug, pressure ulcers, a higher number of associated conditions, living with another person, and biological markers of malnutrition (albumin <35g/l, transthyretin <200mg/l) and inflammation (CRP < or =30mg/l, orosomucoid > or =1.25g/l) were significantly associated with an increase in the risk of death. The logistic regression model retained CRP > or =30mg/l (odds ratio (OR)=3.72, 95% confidence interval (CI)=1.34-10.31; p=0.009) and disability for at least one ADL item (OR=2.16, 95% CI=1.55-2.99; p<0.001) as independent risk factors for death. We conclude that CRP and disability are strong independent risk factors for death in this population, and special attention should be paid to these patients in an integrated therapeutic approach to geriatric care.


Giant intracranial aneurysms of the anterior circulation: clinical characteristics and diagnosis by computed tomography.
The computed tomography (CT) characteristics and clinical features of giant (globoid) aneurysms of the anterior circulation are reviewed. These lesions appear on the CT scan as smoothly encapsulated ovoid masses, within which a partially patent lumen is seen after the infusion of iodinated contrast material. With careful analysis of the CT scan it may be possible to differentiate giant internal carotid artery, anterior cerebral artery, and middle cerebral artery aneurysms from other parasellar and hemispheric lesions.


Sulfonylureas blockade of neural and cardiac HERG channels.
The human ether-a-go-go-related gene (herg) encodes a K+ current (I(HERG)) which plays a fundamental role in heart excitability and in neurons by contributing to action potential repolarization and to spike-frequency adaptation, respectively. In this paper we show that I(HERG), recorded in neuroblastoma cells and guinea-pig ventricular myocytes, was reversibly inhibited by the K(ATP) channel blocker glibenclamide (IC50 = 74 microM). The voltage and use dependence of glibenclamide blockade were also evaluated. Another sulfonylurea, glimepiride, had less effective results in blocking I(HERG). The findings of this study are relevant to the interpretation of glibenclamide effects on cellular electrophysiology and suggest that oral antidiabetic therapy with sulfonylureas may contribute to iatrogenic QT prolongation and related arrhythmias.


Tracheal collapse after thyroidectomy.
Tracheal collapse after thyroidectomy is uncommon; when it occurs, complete airway obstruction is often sudden, unexpected and fatal. In this paper a patient treated for tracheal collapse by tracheostomy and followed up for 1 year is described and, from a review of the literature, a further 9 cases are presented. The aetiology of the condition, the patient at risk and the technique of management are discussed.


Effects of cardiac rehabilitation and exercise training on indexes of dispersion of ventricular repolarization in patients after acute myocardial infarction.
We studied 50 consecutive patients with relatively preserved systolic function (ejection fraction >40%, mean 53 +/- 11%) after acute myocardial infarction, and assessed indexes of dispersion of ventricular repolarization before and after a formal, phase II cardiac rehabilitation and exercise training program. After cardiac rehabilitation, statistically significant reductions occurred in QT dispersion, JT dispersion, and in the heart rate corrected indexes. These benefits add to the proven benefits of formal cardiac rehabilitation and exercise training programs and may reduce the subsequent risks of malignant ventricular arrhythmias and sudden cardiac death.


Prevalence of hepatitis C virus infection in hemodialysis patients: a longitudinal study comparing the results of RNA and antibody assays.
We longitudinally studied 51 patients from two hemodialysis centers to determine the prevalence of hepatitis C virus infection in hemodialysis patients. Serum samples were tested for antibody to HCV by first- and second-generation enzyme immunoassays and for hepatitis C virus RNA by nested polymerase chain reaction assay. Antibody to hepatitis C virus was detected in the initial serum samples by first-generation enzyme immunoassay and second-generation enzyme immunoassay in 6 (11.8%) and 11 (21.6%) patients, respectively. First-generation enzyme immunoassay had a false-positive rate of 33.3% and a false-negative rate of 63.6%. Hepatitis C virus RNA was found in eight second-generation enzyme immunoassay-positive patients (72.7%) and in one patient negative for antibody to hepatitis C virus (2.5%) giving an overall positivity rate of 17.6%. After 19 mo, antibody to hepatitis C virus was detected in 15 patients (29.4%) on second-generation enzyme immunoassay; hepatitis C virus RNA was found in 13 patients (25.5%). Hepatitis C virus markers persisted in all 12 patients with initial evidence of hepatitis C virus infection. Three patients acquired hepatitis C virus infection during the interim, giving a new infection rate of 4.9% per patient-year. Antibody to hepatitis C virus, hepatitis C virus RNA or both was detected in 55.6% of patients with biochemical changes suggestive of non-A, non-B hepatitis. Of the 15 antibody to hepatitis C virus, second-generation enzyme immunoassay-positive patients, 66.7% had persistently normal serum transaminase levels. In summary, hepatitis C virus infection is common among hemodialysis patients. First-generation enzyme immunoassay is an unreliable assay for antibody to hepatitis C virus in these patients.(ABSTRACT TRUNCATED AT 250 WORDS)


Hyperactive children and peer interaction: knowledge and performance of social skills.
This study investigated hyperactive children's peer relations using the framework of social skills theory. Subjects' (15 hyperactive and 15 control boys aged 7 through 11) knowledge of socially appropriate behavior was assessed using the Social Knowledge Interview (Geraci & Asher, 1980). Additionally, performance of social skills with peers was rated by independent judges during free play, a cooperative puzzle task, and a persuasion task. Peers also rated subjects' desirability as partners for work, play, and friendship. Analyses showed that hyperactive subjects had deficits in knowledge of how to maintain relationships and handle interpersonal conflict, and demonstrated more negative behavior in the cooperative puzzle task than did controls. Hyperactive subjects also were rated by judges as less likely to achieve academic success than controls and were rated by peers as less desirable potential work partners in school. Significant correlations between social knowledge and performance with peers were found. It was concluded that hyperactive boys exhibit deficits both in their social knowledge and in their performance of socially skilled behavior.


Luminescent coordination polymer gels based on rigid terpyridyl phosphine and Ag(I).
Rigid bridging terpyridyl phosphine and AgOTf form nanofibres to induce gelation of organic solvents, and the gel emits blue luminescence by suppressing π-π interactions between ligands.


CDH1 gene polymorphisms, plasma CDH1 levels and risk of gastric cancer in a Chinese population.
The genetic polymorphisms in E-cadherin gene (CDH1) may affect invasive/metastatic development of gastric cancer by altering gene transcriptional activity of epithelial cell. Our study aims to explore the associations among CDH1 gene polymorphisms, and predisposition of gastric cancer. We genotyped four potentially functional polymorphisms (rs13689, rs1801552, rs16260 and rs17690554) of the CDH1 gene in a case-control study of 387 incident gastric cancer cases and 392 healthy controls by polymerase chain reaction-ligation detection reaction methods (PCR-LDR) and measured the plasma CDH1 levels using enzyme immunoassay among the subjects. The median and inter-quartile range were adopted for representing the mean level of non-normally distributed data, and we found the level of plasma CDH1 in gastric cancer patients (median: 171.00 pg/ml; inter-quartile range: 257.10 pg/ml) were significantly higher than that of controls (median: 137.40 pg/ml; inter-quartile range: 83.90 pg/ml, P = 0.003). However, none of the four polymorphisms or their haplotypes achieved significant differences in their distributions between gastric cancer cases and controls, and interestingly, in the subgroup analysis of gastric cancer, we found that CA genotype of rs26160 and CG genotype of rs17690554 were associated with the risk of diffuse gastric cancer, compared with their wild genotypes (OR = 2.98, 95 % CI: 1.60-5.53; OR = 2.10, 95 % CI: 1.14-3.85, respectively, P < 0.05). In conclusion, our results indicated that plasma CDH1 levels may serve as a risk marker against gastric cancer and variant genotypes of rs26160 and rs17690554 may contribute to the etiology of diffuse gastric cancer in this study. Further studies are warranted to verify these findings.


Quantitative structure-activity relationships of methotrexate and methotrexate analogues transported by the rat multispecific resistance-associated protein 2 (rMrp2).
Quantitative structure-activity relationship (QSAR) computational methods were performed to characterize structural requirements and molecular features for rMrp2-mediated methotrexate (MTX) transport. The compounds used in this analysis included MTX and 24 MTX analogues, with activity assessed by measuring inhibition of (3)H-DNP-SG ((3)H-S-(2,4)-dinitrophenyl glutathione) uptake in rat canalicular membrane vesicles. 2D-QSAR modeling using simulated annealing partial least squares (SA-PLS) method identified octanol/water partition coefficient, hydrophobicity, and negative charge as three important factors for MTX and MTX analogue affinity to rMrp2. Further analysis using 3D-QSAR method identified a pharmacophore model consisting of two hydrophobes, two aromatic rings, and a negative ionizable group as the critical molecular features that predict binding affinity of these compounds to rMRP2. The addition of a benzoyl ornithine group at a 9.3A distance and 136.5 degrees vector from the negative ionizable structure of MTX resulted in a 40-fold more potent inhibition of DNP-SG transport, suggesting that this chemical modification, while not essential for activity, contributes to the transport of MTX analogue by rMrp2. These observations provide important insights to the rationale development of analogues of MTX for the treatment of neoplastic and immunological diseases that may be devoid of hepatotoxicity or lack drug resistance.


Association Between Family History and Hypertension Among Chinese Elderly.
This study aimed to evaluate the association between family history and prevalence of hypertension among Chinese community elderly, and also explore the gender difference. A population-based cross-sectional study was conducted in Miyun district of Beijing, in 2014. The family history information was obtained from each subject and was divided into 3 categories, no family history (FH0), 1 generation of first-degree relatives with hypertension (FH1), and 2 generations of first-degree relatives with hypertension (FH2). The prevalence of hypertension was 53.0%. Participants with positive family history had a significantly higher prevalence of hypertension (67.5%, 95% CI: 63.3-71.7) than those without (47.9%, 95% CI: 45.2-50.6), and even among participants without hypertension, the blood pressure levels were higher with positive FH. Multiple logistic regression analysis showed that a significantly linear-trend increase in hypertension according to family history of first degree relative numbers was observed in both genders (P for trend < 0.001). This study suggests that family history had not only a significant but also graded association with hypertension and with blood pressure levels, and this association exists even among those without hypertension.


Comparison of usefulness of percutaneous coronary intervention guided by angiography plus computed tomography versus angiography alone using intravascular ultrasound end points.
The aim of our study was to assess the impact of coronary computed tomographic angiographic (CTCA) guidance on outcomes of percutaneous coronary intervention (PCI). The study was a randomized single-center trial. Consecutive eligible patients with CTCA-detected significant coronary lesions who were scheduled for PCI were randomized to an angiographically guided versus an angiographically plus computed tomographically guided (ACTG) group. In the ACTG group the operator preliminarily planned PCI based on computed tomographic angiogram. The coprimary end points were minimal stent area and minimal reference lumen area assessed in all patients with intravascular ultrasound performed after achieving optimal angiographic results. Seventy-one patients (50 men, mean age 65 ± 8 years) were randomized. After invasive angiography, PCI of 32 lesions (30 patients) in the ACTG and in 32 lesions (30 patients) in the angiographically guided group was performed. A stented segment length was longer and nominal stent diameter tended to be larger in the ACTG group (23.8 ± 6.7 vs 19.5 ± 6.5 mm, p = 0.01; 3.27 ± 0.44 vs 3.09 ± 0.41 mm(2), p = 0.110). Minimal stent area tended to be larger (6.62 ± 2.01 vs 5.80 ± 2.02 mm(2), p = 0.100) and the smallest peri-stent reference lumen area was significantly larger in the ACTG group (6.76 ± 3.01 vs 5.0 ± 1.62 mm(2), p = 0.006) with a smaller plaque burden (50 ± 16% vs 58 ± 13%, p = 0.025). In conclusion, CTCA analysis before PCI significantly influences treatment strategy and results in better lesion coverage as defined by intravascular criteria.


Pharmacology of [3H]-pyrilamine binding and of the histamine-induced inositol phosphates generation, intracellular Ca2+ -mobilization and cytokine release from human corneal epithelial cells.
We recently reported on the successful generation of immortalized (CEPI-17-CL4) cells from primary human corneal epithelial (P-CEPI) cells which exhibited phenotypic, immunohistochemical and metabolic characteristics akin to the P-CEPI cells. The aims of the present studies were to investigate the ligand binding and functional coupling of the histamine receptors to various biochemical and physiological systems in the P-CEPI and CEPI-17-CL4 cells and to relate these findings to the normal and/or pathophysiological role of histamine on the human ocular surface. Specific [3H]-pyrilamine binding to CEPI-17-CL4 cell homogenates comprised >93% of the total binding and represented interaction with an apparent single population of high affinity (Kd=3.76+/-0.78 nM; n=4) and saturable (Bmax = 1582+/-161 fmol g(-1) tissue) number of histamine-1 (H1) receptor binding sites on CEPI-17-CL4 cell homogenates. The H1-receptor selective antagonists, pyrilamine (Ki=3.6+/-0.84 nM, n=4) and triprolidine (Ki = 7.7+/-2.6 nM, n=3), potently displaced [3H]-pyrilamine binding, while the H2- and H3-receptor selective antagonists, ranitidine and clobenpropit, were weak inhibitors (K(i)s>13 microM). Histamine induced phosphoinositide (PI) hydrolysis 2.7-4.4 fold above basal levels and with a potency of 14.9+/-4.9 microM (n=9) and 4.7+/-0.2 microM (n=9) in P-CEPI and CEPI-17-CL4 cells, respectively. Histamine-induced PI turnover was antagonized by H1-receptor selective antagonist, triprolidine, with a potency (Ki) of 3.2+/-0.66 nM (n=10) and 3.03+/-0.8 nM (n=4) in P-CEPI and CEPI-17-CL4 cells, respectively, but weakly effected by 10 microM cimetidine and clobenpropit, H2- and H3-receptor antagonists. The PI turnover response was attenuated by pre-treatment of the cells with the selective phospholipase C inhibitor, U73122 (1-(6-((17beta-3-methoxyestra- 1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione) (IC50=4.8+/-2.4 microM, n = 3). Histamine stimulated intracellular Ca2+ ([Ca2+]i) mobilization in CEPI-17-CL4 cells with a potency of 6.3+/-1.5 microM (n=4). The histamine-induced [Ca2+]i mobilization was reduced by about 28% following pre-incubation of the cells with 4 mM EGTA. While triprolidine completely inhibited histamine-induced [Ca2+]i mobilization, it did not influence the bradykinin-induced [Ca2+]i mobilization response. Histamine (EC50s = 1.28-2.77 microM, n=3-4) concentration-dependently stimulated the release of interleukin-6 (IL-6), IL-8 and granulocyte macrophage colony-stimulating factor, but it did not significantly alter release of tumour necrosis factor-alpha, PGE2 or collagenase-1 (matrix metalloproteinase-1; MMP-1) from CEPI cells. However, IL-1 (10 ng ml(-1)), foetal bovine serum (10%) and phorbol-12-myristate-13-acetate (3 microg ml(-1)) were effective positive control secretagogues of all the cytokines, PGE2 and MMP-1, respectively, from these cells. It is concluded that the CEPI cells express H1-histamine receptors which are positively coupled to PI turnover and [Ca2+]i mobilization which may be directly or indirectly responsible for the release of various cytokines from these cells at physiologically and/or pathologically relevant concentrations.


Natural vs. Synthetic Phosphate as Efficient Heterogeneous Compounds for Synthesis of Quinoxalines.
Natural phosphate (NP) and synthetic fluorapatite phosphate (SFAP) were proposed as stable, inexpensive, readily available and recyclable catalysts for the condensation of 1,2-diamines with 1,2-dicarbonyls in methanol to afford quinoxaline at room temperature. NP provided as high as 92-99% yield for quinoxalines in short reaction times (i.e., 1-45 min), while SFAP created quinoxalines with 87-97% yield in 60-120 min. From the chemical analyses, X-ray fluoresecency, X-ray diffraction, energy dispersive X-ray and Fourier-transform infrared spectroscopy methods, two main phases (CaO, P2O5) appeared in NP together with other low content phases (SiO2, Fe2O3). Compared to other phases, apatite (CaO and P2O5 as Ca10(PO4)6) played a major role in the catalytic activity of NP. SFAP with similar Ca/P atomic ratio showed a relatively lower catalytic activity than NP for the condensation of 1,2-diamine with 1,2-dicarbonyl in methanol at ambient temperature. To investigate the recyclability of catalysts, the surface properties of NP and 6-recycled NP were investigated using scanning electron microscopy, energy dispersive X-ray and Brunauer-Emmett-Teller and Barrett-Joyner-Halenda methods. Some differences were observed in NP and 6-recycled NP's particle size, surface area, the volume and size of pores, and the content of elements; nevertheless, the use-reuse process did not noticeably change the catalytic property of NP.


Quantitative structure-activity relationships in amphotericin B derivatives.
The quantitative structure-activity relationships studies of amphotericin B and its 16 semisynthetic derivatives obtained by modification at carboxyl and amino groups have been done. The results of five biological tests were subjected to principal component analysis, a numerical method useful in the investigation of large sets of data. For some compounds, also, interaction with lipidic vesicles was investigated by spectroscopic methods. The results obtained indicate that: (i) The presence of positively charged nitrogen atom (protonable or bearing fixed charge) is indispensable for biological activity and antibiotic-sterol interaction; (ii) The lack of free carboxyl group in the molecule favours the differentiation between cholesterol and ergosterol containing cells.


Do chemical modifications dissociate between the enzymatic and pharmacological activities of beta bungarotoxin and notexin?
We have measured enzymatic, hemolytic and anticoagulant activities, lethal potencies and effects on contractions of the phrenic nerve-diaphragm preparation, by chemically modified derivatives of beta bungarotoxin (beta BuTX) and notexin, two presynaptically acting toxins which have PLA2 activity. The following chemical modifications of beta BuTX were tested: alkylation and methylation of histidine 48, alkylation of tryptophan 19, sulfonylation of tyrosine 68, oxidation of methionines 6 and 8, semicarbazide addition under varied conditions to carboxyl groups, varied extents of carbamylation or trinitrophenylation of lysines and guanidination of all lysines with or without trinitrophenylation of the N-terminal asparagine. Only the histidine, tryptophan and tyrosine residues were modified in notexin. The results obtained were compared with those previously obtained using chemically modified derivatives of Naja nigricollis and Naja naja atra PLA2 enzymes which do not have a specific presynaptic site of action. The results with oxidized methionine and lysine-modified derivatives of beta BuTX are supportive of the suggestions of others that the N-terminal region and basic residues away from the enzymatic active region contribute towards the beta type presynaptic neurotoxicity of the PLA2 toxins. Using modified derivatives of beta BuTX and notexin, the dissociations between enzymatic activities and pharmacological properties were not as marked as previously observed with N. nigricollis and N. n. atra PLA2; nevertheless, several dissociations were noted. We conclude that, just as with non-presynaptically acting PLA2 enzymes, some pharmacological actions of presynaptically acting PLA2 toxins may occur independently of phospholipid hydrolysis.


A randomised controlled trial of simple compared with complex antenatal fetal monitoring after 42 weeks of gestation.
To compare the impact on perinatal outcome of two different protocols for antenatal fetal monitoring after 42 weeks gestation. A prospective randomised controlled trial. Liverpool Maternity Hospital. One hundred and forty-five women with singleton, uncomplicated pregnancies after 42 weeks of gestation. Random allocation to fetal monitoring by either: 1. a modified biophysical profile comprising of computerised cardiotocography, amniotic fluid index, and assessment of fetal breathing, tone and gross body movements; or 2. standard cardiotocography and maximum pool depth. Cord pH at delivery, number of abnormal monitoring tests, intrapartum management, mode of delivery and neonatal outcome. There were significantly more abnormal antenatal monitoring results in the modified biophysical profile group (47.2% vs 20.5%; odds ratio = 3.5, 99% CI = 1.3-9.1). There were no differences in cord blood gases, neonatal outcome, or in outcomes related to labour and delivery between the two groups, but a trend towards more obstetric interventions in the modified biophysical profile group was noted. Amniotic fluid volume after 42 weeks was more likely to be labelled as abnormal with amniotic fluid index than with maximum pool depth (44.4% vs 15.1%; odds ratio = 4.5, 99% CI = 1.6-12.8). The results suggest that after 42 weeks fetal monitoring with the modified biophysical profile does not improve pregnancy outcome as measured by umbilical cord pH, but is more likely to yield an abnormal result. The higher incidence of abnormal monitoring results in the modified biophysical profile group was likely to be caused by different methods of amniotic fluid assessment in the modified biophysical profile group (amniotic fluid index) and simple monitoring group (maximum pool depth). The use of amniotic fluid index as a test of fetal wellbeing in prolonged pregnancy may lead to more obstetric interventions with, as yet, unclear impact on the perinatal outcome.


Measles immunity testing: comparison of two measles IgG ELISAs with plaque reduction neutralisation assay.
Two commercial IgG ELISAs, one based on recombinant nucleocapsid antigen and one based on cell culture grown native virus antigens, were evaluated for measles immunity testing by comparison with plaque reduction neutralisation test (PRNT). Qualitative results of the two ELISAs showed 92% agreement with those of PRNT. The sensitivity of the two ELISAs was 89.6%. False negative ELISA results were obtained in 10% of sera, mainly sera containing low levels of neutralising antibody. The specificity of both ELISAs was 100%. Measles IgG ELISAs perform adequately for immunity testing, correctly identifying seronegative individuals for vaccination.


Single- and combination-antibiotic therapy for experimental endocarditis caused by methicillin-resistant Staphylococcus aureus.
The efficacy of fosfomycin in combination with vancomycin or gentamicin was evaluated in experimental endocarditis caused by methicillin-resistant Staphylococcus aureus. After 5 days of therapy, both combinations proved to be highly effective since all rabbits had sterile vegetations.


Continuous positive airway pressure for term and ≥34+0 weeks' gestation newborns at birth: A systematic review.
Respiratory distress is common during transition after birth, but the effect of continuous positive airway pressure applied in the delivery room has not been systematically evaluated in spontaneously breathing term and ≥34+0 weeks' gestation infants.We aimed to compare delivery room continuous positive airway pressure with no delivery room continuous positive airway pressure for term and ≥34+0 weeks' gestation newborn infants at birth. Information sources: Medline, Embase, Cochrane Databases, Database of Abstracts of Reviews of Effects, and Cumulative Index to Nursing and Allied Health Literature. The Databases were last searched in October 2021.Eligibility criteria: Randomized, quasi-randomized, interrupted time series, controlled before-after, and cohort studies with English abstracts.Synthesis of results: Two authors independently extracted data, assessed risk of bias, and certainty of evidence. The main outcome was admission to the neonatal intensive care unit (NICU) or higher level of care receiving any positive pressure support. Data were pooled using fixed effects models.Risk of bias: Was assessed using the Cochrane Risk of Bias Tool for randomized trials and the Non-Randomized Studies of Interventions Tool (ROBINS-I) for observational studies. In this meta-analysis, two randomized control trials (323 newborns delivered by cesarean section) showed that delivery room continuous positive airway pressure decreased the likelihood of NICU admission (risk ratio (RR) 95% confidence interval (CI) 0.27 (0.11-0.66), p < 0.005) and NICU respiratory support (RR (95% CI) 0.18 (0.05-0.60), p = 0.005) when compared with no delivery room continuous positive airway pressure. However, in two before-after studies (8,476 newborns), delivery room continuous positive airway pressure use was associated with an increased risk of air leak syndrome when compared with no delivery room continuous positive airway pressure. Certainty of evidence was very low for all outcomes. Among term and ≥34+0 weeks' gestation infants having or at risk of having respiratory distress, there is insufficient evidence to suggest for or against routine use of continuous positive airway pressure in the delivery room.Funding: No Funding has been received to conduct this study.Clinical Trial Registration: This systematic review has been registered with the International Prospective Register of Systematic Reviews (http://www.crd.york.ac.uk/prospero/) [identifier: CRD42021225812].


Cysteine protease falcipain 1 in Plasmodium falciparum is biochemically distinct from its isozymes.
Falcipains form a class of papain-like cysteine proteases found in Plasmodium falciparum. This group of proteases has been suggested to be promising targets for anti-malarial chemotherapy. Despite being the first falcipain to be identified, the physiological role(s) of falcipain 1 (fp1) remains a mystery. Its suggested functions include haemoglobin degradation, erythrocytic invasion and oocyst production. In this study, the procurement of the gene coding for fp1 and its soluble expression in a heterologous host, Escherichia coli, have enabled further enzyme characterization. The recombinant fp1 protease was found to be unlike falcipain 2 (fp2A) in being more active at neutral pH than at acidic pH against the Z-LR-AMC fluorogenic substrate, suggesting a probable localization in the cytosol and not in the food vacuole. Interestingly, a common cysteine specific inhibitor, E64, did not inhibit fp1 activity, indicating dissimilar biochemical characteristics of fp1 from the other falcipains. This may be explained by computational analysis of the primary structures of the falcipain isozymes, as well as that of papain. The analysis revealed that Tyr61 (papain numbering), which is correspondingly absent in fp1, might be an important residue involved in E64 substrate binding.


Methylphenidate is not clastogenic in cultured human lymphocytes and in the mouse bone-marrow micronucleus test.
Methylphenidate (MPH) is one of the most frequently prescribed drugs for the treatment of attention deficit hyperactivity disorder (ADHD). A report on cytogenetic effects observed in peripheral lymphocytes from children treated for 3 months with MPH raised questions about the genetic toxicity of this compound. A critical review of this data concluded that the cytogenetic effects in treated children remain unexplained. A literature review showed that MPH was found negative in most genetox studies performed, but no in vitro chromosome aberration data in human lymphocytes have been published. Therefore, we conducted a chromosomal aberration study in cultured human peripheral lymphocytes. The results of this investigation showed that d,l-methylphenidate (MPH, Ritalin) in concentrations up to 10 mM did neither induce structural nor numerical chromosome abnormalities. An oral mouse bone-marrow micronucleus test in B6C3F(1) mice, with doses up to 250 mg/kg bw, was negative too. The data of these studies confirm the absence of clastogenic activity of MPH in non-clinical studies.


High temperature, heat index, and mortality in 6 major cities in South Korea.
The authors conducted a time-series analysis to estimate the acute effects of high temperature in 6 cities in Korea and to compare thresholds of temperature on daily mortality among the cities. They examined the association between total mortality and the daily mean temperature and heat index during the summers in Korea from 1994 to 2003. The threshold temperature was estimated to be between 27.0 degrees C and 29.7 degrees C for 4 cities. For a daily mean temperature increase of 1 degrees C above the thresholds in Seoul, Daegu, Incheon, and Gwangju, estimated percentage increases in daily mortality were 16.3 (95% confidence interval [CI] = 14.2-18.4), 9.10 (CI = 5.12-13.2), 7.01 (CI = 4.42-9.66), and 6.73 (CI = 2.47-11.2), respectively. These city-specific threshold temperatures and the magnitude of the effects of hot temperature indicate that any analysis of the impact of climate change should take into account regional differences.


Charge filling factors in clean and disordered arrays of tunnel junctions.
We simulate one-dimensional arrays of tunnel junctions using the kinetic Monte Carlo method to study charge filling behaviour in the large charging energy limit. By applying a small fixed voltage bias and varying the offset voltage, we investigate this behaviour in clean and disordered arrays (both weak and strong disorder effects). The offset voltage dependent modulation of the current is highly sensitive to background charge disorder and exhibits substantial variation depending on the strength of the disorder. We show that while small fractional charge filling factors are likely to be washed out in experimental devices due to strong background charge disorder, larger factors may be observable.


Use it too much and lose everything? The effects of hours of work on health.
In this paper, we extend the 'use it or lose it' hypothesis to analyse whether the negative effects of working hours eventually dominate the positive effects of work as the hours of work increase. Using panel data from the HILDA survey, we estimate the optimal hours of work for the health status of middle age and elderly workers. We deal with the potential endogeneity of working hours by using the instrumental variable estimation technique with instruments based on the age for pension eligibility. For males working relatively moderate hours (up to around 24-27 h a week), an increase in working hours has a positive impact on their health outcomes, but thereafter an increase in working hours has a negative impact on health outcomes. When weekly working hours exceed 50 h, an individual's health status is worse off than when he is not working at all.


Novel tacrine platinum(II) complexes display high anticancer activity via inhibition of telomerase activity, dysfunction of mitochondria, and activation of the p53 signaling pathway.
In this work, we designed and synthesized tacrine platinum(II) complexes [PtClL(DMSO)]⋅CH3OH (Pt1), [PtClL(DMP)] (Pt2), [PtClL(DPPTH)] (Pt3), [PtClL(PTH)] (Pt4), [PtClL(PIPTH)] (Pt5), [PtClL(PM)] (Pt6) and [PtClL(en)] (Pt7) with 4,4'-dimethyl-2,2'-bipyridine (DMP), 4,7-diphenyl-1,10-phenanthroline (DPPTH), 1,10-phenanthroline (PTH), 2-(1-pyrenecarboxaldehyde) imidazo [4,5-f]-[1,10] phenanthroline (PIPTH), 2-picolylamine (PM) and 1,2-ethylenediamine (en) as telomerase inhibitors and p53 activators. Biological evaluations demonstrated that Pt1Pt7 exhibited cytotoxic activity against the tested NCIH460, Hep-G2, SK-OV-3, SK-OV-3/DDP and MGC80-3 cancer cell lines, with Pt5 displaying the highest cytotoxicity. Pt5 exhibited an IC50 value of 0.13 ± 0.16 μM against SK-OV-3/DDP cancer cells and significantly reduced tumor growth in a Hep-G2 xenograft mouse model (tumor growth inhibition (TGI) = 40.8%, p < 0.05) at a dose of 15.0 mg/kg. Interestingly, Pt1Pt7 displayed low cytotoxicity against normal HL-7702 cells. Mechanistic studies revealed that these compounds caused cell cycle arrest at the G2/M and S phases, and regulated the expression of CDK2, cyclin A, p21, p53 and p27. Further mechanistic studies showed that Pt5 induced SK-OV3/DDP cell apoptosis via dysfunction of mitochondria, inhibition of the telomerase activity by directly targeting the c-myc promoter, and activation of the p53 signaling pathway. Taken together, Pt5 has the potential to be further developed as a new antitumor drug.


Anal Neoplasia in Inflammatory Bowel Disease Is Associated With HPV and Perianal Disease.
Literature describing the risk factors predisposing inflammatory bowel disease (IBD) patients to anal squamous neoplasia is very scarce. Case reports and small case series have implicated perianal Crohn's disease (CD), long-standing IBD, human papillomavirus (HPV) infection, and immunosuppressive treatment. In this study, we retrospectively examined the association between HPV infection and anal squamous neoplastic lesions among IBD patients from our center. We reviewed the pathology records and slides of IBD patients diagnosed with anal squamous cell carcinomas (SCCs), high-grade squamous intraepithelial lesions (HSILs), and low-grade squamous intraepithelial lesions (LSILs) who presented at our center between 1 March 1994 and 9 September 2014. The HPV status of the neoplasms was assessed histologically, by immunohistochemical staining for p16 overexpression, and by global and type-specific HPV PCR. SCCs, HSILs, LSILs, and small cell carcinoma were identified, respectively, in six, nine, two, and one IBD patients. All six patients with SCC had CD with perianal involvement. HPV-related neoplasia was identified in 3/6 cases of SCC (all HPV-16), 1/1 small cell carcinoma (HPV-18), and 9/9 HSIL (7 HPV-16, 2 not typed); 2/2 LSILs were negative for high-risk HPV. In our experience, anal squamous neoplastic lesions in IBD are associated with HPV infection and SCC seem to be associated with perianal CD. Prospective studies are needed to confirm these results.


Uttarakhand Disaster 2013: A Report on Psychosocial Adversities Experienced by Children and Adolescents.
To report the psychosocial adversities faced by children and adolescents in the Uttarkashi, district of Uttarakhand, experienced immediately after the Himalayan Tsunami in June 2013. Also to discuss issues pertinent to the disaster management including the needs of the disaster affected areas and future challenges. This is a cross sectional observational report from the community assessment and interventions that were carried out as part of the disaster relief work by National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore within 1 mo of the disaster. Assessments and interventions were done by a team consisting of psychiatry resident, clinical psychologist, psychiatric social worker and a nurse. All diagnosis were made using International Classification of Diseases 10 (ICD 10) and the data was analysed using descriptive statistics and chi-square tests. A total of 300 children were screened; the mean age of the sample was 11.5 y and 65(32.5%) were boys. Two hundred (66.7%) children/adolescents reported one or the other psychosocial adversities attributable to the disaster. Psychological distress was present in 54/300 (18%) of the individuals. Loss of shelter and loss of playing space were the social issues having a statistically significant association with psychological distress signals such as feelings of anxiety, helplessness, insecurity, grief and uncertainty. Stress induced diagnosable psychiatric disorder was not present in any child or adolescent, however stress related psychiatric symptoms were present in around 13%. Himalayan tsunami of Uttarakhand in 2013 was associated with considerable psychosocial adversities among the resident children and adolescents. As children are a vulnerable population, a public health approach towards assessment and management of the psychosocial adversities in this population is urgently required at the state and national levels.


Diagnosing thyrotoxic periodic paralysis in the ED.
Thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) are the most common causes of hypokalemic periodic paralysis (HPP) in EDs in Asia. Their neuromuscular presentations are almost indistinguishable. We conducted this study to identify clinical clues that can help EPs distinguish between TPP and SPP. Thirty-four patients presenting to the ED with HPP were enrolled during a 3-year period. They did not have known hyperthyroidism before the attack and no family history of paralysis. They all had low K(+) excretion rates. Vital signs and blood biochemistry, including acid-base and electrolytes, were measured. TPP was subsequently established by thyroid function tests. Twenty patients had TPP and 14 patients had SPP. There was no significant difference in age and sex distribution between them. Systolic (SBP) but not diastolic blood pressure (SBP 145 +/- 4 vs 128 +/- 4 mm Hg, P < 0.001) and heart rate (106 +/- 3 vs 73 +/- 3 beats/min, P < 0.001) were significantly higher in those experiencing TPP than SPP. Among the biochemical factors, only plasma phosphate concentration (2.2 +/- 0.2 vs 3.2 +/- 0.2 mg/dL, P < 0.001) was significantly lower in those experiencing TPP than SPP. Systolic hypertension, tachycardia, and hypophosphatemia are clinical clues favoring the diagnosis of TPP.


Physical Exercise as a Potential Treatment for Fatigue in Parkinson's Disease? A Systematic Review and Meta-Analysis of Pharmacological and Non-Pharmacological Interventions.
Fatigue is one of the most common and debilitating non-motor symptoms among patients with Parkinson's disease (PD) and significantly impacts quality of life. Therefore, effective treatment options are needed. To provide an update on randomized controlled trials (RCTs) including pharmacological and non-pharmacological (but non-surgical) treatments that examine the effects of fatigue on PD patients. We searched the MEDLINE, EMBASE, PsycINFO, CENTRAL, and CINAHL databases for (cross-over) RCTs on pharmacological and non-pharmacological interventions for treating fatigue in PD patients until May 2021. Meta-analyses for random-effects models were calculated when two or more studies on the same treatment option were available using standardized mean differences (SMDs) with 95% confidence intervals (CIs). Fourteen pharmacological and 16 non-pharmacological intervention RCTs were identified. For pharmacological approaches, a meta-analysis could only be performed for modafinil compared to placebo (n = 2) revealing a non-significant effect on fatigue (SMD = - 0.21, 95% CI - 0.74-0.31, p = 0.43). Regarding non-pharmacological approaches, physical exercise (n = 8) following different training approaches versus passive or placebo control groups showed a small significant effect (SMD = - 0.37, 95% CI - 0.69- - 0.05, p = 0.02) which could not be demonstrated for acupuncture vs. sham-acupuncture (SMD = 0.16, 95% CI - 0.19-0.50, p = 0.37). Physical exercise may be a promising strategy to treat fatigue in PD patients. Further research is required to examine the efficacy of this treatment strategy and further interventions. Future studies should differentiate treatment effects on physical and mental fatigue as the different underlying mechanisms of these symptoms may lead to different treatment responses. More effort is required to develop, evaluate, and implement holistic fatigue management strategies for PD patients.


Failed induction of labour.
Over a 15-month period 1,057 consecutive inductions of labour were performed representing a 10% induction rate; 174 (16.5%) of these patients were delivered by Caesarean section of which 74 (7.0%) were for failed induction of labour, 58 (5.5%) for fetal distress, 19 (1.8%) for cephalopelvic disproportion, 6 for malposition and 17 for other reasons. The mean cervical score at induction of labour was 5.7 and 5.5 for cephalopelvic disproportion (CPD) and malposition respectively but was 4.0 for failed induction. The mean cervical dilatation at the time of Caesarean section was 5.7 cm and 6.6 cm for CPD and malposition respectively whereas it was 3.5 cm for failed induction. Mean maximum dose of oxytocin was 19.2 milliunits per minute (mu/min) and 22.5 mu/min for CPD and malposition respectively whereas it was 24.7 mu/min for cases of failed induction. Nulliparas with a cervical score of 3 or less had a 65.4% Caesarean section rate of which more than two-thirds were for failed induction of labour. Analysis of indications for induction of labour revealed that a fair number of inductions had debatable obstetric indications. Tailoring induction of labour to the cervical score and indication might reduce the Caesarean section rate for failed induction of labour. Rational management to ensure an adequate dose of oxytocin and sufficient time in the first stage of labour is important. Failed induction of labour may be differentiated from failure of labour progress due to CPD or malposition.


Postictal psychosis: common, dangerous, and treatable.
Postical psychosis often complicates chronic epilepsy, especially in patients with seizure clusters that include tonic-clonic seizures, bilateral cerebral dysfunction (e.g., bilateral epileptiform activity or history of encephalitis), and a family history of psychiatric illness. Psychosis includes delusions, auditory and visual hallucinations, mood changes, and aggressive behavior. It typically emerges after a lucid interval of hours or days after the last seizure. This treatable disorder is associated with serious morbidity and mortality.


Ventricular shunt complications in patients undergoing posterior vault distraction osteogenesis.
The primary objective of this study is to investigate post-operative morbidity and shunt revision rates of patients with shunt-dependent hydrocephalus (SDH) undergoing posterior vault distraction osteogenesis (PVDO) compared to patients undergoing conventional posterior vault reconstruction (PVR). A retrospective case-controlled cohort analysis of all patients with SDH undergoing PVDO and PVR for syndromic or complex craniosynostosis was performed. Demographic information, perioperative variables, distraction protocols, and shunt-related complications-infection, surgical revision of shunt, increased length of stay (LOS), and readmission within 90 days of surgery-were compared using the appropriate statistical tests. Fourteen patients with ventricular shunts who underwent PVDO and eight patients with shunts who underwent PVR were identified. Shunt-related complication rates were significantly higher with PVDO (n = 5) compared to PVR (n = 0), p = 0.0093. Among the five patients who suffered complications, the most common were shunt infection (n = 4), shunt malfunction (n = 4), and wound infections (n = 3). All patients with complications required additional operations for shunt revision and/or replacement; four patients required multiple takebacks for such procedures, with an average of three additional procedures per patient. In complex or syndromic craniosynostosis patients who have previously undergone ventricular shunting, PVDO is associated with higher shunt-related complications and need for additional procedures when compared to traditional PVR. While the benefits of PVDO in the treatment of syndromic craniosynostosis are well documented, the risks of PVDO in the face of a VP shunt must be considered. Further investigation into patient-specific risk factors and risk reduction strategies is warranted.


Pathogenesis of ganglion "cell death" in glaucoma and neuroprotection: focus on ganglion cell axonal mitochondria.
Retinal ganglion cell axons within the globe are functionally specialized being richly provided with many mitochondria. The mitochondria produce the high energy requirement for nerve conduction in the unmyelinated part of the ganglion cell axons. We have proposed that in the initiation of glaucoma, an alteration in the quality of blood flow dynamics in the optic nerve head causes a compromise in the retinal ganglion cell axon energy requirement, rendering the ganglion cells susceptible to additional insults. One secondary insult might be light entering the eye to further affect ganglion cell axon mitochondrial function. Other insults to the ganglion cells might be substances (e.g., glutamate, nitric oxide, TNF-alpha) released from astrocytes. These effects ultimately cause ganglion cell death because of the inability of mitochondria to maintain normal function. We therefore suggest that ganglion cell apoptosis in glaucoma is both receptor and mitochondrial mediated. Agents targeted specifically at enhancing ganglion cell mitochondrial energy production should therefore be beneficial in a disease like glaucoma. Ganglion cell death in glaucoma might therefore, in principle, not be unlike the pathophysiology of numerous neurological disorders involving energy dysregulation and oxidative stress. The trigger(s) for ganglion cell apoptosis in glaucoma is/are likely to be multifactorial, and the rationale for targeting impaired energy production as a possibility of improving a patient's quality of life is based on logic derived from laboratory studies where neuronal apoptosis is shown to occur via different mechanisms. Light-induced neuronal apoptosis is likely to be more relevant to ganglion cell death in glaucoma than, for example, neuronal apoptosis associated with Parkinson's disease. Logic suggests that enhancing mitochondrial function generally will slow down ganglion cell apoptosis and therefore benefit glaucoma patients. On the basis of our laboratory studies, we suggest that supplements such as creatine, alpha-lipoic acid, nicotinamide, and epigallocatechin gallate (EGCG), all of which counteract oxidative stress induced by light and other triggers, are worthy of consideration for the treatment of such patients as they can be taken orally to reach the retina without having significant side effects.


Analysis of caretaker histories in abuse: comparing initial histories with subsequent confessions.
We hypothesize that perpetrators of abuse include elements of truth in their initial history and that an analysis of perpetrator confessions can teach professionals how to identify these initial truths. The information from a consecutive sample of perpetrators' confessions concerning 41 children hospitalized because of injuries caused by child abuse was reviewed. The details about the injuries contained in the confessions were compared with the details provided when these children initially presented for medical care. Information about the perpetrator's gender and relationship to the child, the victim's age and gender, type of injury, family risk factors, the trigger of the abusive event, the circumstances surrounding the event, and the type of trauma were collected. A total of 45 perpetrators abused 41 children; 76% of perpetrators were male; 56% were the child's father; 34% were the child's mother. The perpetrators initially provided no explanation about how 68% of the children received an injury. In 91% of their initial histories, the perpetrators provided some element of truth about the circumstances or triggering event for the abuse. In 67% of confessions, crying was the circumstance that triggered the abuse. Mothers were more likely to describe the situation that triggered the abuse (85% of mothers versus 58% of fathers, p=ns), while fathers were more likely to describe accurately the circumstances surrounding the abuse (79% of fathers versus 62% of mothers, p=ns). Perpetrators of abuse provide initial truths in their presenting history. Child abuse professionals must take a careful history from all caretakers and "listen" for the "elements of truth." These truths are the child's behavior or circumstance that increased stress and triggered the abuse. Employing this method in a careful analysis of confessions can make a significant contribution to the capacity to identify child abuse. In addition, more information about the role of triggers may help to focus child abuse prevention strategies.


Design and Application of DNA Modification-Specific Transcription-Activator-Like Effectors.
Transcription-activator like effectors (TALEs) are DNA-binding proteins used for genome targeting. TALEs contain a central domain of concatenated repeats, of which each selectively recognizes one nucleobase at the DNA major groove. Based on this simple and predictable interaction with little context dependence, TALEs offer programmable targeting of user-defined DNA sequences. Since many epigenetic DNA modifications protrude into the DNA major groove, natural and engineered TALE repeats can provide "epigenetic" selectivity, making TALEs a flexible platform to design probes for the analysis of epigenetic DNA modifications. Here, we describe guidelines for the design of TALE proteins with selectivity for epigenetic cytosine 5-modifications, the validation of their interaction with modified DNA nucleobases, and their employment in affinity enrichment assays. These techniques enable quantification of epigenetic nucleobases in user-defined genomic DNA sequences with nucleotide and strand resolution.


Getting to the heart of COX-2 inhibition.
Aspirin protects against heart disease, while COX-2 Inhibitors appear to injure the heart. The studies by [this Issue of Cell Metabolism]) shed light on two distinct prostaglandin receptors contributing to these conflicting cardiovascular effects.


Review of the clinical development of fexuprazan for gastroesophageal reflux-related disease.
Proton pump inhibitors (PPIs) are a mainstay treatment for acid peptic disorders such as gastroesophageal reflux disease (GERD). Although PPIs are considered first-line medications for acid suppression, they have notable limitations such as requiring acid-mediated activation, short half-life and duration of action, and metabolic variability. Fexuprazan is a newly developed potassium-competitive acid blocker (P-CAB), which inhibits acid generation and secretion in a competitive and reversible manner. Fexuprazan, like other P-CABs, has significantly different pharmacodynamic and pharmacokinetic properties than PPIs with potential advantages including rapid, robust, and durable acid suppression, lack of CYP2C19 metabolism, independence from food intake, and no requirement for activation into an active form. Completed clinical trials of fexuprazan have demonstrated comparable efficacy to PPIs for the healing of erosive esophagitis and relief of GERD-related esophageal symptoms without concerning safety signals. Ongoing clinical trials are evaluating fexuprazan for the prevention of NSAID-induced peptic ulcer disease, non-erosive GERD, and acute and chronic gastritis, as well as healing efficacy and maintenance of erosive esophagitis (EE). Fexuprazan is approved in South Korea for the treatment of EE and at the time of this writing is being considered for regulatory approval in several other countries. In this article, we summarize and discuss the pharmacology, efficacy, and safety of fexuprazan.


Variation in psychiatric and behavioural symptoms at different stages of dementia: data from physicians' examinations and informants' reports.
An investigation was carried out of psychiatric and behavioural symptoms in non-demented and demented subjects derived from a population study of the very elderly. Information on psychiatric and behavioural symptoms came from two independent sources: a physician's examination and an interview with an informant. The symptoms were grouped into clusters using principal-components analysis. Little agreement was found between the two sources of information on symptoms of anxiety, depression and psychosis. However, there was agreement about an increase in inactivity symptoms as the severity of dementia increased.


Lactate transport in insulin-secreting beta-cells: contrast between rat islets and HIT-T15 insulinoma cells.
The transport of L- and D-lactate into rat pancreatic islets and HIT-T15 insulinoma cells was studied by measuring uptake of 14C-labelled substrate at room temperature and by following changes in intracellular pH (pHi) in islets and HIT-T15 cells loaded with 2',7'-bis(carboxyethyl)-5'(6')-carboxyfluorescein (BCECF). Uptake of L-lactate into HIT-T15 cells was rapid, reaching equilibrium after 5 min with an apparent Km value of 4.8 mM. Transport was markedly inhibited by alpha-cyano-4-hydroxycinnamate, alpha-fluorocinnamate, quercetin and p-chloromercuribenzenesulphonate (pCMBS), and was enhanced in citrate medium. Uptake of D-lactate was less rapid, apparent equilibrium not being reached within 10 min. In contrast to HIT-T15 cells, rat pancreatic islets showed greatly reduced rates of transport of L- and D-lactate together with a correspondingly lower degree of inhibition by alpha-cyano-4-hydroxycinnamate. The addition of L- or D-lactate to HIT-T15 cells, but not dispersed islet cells, resulted in a marked and rapid intracellular acidification followed by a gradual recovery. In both HIT-T15 cells and isolated islets, the rates of transport of both L- and D-lactate in the presence of alpha-cyano-4-hydroxycinnamate were significantly greater in a depolarising K+ medium compared to the normal Na+ medium. These observations suggest that native rat islet cells have considerably reduced activity of the lactate-/H+ transport system compared to HIT-T15 insulinoma cells. There is evidence in both cell types of an additional electrogenic pathway for lactate which might play a role in coupling lactate efflux to beta-cell depolarisation.


The derivation of the oxygen atoms of the 13(1)-oxo and 3-acetyl groups of bacteriochlorophyll a from water in Rhodobacter sphaeroides cells adapting from respiratory to photosynthetic conditions: evidence for an anaerobic pathway for the formation of isocyclic ring E.
Using mass spectrometry, we have demonstrated 18O-labelling of both the 13(1)-oxo and 3-acetyl groups of newly-formed bacteriochlorophyll a synthesized by Rhodobacter sphaeroides cells during adaptation from respiratory to photosynthetic conditions in the presence of H218O. This derivation of the 13(1)-oxo group of bacteriochlorophyll a from water provides a stark contrast with that of chlorophylls in higher plants where ring E formation is an aerobic process in which the 13(1)-oxo group arises from molecular oxygen via an oxygenase activity. The formation of the 3-acetyl group of bacteriochlorophyll a, however, is consistent with the enzymic hydration of the 3-vinyl group of a derivative of chlorophyll a.


Frequency and significance of mitral anular calcium in hypertrophic cardiomyopathy: analysis of 200 necropsy patients.
To determine the frequency and significance of mitral anular calcium (MAC) in hypertrophic cardiomyopathy (HC), 43 clinical and morphologic variables in 200 necropsy cases of HC were examined. Of 100 patients less than 40 years of age, none had MAC. Of the 100 necropsy patients greater than 40 years, 30 (30%) had MAC, 21 (70%) of whom were women. The mean age of the 30 MAC patients was older than that of the 70 non-MAC patients greater than 40 years of age (66 years vs 53 years). The frequency of MAC increased with age. MAC was present in 3 of 31 patients (10%) aged 41 to 50 years; in 6 of 34 patients (18%) aged 51 to 60 years; in 11 of 21 patients (52%) aged 61 to 70 years; and in 10 of 14 patients (71%) aged 71 to 90 years. Compared with the 70 patients greater than 40 years of age without MAC, the 30 patients greater than 40 years of age with MAC had higher average systemic arterial peak systolic pressure (133 mm Hg vs 113 mm Hg); a larger percentage of the MAC patients had calcific deposits in the epicardial coronary arteries (93% vs 41%) and in the aortic valve cusps (33% vs 6%); and a larger percentage of the MAC patients had severe narrowing by atherosclerotic plaques of 1 or more of the 4 major epicardial coronary arteries (47% vs 24%). The frequency of a history of systemic hypertension, diabetes mellitus and total serum cholesterol levels greater than 200 mg/dl in the patients with and without MAC was similar.(ABSTRACT TRUNCATED AT 250 WORDS)


Relation between age and head and neck cancer recurrence after surgery: a multivariate analysis.
Recent reports have described an increase in squamous cell carcinoma of the upper aerodigestive tract in young adults. As the preponderance of epidemiologic data exists for the population between 50 and 70 years of age, controversy has developed regarding the clinical course of head and neck cancer in youth. Some authors advocate more aggressive management, calling attention to the lack of "classic" predisposing factors and suggesting genetic disorders or immunodeficiency. Basic science researchers have reported greater DNA fragility, sensitivity to carcinogens, and altered immune responses in young patients with carcinoma. To further elucidate the clinical aspects of this controversy, we performed a retrospective review using multivariate analysis to determine factors that affect recurrence. After screening 820 charts, 155 patients were found who met strict entrance criteria to the study. The patients were separated into five age groups, and 16 clinical variables were collected on each patient. Cox proportional hazards modeling revealed no significantly higher likelihood of recurrence in the 15- to 39-year-old age group. The model did find that metastatic adenopathy was predictive of recurrence (p = 0.034). The overall model further suggested a trend toward higher relative risk of recurrence in the middle-aged groups (p = 0.0541). In our review of the English biomedical literature, this is the first study to directly compare the outcome of young head and neck cancer patients with that of old patients using multivariate analysis. Future research is indicated in developing precise outcome predictions according to TNM staging, aneuploidy status, and DNA fragility in young patients. Efforts at limiting carcinogen exposure should continue.


A comparison of the effects of dialysed and non-dialysed transfer factor preparations on Haemonchus contortus infections in young lambs.
Significant reductions in worm burdens were achieved in lambs treated with dialysed transfer factor and challenged with 10,000 Haemonchus contortus larvae, when compared with challenged control animals. Non-dialysed transfer factor, from the same leucocyte pool, produced no protection, but was successful in reducing worm burdens when given after a primary infection of 1,000 H. contortus larvae with subsequent challenge of 10,000 larvae. While the results confirmed the previously reported inconsistencies of transfer factor activity, the histological abomasal changes in all the dialysed and non-dialysed transfer factor treated groups, irrespective of measurable effects on worm burdens, were consistent and corresponded to immediate type hypersensitivity responses. The similarity of these responses with self cure in haemonchosis and the possibility of genetic factors influencing the quantitative expression of protection to the effects of transfer factor treatments is discussed.


Statistical correlation between waste macromolecular composition and anaerobic fermentation temperature for specific short-chain fatty acid production.
To properly exploit short-chain fatty acids (SCFAs) in the chemical industry, it is of foremost importance to ensure stable SCFA profile production via anaerobic fermentation (AF). The different macromolecular distribution of food wastes (FWs) used as feedstock might be crucial for process outcome. Targeting at a specific SCFAs profile and yield, this study explored the statistical correlation between the macromolecular composition of FWs and the produced SCFAs in batch-AFs at 25 °C and 55 °C. Principal Component Analysis (PCA) revealed that the carbohydrates fraction was directly related with butyric acid accumulation, regardless of process temperature. Nevertheless, operational temperature resulted in a pH change, which ultimately affected the process fate. PCA of 25 °C-batch-AF showed a positive correlation between high carbohydrate content and longer-chain acids accumulation. By contrast, 55 °C-AF resulted in higher product specificity than at 25 °C, mainly due to butyrate-type fermentation of carbohydrates. Batch results were further validated in a semicontinuous reactor. Prevailing SCFAs and high bioconversion efficiencies relied on 3 main FWs characteristics: high carbohydrate content (>77% w/w), high carbohydrate/protein ratio (≥10) and high soluble organic matter content. Results obtained herein allowed predicting a specific SCFAs profile based on FWs composition, which is relevant for setting proper downstream technologies.


Prevalence of upper respiratory tract infections and associated factors among children in Turkey.
Upper respiratory tract infections (URIs) are the most common diseases observed in children aged 0-6 years in Turkey. This study was conducted to investigate URIs in 0-6 year-old children in Turkey. Data of children aged 0-6 years who were included in the 2014 Turkey Health Survey conducted by the Turkish Statistical Institute were collected from their parents. In total, 1,293 and 1,732 children with and without URIs, respectively, were identified. The weighted point prevalence of URIs was 42.23%. Compared with the uninsured and female children belonging to high-income families, insured male children belonging to low-income families were more likely to develop URIs (p < .001). Moreover, comorbidities such as communicable diseases, anemia and diarrhea, and factors like health services utilization were associated with URIs. Analysis of health services utilization highlights that URIs were reported more among the children who had not visited a hospital than among those who had visited a hospital, with an odds ratio of 1.23. The results of this study provide a deeper understanding of sociodemographic, comorbid, and health services utilization factors associated with URIs. These results provide useful insights for pediatric nursing professionals to improve the quality and efficiency of pediatric respiratory nursing services. Collaborative networks with other health professionals, parents, and public health policy-makers are essential to decrease the prevalence of URIs in Turkey. These study results provide several insights for health professionals to improve pediatric action plans for ultimately improving child health status.


Genome dynamics of multidrug-resistant Acinetobacter baumannii during infection and treatment.
Limited treatment options are available for patients infected with multidrug (MDR)- or pan-drug (PDR)-resistant bacterial pathogens, resulting in infections that can persist for weeks or months. In order to better understand transmission and evolutionary dynamics of MDR Acinetobacter baumannii (Ab) during long-term infection, we analyzed genomes from a series of isolates from individual patients at isolate-specific, patient-specific, and population levels. Whole genome analysis of longitudinal isolates (range 2-10 isolates per patient spanning 0-829 days) from 40 patients included detection of single-nucleotide variants (SNVs), insertion sequence (IS) mapping, and gene content changes. Phylogenetic analysis revealed that a significant fraction of apparently persistent infections are in fact due to re-infection with new strains. SNVs primarily resulted in protein coding changes, and IS events primarily interrupted genes or were in an orientation such that the adjacent gene would be over-expressed. Mutations acquired during infection were over-represented in transcriptional regulators, notably pmrAB and adeRS, which can mediate resistance to the last line therapies colistin and tigecycline, respectively, as well as transporters, surface structures, and iron acquisition genes. Most SNVs and IS events were isolate-specific indicating these mutations did not become fixed on the time scale investigated, yet over-representation of independent mutations in some genes or functional categories suggests that they are under selective pressure. Genome analysis at the population-level suggests that gene transfer including recombination also contributes to Ab evolutionary dynamics. These findings provide important insight into the transmission dynamics of Ab and the identification of patients with repeat infections has implications for infection control programs targeted to this pathogen.


Renal affection in patients with ankylosing spondylitis and psoriatic arthritis.
In a retrospective study of 148 patients with well-defined ankylosing spondylitis (AS), psoriatic arthritis (PSA) or reactive arthritis (ReA) an 11% prevalence of idiopathic hematuria, proteinuria, or cylinduria was found in the former two groups. None of the patients with ReA had unexplained pathological urinary findings. Such findings were associated with raised ESR and presence of peripheral arthritis in AS and with the duration of disease in PSA. No patient lacking sacroiliitis showed pathological urinary findings. We believe that such findings may reflect nephropathy associated with AS and PSA.


Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy.
Mucosal head and neck squamous cell carcinoma (HNSCC) are the seventh most common cancer, with approximately 50% of patients living beyond 5 years. Immune checkpoint inhibitors (ICIs) have shown promising results in patients with recurrent or metastatic (R/M) disease, however, only a subset of patients benefit from immunotherapy. Studies have implicated the tumor microenvironment (TME) of HNSCC as a major factor in therapy response, highlighting the need to better understand the TME, particularly by spatially resolved means to determine cellular and molecular components. Here, we employed targeted spatial profiling of proteins on a cohort of pre-treatment tissues from patients with R/M disease to identify novel biomarkers of response within the tumor and stromal margins. By grouping patient outcome categories into response or non-response, based on Response Evaluation Criteria in Solid Tumors (RECIST) we show that immune checkpoint molecules, including PD-L1, B7-H3, and VISTA, were differentially expressed. Patient responders possessed significantly higher tumor expression of PD-L1 and B7-H3, but lower expression of VISTA. Analysis of response subgroups indicated that tumor necrosis factor receptor (TNFR) superfamily members including OX40L, CD27, 4-1BB, CD40, and CD95/Fas, were associated with immunotherapy outcome. CD40 expression was higher in patient-responders than non responders, while CD95/Fas expression was lower in patients with partial response (PR) relative to those with stable disease (SD) and progressive disease (PD). Furthermore, we found that high 4-1BB expression in the tumor compartment, but not in the stroma, was associated with better overall survival (OS) (HR= 0.28, p-adjusted= 0.040). Moreover, high CD40 expression in tumor regions (HR= 0.27, p-adjusted= 0.035), and high CD27 expression in the stroma (HR= 0.2, p-adjusted=0.032) were associated with better survival outcomes. Taken together, this study supports the role of immune checkpoint molecules and implicates the TNFR superfamily as key players in immunotherapy response in our cohort of HNSCC. Validation of these findings in a prospective study is required to determine the robustness of these tissue signatures.


A high-affinity human PD-1/PD-L2 complex informs avenues for small-molecule immune checkpoint drug discovery.
Immune checkpoint blockade of programmed death-1 (PD-1) by monoclonal antibody drugs has delivered breakthroughs in the treatment of cancer. Nonetheless, small-molecule PD-1 inhibitors could lead to increases in treatment efficacy, safety, and global access. While the ligand-binding surface of apo-PD-1 is relatively flat, it harbors a striking pocket in the murine PD-1/PD-L2 structure. An analogous pocket in human PD-1 may serve as a small-molecule drug target, but the structure of the human complex is unknown. Because the CC' and FG loops in murine PD-1 adopt new conformations upon binding PD-L2, we hypothesized that mutations in these two loops could be coupled to pocket formation and alter PD-1's affinity for PD-L2. Here, we conducted deep mutational scanning in these loops and used yeast surface display to select for enhanced PD-L2 binding. A PD-1 variant with three substitutions binds PD-L2 with an affinity two orders of magnitude higher than that of the wild-type protein, permitting crystallization of the complex. We determined the X-ray crystal structures of the human triple-mutant PD-1/PD-L2 complex and the apo triple-mutant PD-1 variant at 2.0 Å and 1.2 Å resolution, respectively. Binding of PD-L2 is accompanied by formation of a prominent pocket in human PD-1, as well as substantial conformational changes in the CC' and FG loops. The structure of the apo triple-mutant PD-1 shows that the CC' loop adopts the ligand-bound conformation, providing support for allostery between the loop and pocket. This human PD-1/PD-L2 structure provide critical insights for the design and discovery of small-molecule PD-1 inhibitors.


[Associative learning in a neuromimetic network with local competitions].
Presented here is a neuromimetic model for the learning of associations between activity patterns originating from recoding layers. These layers are described as networks of cellular clusters made up of competitive formal neurons. A rule of synaptic plasticity with improved neurobiological realism is proposed; it allows for fast learning of large sets of associations.


Influenza-related hospitalisation and death in Australians aged 50 years and older.
Estimating the true burden of influenza is problematic because relatively few hospitalisations or deaths are specifically coded as influenza related. Statistical regression techniques using influenza and respiratory syncytial virus surveillance data were used to estimate the number of excess hospitalisations and deaths attributable to influenza. Several International Classification of Diseases 10th Revision (ICD-10) groupings were used for both hospitalisation and mortality estimates, including influenza and pneumonia, other respiratory disorders, and circulatory disorders. For Australians aged 50-64 years, the annual excess hospitalisations attributable to influenza were 33.3 (95%CI: 23.2-43.4) per 100,000 for influenza and pneumonia and 57.6 (95%CI: 32.5-82.8) per 100,000 for other respiratory disorders. For Australians aged > or =65 years, the annual excess hospitalisations attributable to influenza were 157.4 (95%CI: 108.4-206.5) per 100,000 for influenza and pneumonia and 282.0 (95%CI: 183.7-380.3) per 100,000 for other respiratory disorders. The annual excess all-cause mortality attributable to influenza was 6.4 (95%CI: 2.6-10.2) per 100,000 and 116.4 (95%CI: 71.3-161.5) per 100,000, for Australians aged 50-64 years and those aged > or =65 years, respectively. In the age-group > or =65 years, a significant association was found between influenza activity and circulatory mortality. We conclude that influenza is responsible for a substantial amount of mortality and morbidity, over and above that which is directly diagnosed as influenza in Australians aged > or =50 years.


Treatment of rotator cuff tears in older individuals: a systematic review.
Rotator cuff disease is common in older adults and may compromise health status and functional independence. However, little evidence exists to guide the treatment of rotator cuff tears (RCTs) in the older patient. This study evaluated the evidence regarding treatment of RCTs in patients with a mean age of 60 years or older. PubMed, SCOPUS, Science Citation Index (Web of Knowledge), Sport Discus, CINAHL, The Cochrane Controlled Trials registry, podium and poster presentations, proceedings, and abstracts from American Academy of Orthopaedic Surgeons, American Orthopaedic Society for Sports Medicine, and American Shoulder and Elbow Surgeons were searched for published and unpublished studies from 1966 to 2009. Inclusion criteria were English language, level of evidence I to III or greater, a full-thickness RCT, and treatment (surgery, physical therapy, injections, medications, or observation). Exclusion criteria included purely retrospective studies, isolated tears of the subscapularis, partial RCTs, revision surgery, and grafting or tendon transfer procedures. The blinded studies were independently evaluated using principles in the CONSORT (Consolidated Standards of Reporting Trials, 2001) statement and then collated by level of evidence and treatment strategy. Eight studies (1 level I, 4 level II, and 3 level III) evaluated treatment outcomes in patients aged older than 60 years. Review of the included operative studies suggests possible efficacy with operative intervention. However, heterogeneity of these studies and bias did not allow for a valid consensus on the best treatment approach. There is insufficient evidence to suggest efficacy in operative or nonoperative treatment of RCTs in older patients. The results presented here suggest possible favorable outcomes with operative management of RCTs.


Acanthamoeba keratitis in noncompliant soft contact lenses users: Genotyping and risk factors, a study from Cairo, Egypt.
Acanthamoeba keratitis (AK) is a severe corneal infection that may occur as a serious outcome of improper use of contact lenses (CL). The study aimed to diagnose AK in soft CL users presenting with infectious keratitis, and to identify the prevalent genotypes isolated from different cases. Another aim was to determine the CL hygiene-related risk behaviors, and to explore the risk of water exposure for developing AK. A cross sectional study was performed. A questionnaire was carried out including 260 clinically diagnosed cases as infectious keratitis (170 females and 90 males); all of them were soft CL users for the suspected risk factors. Corneal scrapes from the affected eyes were cultured to diagnose bacterial and AK. PCR was performed and the amplified products were sequenced and compared with GenBank data. The parasite was positively amplified from 32 samples (12.3%). Acanthamoeba T4 genotype was identified in 27/32 (84.4%) of isolates. Other detected genotypes belonged to T5 and T3 genotypes at rates of 9.4%, and 6.25%, respectively. The most important risk factors associated with development of AK were female sex, sleeping while wearing CL, and exposure to water resources through different practices. These practices included rinsing the CL case in tap water, swimming and/or showering while wearing CL, using multipurpose solution for cleaning the lenses, using water from over-building tanks. Rubbing the eyes due to discomfort when applying CL was an additional important risk factor associated with AK. The protective factor was regular hand washing before using CL. CL users were more exposed to AK and should gain enough health education regarding proper lens hygiene and dangers of tap water exposure.


Intramuscular administration of very high dose of alpha-tocopherol protects liver from severe ischemia/reperfusion injury.
The effect of intramuscular administration of high (30 mg/kg body weight for 3 days) or very high (300 mg/kg body weight for 3 days) doses of a-tocopherol to Wistar rats subjected to total severe warm hepatic ischemia and reperfusion was investigated. After a 60-minute period of total hepatic ischemia and 120 minutes of reperfusion, animals were killed, and liver samples were taken for determination of malondialdehyde (MDA) and histological examinations. Blood samples were also taken for assay of serum a-tocopherol, alanine transaminase (ALT), aspartate transaminase (AST), and lactic dehydrogenase (LDH). Additional animals were followed for a 7-day survival rate determination. Results showed that ischemia and reperfusion decreased the survival rate to 10%, whereas the levels of AST, ALT, and LDH in serum were increased compared with levels in animals that were sham operated. The MDA concentrations in liver were also increased, from 1.142 to 1.567 nmoles/g, whereas the levels of a-tocopherol in serum were decreased from 10.20 to 1.80 mmol/L. Pretreatment with a-tocopherol increased the viability to 50% and 70%, for the high and very high doses, respectively, and decreased the levels of AST, ALT, and LDH in serum. It also decreased the MDA concentrations in liver to 0.975 and 0.774 nmoles/g for the high and very high doses of a-tocopherol, respectively, whereas it increased the level of a-tocopherol in serum to 11.25 and 13.02 mmol/L for the high and very high doses, respectively. Histological examinations showed protection of the liver parenchyma in the animals treated with a-tocopherol.


The Adaptation of Maslow's Hierarchy of Needs to the Hierarchy of Dogs' Needs Using a Consensus Building Approach.
It is crucial for good dog welfare that humans be able to accurately and adequately recognize and meet dogs' needs. However, humans may do a poor job of recognizing dogs' needs due to their tendency to anthropomorphize. The aim of this study was to develop a framework for dogs' needs that would help humans to recognize and meet their actual needs, thereby improving dogs' quality of life. Using the Delphi method, to reach as close to a consensus as possible from an expert panel, Maslow's Hierarchy of Needs was adapted to become the Dogs' Hierarchy of Needs. To do so, the relevant scientific literature was reviewed to identify 37 specific dog needs, which were group into seven need groups. Those groups were then organized onto five need levels, which were as analogous to Maslow's Hierarchy of Needs as possible. The expert panel was asked to assess various aspects of the adapted hierarchy in comparison to the original, including face validity, whether they agreed with how the need levels were ordered in terms of importance/priority, and whether they felt that any need groups should be more or less prioritized for any specific dog categories (e.g., senior dogs). After three rounds of expert feedback, there was sufficient consensus for all aspects except items pertaining to the prioritization of any need groups for specific dog categories. That aspect of the adapted hierarchy will need to be readdressed in the next phase of this project: the development of a tool to assess the quality of life of dogs that reside in shelters/rescue organizations and post-adoption once they have been rehomed.


Encoding of Multiple Reward-Related Computations in Transient and Sustained High-Frequency Activity in Human OFC.
Human orbitofrontal cortex (OFC) has long been implicated in value-based decision making. In recent years, convergent evidence from human and model organisms has further elucidated its role in representing reward-related computations underlying decision making. However, a detailed description of these processes remains elusive due in part to (1) limitations in our ability to observe human OFC neural dynamics at the timescale of decision processes and (2) methodological and interspecies differences that make it challenging to connect human and animal findings or to resolve discrepancies when they arise. Here, we sought to address these challenges by conducting multi-electrode electrocorticography (ECoG) recordings in neurosurgical patients during economic decision making to elucidate the electrophysiological signature, sub-second temporal profile, and anatomical distribution of reward-related computations within human OFC. We found that high-frequency activity (HFA) (70-200 Hz) reflected multiple valuation components grouped in two classes of valuation signals that were dissociable in temporal profile and information content: (1) fast, transient responses reflecting signals associated with choice and outcome processing, including anticipated risk and outcome regret, and (2) sustained responses explicitly encoding what happened in the immediately preceding trial. Anatomically, these responses were widely distributed in partially overlapping networks, including regions in the central OFC (Brodmann areas 11 and 13), which have been consistently implicated in reward processing in animal single-unit studies. Together, these results integrate insights drawn from human and animal studies and provide evidence for a role of human OFC in representing multiple reward computations.