Effect of altering the regime of oral rifampicin therapy in the treatment of persistent central serous chorioretinopathy.
To study the effect of reducing the duration of rifampicin therapy in the treatment of Chronic Central Serous Chorioretinopathy. This is interventional study conducted in Layton Rahmatullah Benevolent Trust, Free Base Eye Hospital Korangi, Karachi from February 2017 - December 2018. This randomized controlled comparative study included two groups, Groups-A comprised of 48 eyes of 40 cases with Chronic Central Serous Chorioretinopathy who were given reduced dose of oral rifampicin i.e. 600mg for one month, and Group-B consisted of 43 eyes of 40 controls with Chronic Central Serous Chorioretinopathy who were given reduced dose of oral rifampicin i.e. 300mg once daily for three months as previously stated in literature. To access the effect of therapy in both the groups, pre-treatment visual acuity on the logMAR and Optical Coherent Tomography (OCT, Heidelberg spectralis) for CMT were performed and repeated on the 1st and 3rd month post-treatment. Patients were also followed for 6 months to access any recurrence. On comparing the two groups, Group-A had improvement in VA and CMT after one month therapy of Rifampicin, Pre-treatment mean VA in Group-A was 0.85 ± 0.19 as compared to the pre-treatment mean VA in Group-B i.e. 0.74+/- 0.208, while the pre-treatment mean CMT was 609.0 ± 178.29 µm in Group-A, and 600.0 +/- 155.09 µm in Group-B respectively. After 1 month of therapy, the visual status, and CMT in Group-A was 0.29+/- 0.21 and 311.6 +/- 89.9, while Group-B, VA was 0.598 +/- 0.23 (p value 0.001%) and CMT was 512.30 +/- 148.37 (p-value 0.001%). Rifampicin was continued in Group-B till three months, and patients were re-accessed but there was no difference in VA and CMT statically. During the 3rd and 6th months of follow up no relapses were reported. This comparative study showed that the group receiving oral rifampicin 600mg for one month showed better outcome at one month and third month than the group receiving oral rifampicin at a dose of 300mg once daily for three months. This gives a better compliance and lower the risk of drug induced side effects.


Psychological and physiological correlates of childhood obesity in Taiwan.
Evidence of associations between psychopathology and obesity in childhood remains inconsistent, and most studies have been conducted in Western countries. This study investigated psychological and physiological correlates of obesity in a community sample of children in Taiwan. In total, 302 children (157 overweight/obese and 145 healthy-weight children) were selected from first- and fourth-grade schoolchildren in eight elementary schools in 2009. These children participated in a comprehensive health examination, including a physical examination, blood sample analysis, and questionnaire administration. We found that regarding physiological characteristics, compared with the healthy-weight children, the overweight/obese children had significantly higher values for body fat estimated using the bioelectrical impedance method (p < 0.001), systolic blood pressure (p < 0.001), and diastolic blood pressure (p = 0.001); lower values for high-density lipoprotein (p < 0.001); and worse values for glutamic-pyruvic transaminase (p < 0.001), triglycerides (p < 0.001), and fasting blood glucose (p = 0.049). In logistic models adjusted for parental and child traits and physiological characteristics, children's overweight/obesity was significantly associated with lower self-concept (odds ratio [OR] = 0.96, 95% confidence interval [CI] = 0.93-0.99) and less disruptive behavior (OR = 0.96, 95% CI = 0.92-0.99). Less disruptive behavior and the lack of a higher prevalence of anxiety and depression in childhood obesity appear to be a unique pattern in Taiwan that warrants further investigation.


Numerical simulation of thermal water delivery in the human nasal cavity.
This work describes an extensive numerical investigation of thermal water delivery for the treatment of inflammatory disorders in the human nasal cavity. The numerical simulation of the multiphase air-droplets flow is based upon the Large Eddy Simulation (LES) technique, with droplets of thermal water described via a Lagrangian approach. Droplet deposition is studied for different sizes of water droplets, corresponding to two different thermal treatments, i.e. aerosol and inhalation. Numerical simulations are conducted on a patient-specific anatomy, employing two different grid sizes, under steady inspiration at two breathing intensities. The results are compared with published in vivo and in vitro data. The effectiveness of the various thermal treatments is then assessed qualitatively and quantitatively, by a detailed analysis of the deposition patterns of the droplets. Discretization effects on the deposition dynamics are addressed. The level of detail of the present work, together with the accuracy afforded by the LES approach, leads to an improved understanding of how the mixture of air-water droplets is distributed within the nose and the paranasal sinuses.


Maintenance efficacy of divalproex in the prevention of bipolar depression.
Breakthrough depression is a common problem in the treatment of bipolar disorder. Only one, recently published, double-blind, placebo-controlled trial has examined the efficacy of divalproex in the prevention of depressive episodes in bipolar patients. This report describes, in further detail, the findings from that trial of the effect of divalproex on multiple dimensions of depressive morbidity in bipolar disorder. A randomized, double-blind, parallel-group, multicenter study was conducted over a 52-week maintenance period. Bipolar I patients, who may have been treated with open-label lithium or divalproex and who met recovery criteria within 3 months of onset of an index manic episode, were randomized to maintenance treatment with divalproex, lithium, or placebo in a 2 : 1 : 1 ratio. Adjunctive paroxetine or sertraline for breakthrough depression was allowed in maintenance phase. Outcome measures were the rate of early discontinuation for depression, time to depressive relapse, proportion of patients with depressive relapse, mean change in Depressive Syndrome Scale score, proportion of patients receiving antidepressants, and time in the study. Among patients taking an antidepressant, a higher percentage of patients on placebo than divalproex discontinued early for depression. Patients who were previously hospitalized for affective episodes or took divalproex in the open period relapsed later on divalproex than on lithium during the maintenance period. Divalproex-treated patients had less worsening of depressive symptoms than lithium-treated patients during maintenance. Indices of severity of prestudy illness course predicted worse outcome in all treatment groups. Divalproex improved several dimensions of depressive morbidity and reduced the probability of depressive relapse in bipolar disorder, particularly in patients who had responded to divalproex when manic, and among patients with a more severe course of illness.


Reirradiation for locoregionally recurrent non-small cell lung cancer.
Locoregional failure in non-small cell lung cancer (NSCLC) remains high, and the management for recurrent disease in the setting of prior radiotherapy is difficult. Retreatment options such as surgery or systemic therapy are typically limited or frequently result in suboptimal outcomes. Reirradiation (reRT) of thoracic malignancies may be an optimal strategy for providing definitive local control and offering a new chance of cure. Yet, retreatment with radiation therapy can be challenging for fear of excessive toxicities and the inability to safely deliver definitive (≥60 Gy) doses of reRT. However, with recent improvements in radiation delivery techniques and image-guidance, dose-escalation with reRT is possible and outcomes are encouraging. Here, we present a review of various radiation techniques, clinical outcomes and associated toxicities in patients with locoregionally recurrent NSCLC treated primarily with reRT.


Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment.
Chronic heart failure (CHF) is a major cause of morbidity and mortality that requires a novel approach to therapy. Perhexiline is an antianginal drug that augments glucose metabolism by blocking muscle mitochondrial free fatty acid uptake, thereby increasing metabolic efficiency. We assessed the effects of perhexiline treatment in CHF patients. In a double-blind fashion, we randomly assigned patients with optimally medicated CHF to either perhexiline (n=28) or placebo (n=28). The primary end point was peak exercise oxygen consumption (VO2max), an important prognostic marker. In addition, the effect of perhexiline on myocardial function and quality of life was assessed. Quantitative stress echocardiography with tissue Doppler measurements was used to assess regional myocardial function in patients with ischemic CHF. 31P magnetic resonance spectroscopy was used to assess the effect of perhexiline on skeletal muscle energetics in patients with nonischemic CHF. Treatment with perhexiline led to significant improvements in VO2max (16.1+/-0.6 to 18.8+/-1.1 mL . kg(-1) . min(-1); P<0.001), quality of life (Minnesota score reduction from 45+/-5 to 34+/-5; P=0.04), and left ventricular ejection fraction (24+/-1% to 34+/-2%; P<0.001). Perhexiline treatment also increased resting and peak dobutamine stress regional myocardial function (by 15% and 24%, respectively) and normalized skeletal muscle phosphocreatine recovery after exercise. There were no adverse effects during the treatment period. In patients with CHF, metabolic modulation with perhexiline improved VO2max, left ventricular ejection fraction, symptoms, resting and peak stress myocardial function, and skeletal muscle energetics. Perhexiline may therefore represent a novel treatment for CHF with a good safety profile, provided that the dosage is adjusted according to plasma levels.


Characterization of nodular neuronal heterotopia in children.
Neuronal heterotopia are seen in various pathologies and are associated with intractable epilepsy. We examined brain tissue from four children with subcortical or periventricular nodular heterotopia of different aetiologies: one with severe epilepsy following focal brain trauma at 17 weeks gestation, one with hemimegalencephaly and intractable epilepsy, one with focal cortical dysplasia and intractable epilepsy, and one dysmorphic term infant with associated hydrocephalus and polymicrogyria. The connectivity of nodules was investigated using histological and carbocyanine dye (DiI) tracing techniques. DiI crystal placement adjacent to heterotopic nodules revealed numerous DiI-labelled fibres within a 2-3 mm radius of the crystals. Although we observed labelled fibres closely surrounding nodules, the majority did not penetrate them. Placement of DiI crystals within nodules also identified a limited number of projections out of the nodules and in one case there was evidence for connectivity between adjacent nodules. The cellular and neurochemical composition of nodules was also examined using immunohistochemistry for calretinin and neuropeptide Y (NPY), which are normally expressed in GABAergic cortical interneurons. Within heterotopic nodules from all cases, numerous calretinin-positive neurons were identified, along with a few cell bodies and many processes positive for NPY. Calretinin-positive neurons within nodules were less morphologically complex than those in the cortex, which may reflect incomplete differentiation into an inhibitory neuronal phenotype. There were also abnormal clusters of calretinin-positive cells in the overlying cortical plate, indicating that the migratory defect which produces heterotopic nodules also affects development of the cortex itself. Thus, heterotopic nodules consisting of multiple neuronal cell types are associated with malformation in the overlying cortical plate, and have limited connectivity with other brain regions. This abnormal development of connectivity may affect neuronal maturation and consequently the balance of excitation and inhibition in neuronal circuits, leading to their epileptogenic potential.


Use of Radiation Therapy in Locally Advanced Pancreatic Cancer Improves Survival: A SEER Database Analysis.
Although both radiation therapy and chemotherapy are frequently used to treat locally advanced pancreatic cancer (LAPC) patients, the role of radiation therapy remains controversial with data evaluating its efficacy mostly derived from small randomized trials. In this study, we evaluate the survival benefit of radiation therapy using SEER dataset in patients with LAPC. The SEER Registry dataset from 2004 to 2011 was queried to identify LAPC (TNM stage III) patients. Patients with survival <2 months, unknown radiation status, or who received postoperative radiation were excluded. Multivariate analyses of prognostic factors related to survival were performed using a Cox proportional hazard-regression model. Propensity scores were estimated using probit regression. Our search identified 4460 patients; 59% who received radiation and 41% who did not. Radiation group patients were younger (below 65 y old: 49% vs. 38%), had smaller tumor size (largest dimension <4.5 cm: 80% vs. 75%), less lymph node involvement (33% vs. 36%), and lower rate of surgical resection (4% vs. 9%). Patients who received radiation therapy had better survival (HR=0.773; 95% CI, 0.687-0.782). The 12-month overall survival in the radiation group and nonradiation group was 43% versus 29%, respectively (P<0.001). On multivariate analyses, radiation was independently associated with improved outcomes. The survival benefit with radiation was observed in propensity score-matched cohort. Radiation therapy was associated with improved survival. Prospective randomized trials are needed to confirm these findings. The optimal schedule and radiation type remain undetermined.


Determinants of death anxiety in patients with advanced cancer.
To examine the presence of death anxiety in patients with advanced cancer and to identify the psychosocial and disease-related factors associated with it. Cross-sectional analysis of baseline data from a phase 2 pilot intervention trial. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada. 60 adult outpatients with metastatic breast, endocrine, gastrointestinal, gynaecological, genitourinary and lung cancer. Death anxiety, as measured by the Death and Dying Distress Scale (DADDS). Thirty-two per cent of the sample reported death anxiety of at least moderate severity. The most distressing concern involved fears about the impact of one's death on others, and the least distressing concerns were related to dying alone or suddenly. According to regression analyses, death anxiety was negatively associated with self-esteem, b=-1.73, CI0.95 (-2.57 to -0.90) and positively associated with physical symptom burden, b=1.38, CI0.95 (0.44 to 2.31), having children under 18 years of age in the family, b=13.3, CI0.95 (2.15 to 24.5), and age, b=0.40, CI0.95 (0.0023 to 0.79). The physical symptoms most strongly associated with death anxiety were changes in physical appearance, b=18.8, CI0.95 (8.21 to29.5), and pain, b=10.1, CI0.95 (0.73 to 19.5). The findings suggest that death anxiety in patients with advanced cancer is common and determined by the interaction of individual factors, family circumstances and physical suffering. Multidimensional interventions that take into account these and other factors may be most likely to be effective to alleviate this death-related distress.


Simple method to measure the visual axis of the human eye.
We propose a simple method to measure the angle "α" that the visual axis (VA) makes with the optical axis of the human eye. In this method, we capture the images of the pupil from three different angles, one along the VA and the other two along angles that are symmetrical with respect to the VA. These views of the pupil are captured simultaneously by a camera in a single photograph using a pair of plane mirrors. Assuming a model eye and with the help of finite ray tracing, we compute the value of α from the measured diameters of the three images of the pupil. Having a simple means to measure the value of α can be useful for optical modeling and analysis of the human eye. Measurement of the VA may also be useful in monitoring progressive myopia.


Cunning factor: macrophage migration inhibitory factor as a redox-regulated target.
Macrophage migration inhibitory factor (MIF) has an amazing history of rediscoveries and controversies surroundings its true biological function. It has been classified as a powerful cytokine capable of inducing tumour necrosis factor (TNF)-alpha, IL-1beta, IL-6, IL-8, PGE2 along with its ability to override glucocorticoid activity in relation to TNF-alpha release from monocytes. However, our recent study has failed to reproduce findings on MIF as a factor with cytokine-inducing properties but it has confirmed that MIF is capable of inducing glucocorticoid-counter regulating activity and amplifying LPS-driven cytokine responses. The aim of this review is to analyse the plethora of data surrounding MIF not just as a cytokine, but also as a hormone-like molecule, enzyme with atypical properties and as a thioredoxin-like protein to address fundamental questions about MIF functionality.


Evaluation of complete blood count results from a new, on-site hemocytometer compared with a laboratory-based hemocytometer.
To compare point-of-care results obtained from an on-site hemocytometer with values provided by an institutional laboratory instrument. A prospective laboratory evaluation. The central laboratory and cardiac surgical intensive care unit of a university-affiliated tertiary care center. Normal range comparison was performed using blood specimens routinely obtained from 48 hospitalized patients for complete blood count analysis. The second evaluation was performed on blood specimens routinely obtained (in the intensive care unit) after cardiac surgery involving extracorporeal circulation in a series of 187 consecutive patients. Hemoglobin concentration, platelet count, mean corpuscular volume, mean platelet volume, and red and white blood cell counts were measured with both on-site (MD 16, Coulter Electronics, Hialeah, FL) and laboratory (STKS, Coulter Electronics) instruments. Hematocrit and red cell distribution width were calculated using measured variables. Blood specimens were obtained from two distinct patients series. To evaluate measurement values within the normal range, a series of 48 routinely obtained blood specimens for complete blood count analysis in our institutional laboratory were utilized for concurrent analysis with the on-site hemocytometer. To evaluate measurement values out of the normal range, a second comparison involved measurements performed on blood specimens obtained in the cardiac surgical intensive care unit for complete blood count analysis. Linear regression demonstrated good correlations between on-site and laboratory hemoglobin concentration (r2 = .97), hematocrit (r2 = .95), platelet count (r2 = .97), mean corpuscular volume (r2 = .91), red cell distribution width (r2 = .80), and red (r2 = .95) and white (r2 = .96) blood cell count results. A marginal correlation was observed between mean platelet volume values (r2 = .47). Bias analysis (mean +/- 2 SD) demonstrated similar measurements between on-site and laboratory hemoglobin concentration, hematocrit, platelet count, red blood cell count, white blood cell count, mean platelet volume, mean corpuscular volume, and red cell distribution width. On-site hemoglobin concentration, hematocrit, white blood cell count, red blood cell count, red cell distribution width, and platelet count values compare well with those results obtained from the laboratory. The MD 16 hemocytometer (Coulter Electronics) provides on-site hematologic results that can provide an accurate and rapid quantitative assessment of platelets, and red and white blood cells. Rapid access to information obtained from this type of system may be clinically useful, especially in critically ill patients.


Health Information Needs and Health Seeking Behavior During the 2014-2016 Ebola Outbreak: A Twitter Content Analysis.
For effective public communication during major disease outbreaks like the 2014-2016 Ebola epidemic, health information needs of the population must be adequately assessed. Through content analysis of social media data, like tweets, public health information needs can be effectively assessed and in turn provide appropriate health information to address such needs. The aim of the current study was to assess health information needs about Ebola, at distinct epidemic time points, through longitudinal tracking. Natural language processing was applied to explore public response to Ebola over time from July 2014 to March 2015. A total 155,647 tweets (unique 68,736, retweet 86,911) mentioning Ebola were analyzed and visualized with infographics. Public fear, frustration, and health information seeking regarding Ebola-related global priorities were observed across time. Our longitudinal content analysis revealed that due to ongoing health information deficiencies, resulting in fear and frustration, social media was at times an impediment and not a vehicle to support health information needs. Content analysis of tweets effectively assessed Ebola information needs. Our study also demonstrates the use of Twitter as a method for capturing real-time data to assess ongoing information needs, fear, and frustration over time.


Effects of exenatide and liraglutide on heart rate, blood pressure and body weight: systematic review and meta-analysis.
To synthesise current evidence for the effects of exenatide and liraglutide on heart rate, blood pressure and body weight. Meta-analysis of available data from randomised controlled trials comparing Glucagon-like peptide-1 (GLP-1) analogues with placebo, active antidiabetic drug therapy or lifestyle intervention. Patients with type 2 diabetes. Weighted mean differences between trial arms for changes in heart rate, blood pressure and body weight, after a minimum of 12-week follow-up. 32 trials were included. Overall, GLP-1 agonists increased the heart rate by 1.86 beats/min (bpm) (95% CI 0.85 to 2.87) versus placebo and 1.90 bpm (1.30 to 2.50) versus active control. This effect was more evident for liraglutide and exenatide long-acting release than for exenatide twice daily. GLP-1 agonists decreased systolic blood pressure by -1.79 mm Hg (-2.94 to -0.64) and -2.39 mm Hg (-3.35 to -1.42) compared to placebo and active control, respectively. Reduction in diastolic blood pressure failed to reach statistical significance (-0.54 mm Hg (-1.15 to 0.07) vs placebo and -0.50 mm Hg (-1.24 to 0.24) vs active control). Body weight decreased by -3.31 kg (-4.05 to -2.57) compared to active control, but by only -1.22 kg (-1.51 to -0.93) compared to placebo. GLP-1 analogues are associated with a small increase in heart rate and modest reductions in body weight and blood pressure. Mechanisms underlying the rise in heart rate require further investigation.


Scaling of brain metabolism with a fixed energy budget per neuron: implications for neuronal activity, plasticity and evolution.
It is usually considered that larger brains have larger neurons, which consume more energy individually, and are therefore accompanied by a larger number of glial cells per neuron. These notions, however, have never been tested. Based on glucose and oxygen metabolic rates in awake animals and their recently determined numbers of neurons, here I show that, contrary to the expected, the estimated glucose use per neuron is remarkably constant, varying only by 40% across the six species of rodents and primates (including humans). The estimated average glucose use per neuron does not correlate with neuronal density in any structure. This suggests that the energy budget of the whole brain per neuron is fixed across species and brain sizes, such that total glucose use by the brain as a whole, by the cerebral cortex and also by the cerebellum alone are linear functions of the number of neurons in the structures across the species (although the average glucose consumption per neuron is at least 10× higher in the cerebral cortex than in the cerebellum). These results indicate that the apparently remarkable use in humans of 20% of the whole body energy budget by a brain that represents only 2% of body mass is explained simply by its large number of neurons. Because synaptic activity is considered the major determinant of metabolic cost, a conserved energy budget per neuron has several profound implications for synaptic homeostasis and the regulation of firing rates, synaptic plasticity, brain imaging, pathologies, and for brain scaling in evolution.


Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice.
Secondary hyperlipidemia is a major cardiovascular risk factor in individuals with type 2 diabetes. Increased hepatic production of apolipoprotein B (apoB)-containing lipoproteins contributes to the elevated plasma levels, but the mechanism is poorly understood. Recent results have established that microsomal triglyceride transfer protein (MTP) is rate limiting for the assembly and secretion of apoB-containing lipoproteins. To better understand the mechanism of type 2 diabetes-associated hyperlipidemia, we quantified hepatic MTP mRNA levels, hepatic microsomal triglyceride transfer activity, and in vivo triglyceride secretion from the liver in two diabetic mouse models. Obese diabetic (ob/ob) mice had 45% higher (P = 0.006) hepatic MTP mRNA levels, 54% higher (P < 0.0001) microsomal triglyceride transfer activity, and 70% higher (P < 0.0001) in vivo triglyceride secretion rates compared with ob/+ control mice. In contrast, in lean streptozotocin-treated diabetic mice, hepatic MTP mRNA levels were unchanged, whereas microsomal triglyceride transfer activity and in vivo triglyceride secretion rates were marginally decreased. These studies suggest that obesity-induced type 2 diabetes in mice confers increases in hepatic MTP expression and secretion of triglyceride-rich lipoproteins. High blood glucose and altered hepatic expression of sterol regulatory element binding protein genes play a minor role in this diabetic response.


ERCC1 expression and RAD51B activity correlate with cell cycle response to platinum drug treatment not DNA repair.
The H69CIS200 and H69OX400 cell lines are novel models of low-level platinum-drug resistance. Resistance was not associated with increased cellular glutathione or decreased accumulation of platinum, rather the resistant cell lines have a cell cycle alteration allowing them to rapidly proliferate post drug treatment. A decrease in ERCC1 protein expression and an increase in RAD51B foci activity was observed in association with the platinum induced cell cycle arrest but these changes did not correlate with resistance or altered DNA repair capacity. The H69 cells and resistant cell lines have a p53 mutation and consequently decrease expression of p21 in response to platinum drug treatment, promoting progression of the cell cycle instead of increasing p21 to maintain the arrest. Decreased ERCC1 protein and increased RAD51B foci may in part be mediating the maintenance of the cell cycle arrest in the sensitive cells. Resistance in the H69CIS200 and H69OX400 cells may therefore involve the regulation of ERCC1 and RAD51B independent of their roles in DNA repair. The novel mechanism of platinum resistance in the H69CIS200 and H69OX400 cells demonstrates the multifactorial nature of platinum resistance which can occur independently of alterations in DNA repair capacity and changes in ERCC1.


Lidocaine-induced methemoglobinemia: a clinical reminder.
Methemoglobinemia is a rare condition in which the iron in hemoglobin is stabilized in the ferric (Fe(3+)) form, making it unable to bind oxygen and leading to tissue hypoxia and possibly death. The condition may be hereditary or acquired, the latter resulting from ingestion or application of common oxidizing agents such as lidocaine. As management of methemoglobinemia depends on prompt recognition, clinicians who administer or prescribe oxidizing agents must be aware of the clinical symptoms of methemoglobinemia, including cyanosis, pulse oximetry values that do not respond to increased oxygen delivery, and altered mental status. Currently, methylene blue is the drug of choice for the management of methemoglobinemia.


A randomized, double-blind study comparing the effects of beclomethasone and fluticasone on bone density over two years.
Cross-sectional studies have suggested that asthmatic patients receiving high dose inhaled corticosteroids and intermittent courses of oral corticosteroids have reduced bone mass. This prospective 2-yr study was undertaken to evaluate changes in bone density of patients receiving high doses of inhaled corticosteroids. Patients (n = 33) (males aged 18-50 yrs, females aged 18-40 yrs) on inhaled corticosteroids 1,000-2,000 microg x day(-1), were randomized in a double-blind fashion to either fluticasone propionate (FP) 1,000 microg x day(-1) or beclomethasone dipropionate (BDP) 2,000 microg x day(-1). In parallel, three open control groups of the same age range were studied: asthmatics (n = 8) receiving low dose inhaled corticosteroids (< or =400 microg x day(-1)) (group A); chronic, severe asthmatics (n = 8) receiving oral corticosteroids (> or =10 mg x day(-1) (group B); and healthy untreated volunteers (n = 7) (group C). Bone densitometry scans (quantitative computed tomography (QCT) of spine; dual X-ray absorptiometry of spine, femoral neck, and single photon absorptiometry of forearm) were performed at baseline and after 6, 12 and 24 months of treatment. Biochemical bone marker measurements (serum osteocalcin, bone alkaline phosphatase, pro-collagen type 1 carboxy terminal propeptide, deoxypyridinoline and C-telopeptide of type 1 collagen) were collected every 3 months. Fifteen FP (mean age 36 yrs, six male) and 9 BDP patients (mean age 33 yrs, five male); completed the study. At 0 months, mean bone mineral density (BMD) was lower in patients receiving inhaled corticosteroids (both low dose and high dose) than in normal volunteers. In the FP-treated group, mean vertebral trabecular BMD quantitative computed tomography remained stable with no evidence of decline, whereas there was some decline in the BDP-treated group. The treatment difference between FP and BDP was statistically significant in favour of FP for quantitative computed tomography measurements after 12 months (p = 0.006) and 24 months (p = 0.004). This study suggests that over 24 months, changes in bone density are minimal in patients on high-dose inhaled corticosteroids.


Repeat associated mechanisms of genome evolution and function revealed by the Mus caroli and Mus pahari genomes.
Understanding the mechanisms driving lineage-specific evolution in both primates and rodents has been hindered by the lack of sister clades with a similar phylogenetic structure having high-quality genome assemblies. Here, we have created chromosome-level assemblies of the Mus caroli and Mus pahari genomes. Together with the Mus musculus and Rattus norvegicus genomes, this set of rodent genomes is similar in divergence times to the Hominidae (human-chimpanzee-gorilla-orangutan). By comparing the evolutionary dynamics between the Muridae and Hominidae, we identified punctate events of chromosome reshuffling that shaped the ancestral karyotype of Mus musculus and Mus caroli between 3 and 6 million yr ago, but that are absent in the Hominidae. Hominidae show between four- and sevenfold lower rates of nucleotide change and feature turnover in both neutral and functional sequences, suggesting an underlying coherence to the Muridae acceleration. Our system of matched, high-quality genome assemblies revealed how specific classes of repeats can play lineage-specific roles in related species. Recent LINE activity has remodeled protein-coding loci to a greater extent across the Muridae than the Hominidae, with functional consequences at the species level such as reproductive isolation. Furthermore, we charted a Muridae-specific retrotransposon expansion at unprecedented resolution, revealing how a single nucleotide mutation transformed a specific SINE element into an active CTCF binding site carrier specifically in Mus caroli, which resulted in thousands of novel, species-specific CTCF binding sites. Our results show that the comparison of matched phylogenetic sets of genomes will be an increasingly powerful strategy for understanding mammalian biology.


Antineoplastic activity of the combination of interferon and cytotoxic agents against experimental and human malignancies: a review.
The combination of interferon (IFN) and conventional chemotherapeutic agents offers a promising therapeutic approach for the treatment of cancer. However, there is as yet no consensus on optimal strategies for combining this family of compounds with other cancer therapies. While in vitro studies have demonstrated both direct cytotoxic and cytokinetic effects for IFN, a more interesting role derives from its ability to synergistically potentiate the activity of a wide variety of cytotoxic agents against multiple human and rodent tumors, both in vitro and in animal models. The interaction between IFN and cytotoxic agents in vitro is complex and depends not only on the choice of cytotoxic agent but also on the concentrations, ratios, duration, and sequence of exposure to the two drugs. Preliminary data suggest that some combinations are not merely additive but rather that IFN may biochemically modulate the cellular uptake or metabolism of the cytotoxic agent resulting in synergistic antineoplastic activity. In vivo interactions between IFN and cytotoxic agents involve an additional layer of complexity because of the potential effects of the biological agent on the host immune system and drug-metabolizing enzymes. Furthermore, IFN may have a protective effect on normal host tissues which theoretically could allow for the delivery of higher doses of cytotoxic agents. The results of early clinical trials using combinations of IFN with chemotherapeutic agents have generally been disappointing. This may be due to the inability of preclinical models to accurately predict the clinical situation or alternatively from a failure to incorporate information on dose, scheduling, and sequence of drug administration into clinical trials. Preliminary clinical studies with IFN-alpha and the fluorinated pyrimidine, 5-fluorouracil, in patients with advanced colorectal carcinoma suggest that IFN may enhance the effects of the antimetabolite. Confirmatory trials are in progress. Further trials designed to exploit the preclinical experience with combinations of IFN and cytotoxic agents are warranted.


The interpretation of low mood and worry by high users of secondary care with medically unexplained symptoms.
Around 1% of adults are repeatedly referred from primary to secondary care with medically unexplained symptoms (MUS); many of these patients have depression and anxiety disorders which are unrecognized or inadequately treated. We aimed to investigate the ways patients with MUS and their General Practitioners (GPs) interpret low mood and worry, whether they regard them as depressive or anxiety disorders and how they relate them causally to symptoms. We carried out semi-structured interviews with 27 patients who had been repeatedly referred to specialists for MUS and their GPs and analysed transcripts by qualitative comparison. The analysis examined themes relating to low mood and worry, and their influence on symptoms. It drew on the concept of "otherness", whereby mental phenomena can be located either within the self or as separate entities. Both patients and GPs acknowledged the presence of low mood and worry. They viewed low mood as either an individual's personal response to circumstances (including their physical symptoms) or as the illness called "depression"; only the latter was amenable to medical intervention. Worry was seen as a trait rather than as a symptom of an anxiety disorder. While low mood and worry were acknowledged to influence physical symptoms, they were considered insufficient to be the main cause by either the patients or their doctors. Patients with MUS who are high users of secondary care services interpret low mood and worry in ways which allow them to be discussed with professionals, but not as the cause of their physical symptoms.


Meiotic Chromosome Association 1 Interacts with TOP3α and Regulates Meiotic Recombination in Rice.
Homologous recombination plays a central role in guaranteeing chromosome segregation during meiosis. The precise regulation of the resolution of recombination intermediates is critical for the success of meiosis. Many proteins, including the RECQ DNA helicases (Sgs1/BLM) and Topoisomerase 3α (TOP3α), have essential functions in managing recombination intermediates. However, many other factors involved in this process remain to be defined. Here, we report the isolation of meiotic chromosome association 1 (MEICA1), a novel protein participating in meiotic recombination in rice (Oryza sativa). Loss of MEICA1 leads to nonhomologous chromosome association, the formation of massive chromosome bridges, and fragmentation. MEICA1 interacts with MSH7, suggesting its role in preventing nonallelic recombination. In addition, MEICA1 has an anticrossover activity revealed by suppressing the defects of crossover formation in msh5 meica1 compared with that in msh5, showing the similar function with its interacted protein TOP3α. Thus, our data establish two pivotal roles for MEICA1 in meiosis: preventing aberrant meiotic recombination and regulating crossover formation.


Crystal structure of an archaebacterial DNA polymerase.
Members of the Pol II family of DNA polymerases are responsible for chromosomal replication in eukaryotes, and carry out highly processive DNA replication when attached to ring-shaped processivity clamps. The sequences of Pol II polymerases are distinct from those of members of the well-studied Pol I family of DNA polymerases. The DNA polymerase from the archaebacterium Desulfurococcus strain Tok (D. Tok Pol) is a member of the Pol II family that retains catalytic activity at elevated temperatures. The crystal structure of D. Tok Pol has been determined at 2.4 A resolution. The architecture of this Pol II type DNA polymerase resembles that of the DNA polymerase from the bacteriophage RB69, with which it shares less than approximately 20% sequence identity. As in RB69, the central catalytic region of the DNA polymerase is located within the 'palm' subdomain and is strikingly similar in structure to the corresponding regions of Pol I type DNA polymerases. The structural scaffold that surrounds the catalytic core in D. Tok Pol is unrelated in structure to that of Pol I type polymerases. The 3'-5' proofreading exonuclease domain of D. Tok Pol resembles the corresponding domains of RB69 Pol and Pol I type DNA polymerases. The exonuclease domain in D. Tok Pol is located in the same position relative to the polymerase domain as seen in RB69, and on the opposite side of the palm subdomain compared to its location in Pol I type polymerases. The N-terminal domain of D. Tok Pol has structural similarity to RNA-binding domains. Sequence alignments suggest that this domain is conserved in the eukaryotic DNA polymerases delta and epsilon. The structure of D. Tok Pol confirms that the modes of binding of the template and extrusion of newly synthesized duplex DNA are likely to be similar in both Pol II and Pol I type DNA polymerases. However, the mechanism by which the newly synthesized product transits in and out of the proofreading exonuclease domain has to be quite different. The discovery of a domain that seems to be an RNA-binding module raises the possibility that Pol II family members interact with RNA.


Conditional deletion of the Bcl-x gene from erythroid cells results in hemolytic anemia and profound splenomegaly.
Bcl-x is a member of the Bcl2 family and has been suggested to be important for the survival and maturation of various cell types including the erythroid lineage. To define the consequences of Bcl-x loss in erythroid cells and other adult tissues, we have generated mice conditionally deficient in the Bcl-x gene using the Cre-loxP recombination system. The temporal and spatial excision of the floxed Bcl-x locus was achieved by expressing the Cre recombinase gene under control of the MMTV-LTR. By the age of five weeks, Bcl-x conditional mutant mice exhibited hyperproliferation of megakaryocytes and a decline in the number of circulating platelets. Three-month-old animals suffered from severe hemolytic anemia, hyperplasia of immature erythroid cells and profound enlargement of the spleen. We demonstrate that Bcl-x is only required for the survival of erythroid cells at the end of maturation, which includes enucleated reticulocytes in circulation. The extensive proliferation of immature erythroid cells in the spleen and bone marrow might be the result of a fast turnover of late red blood cell precursors and accelerated erythropoiesis in response to tissue hypoxia. The increase in cell death of late erythroid cells is independent from the proapoptotic factor Bax, as demonstrated in conditional double mutant mice for Bcl-x and Bax. Mice conditionally deficient in Bcl-x permitted us for the first time to study the effects of Bcl-x deficiency on cell proliferation, maturation and survival under physiological conditions in an adult animal.


Inhibitory Effect of Cuphea aequipetala Extracts on Murine B16F10 Melanoma In Vitro and In Vivo.
Cuphea aequipetala (C. aequipetala) has been used in Mexican traditional medicine since prehispanic times to treat tumors. In this paper, we evaluated the antiproliferative and apoptotic effect of the methanolic and aqueous extracts of C. aequipetala on several cancer cell lines including the B16F10 cell line of murine melanoma and carried a murine model assay. In vitro assay analyzed the effect in the cellular cycle and several indicators of apoptosis, such as the caspase-3 activity, DNA fragmentation, phosphatidylserine exposure (Annexin-V), and induction of cell membrane permeabilization (propidium iodide) in the B16F10 cells. In vivo, groups of C57BL/6 female mice were subcutaneously injected with 5x105 B16F10 cells and treated with 25 mg/mL of C. aequipetala extracts via oral. Aqueous and methanolic extracts showed a cytotoxic effect in MCF-7, HepG2, and B16F10 cell lines. The methanolic extract showed more antiproliferative effect with less concentration, and for this reason, the in vitro experiments were only continued with it. This extract was able to induce accumulation of cells on G1 phase of the cell cycle; moreover, it was able to induce DNA fragmentation and increase the activity of caspase-3 in B16F10 cells. On the other hand, in the murine model of melanoma, the aqueous extract showed a greater reduction of tumor size in comparison with the methanolic extract, showing an 80% reduction versus one of around 31%, both compared with the untreated control, indicating a better antitumor effect of C. aequipetala aqueous extract via oral administration. In conclusion, the in vitro data showed that both C. aequipetala extracts were able to induce cytotoxicity through the apoptosis pathway in B16F10 cells, and in vivo, the oral administration of aqueous extract reduces the melanoma tumoral mass, suggesting an important antitumoral effect and the perspective to search for effector molecules involved in it.


NTP Toxicology and Carcinogenesis Studies of Decabromodiphenyl Oxide (CAS No. 1163-19-5) In F344/N Rats and B6C3F1 Mice (Feed Studies).
Toxicology and carcinogenesis studies of decabromodiphenyl oxide, a flame retardant for plastics and other materials, were conducted by exposing groups of 50 male and 50 female F344/N rats and B6C3F1 mice at 0, 25,000, and 50,000 ppm in the diet for 103 weeks. These concentrations were selected because no toxicity was observed at any dose in the 14-day or 13-week studies and 50,000 ppm chemical in the diet is considered to be the highest dose to which rats and mice can be exposed for extended periods of time without reducing the nutritional value of the diet. No compound-related gross or microscopic pathologic effects were observed in the 14-day or 13-week studies. Body weights of dosed male and female rats and mice in the 2-year studies were comparable to those of the controls. Decreased survival of low dose male rats was not believed to be compound related. No other effects on survival were observed in the 2-year studies. Loss of control male mice (presumably due to fighting) was significant during the first part of the study. In the 2-year studies, nonneoplastic lesions were observed at increased incidences in rats and mice of each sex. Thrombosis and degeneration of the liver, fibrosis of the spleen, and lymphoid hyperplasia were observed in high dose male rats. Degeneration of the eye was observed in low dose female rats. Nonneoplastic lesions observed in dosed mice were granulomas in the liver of low dose males and hypertrophy in the liver of low dose and high dose males. Follicular cell hyperplasia was observed in thyroid glands of dosed male mice (control, 2/50; low dose, 10/50; high dose, 19/50). The incidences of neoplastic nodules in the liver of low and high dose male rats (1/50; 7/50; 15/49) and high dose female rats (1/50; 3/49; 9/50) were significantly greater than those in the controls. Mononuclear cell leukemia occurred in dosed male rats with a positive trend (30/50; 33/50; 35/50); this marginal increase was not considered biologically significant. Acinar cell adenomas were observed in the pancreas of four high dose male rats, and a sarcoma was observed in the spleen of one low dose and one high dose male rat. Hepatocellular adenomas or carcinomas (combined) occurred at marginally increased incidences in dosed male mice (8/50; 22/50; 18/50). The incidences of thyroid gland follicular cell adenomas or carcinomas (combined) were increased in dose male mice (0/50; 4/50; 3/50). A study of decabromodiphenyl oxide absorption from the gastrointestinal tract indicated that absorption was minimal, possibly less than 1%, at the doses administered in the 2-year studies. Additional chemical analysis indicated than the decabromodiphenyl oxide used in these studies contained several less brominated diphenyl oxides. Therefore, since absorption and toxicity of minor impurities are unknown, effects observed in these studies must be attributed to the approximately 95% pure preparation used rather than to pure decabromodiphenyl oxide. Decabromodiphenyl oxide was not mutagenic in strains TA1535, TA1537, TA98, or TA100 of Salmonella typhimurium in the presence or absence of Aroclor 1254-induced Sprague-Dawley male rat or Syrian hamster liver S9 when tested according to the preincubational protocol. Decabromodiphenyl oxide was not mutagenic in the mouse lymphoma L5178Y/TK+/- assay in the presence or absence of Aroclor 1254-induced F344/N male rat liver S9. Decabromodiphenyl oxide did not induce sister-chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells in vitro in the presence or absence of S9 prepared from livers of Aroclor 1254-induced male Sprague-Dawley rats. An audit of experimental data was conducted for these 2-year studies on decabromodiphenyl oxide. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year feed studies of decabromodiphenyl oxide, there was some evidence of carcinogenicity for male and female F344/N rats as shown by increased incidences of neoplastic nodules of the liver in low dose (25,000 ppm) males and high dose (50, and high dose (50,000 ppm) groups of each sex. There was equivocal evidence of carcinogenicity for male B6C3F1 mice as shown by increased incidences of hepatocellular adenomas or carcinomas (combined) in the low dose group and of thyroid gland follicular cell adenomas or carcinomas (combined) in both dosed groups. There was no evidence of carcinogenicity for female B6C3F1 mice receiving 25,000 or 50,000 ppm in the diet. Several nonneoplastic lesions were observed at increased incidences, the most notable being thyroid gland follicular cell hyperplasia in male mice. Synonyms: decabromodiphenyl ether; bis(pentabromophenyl)ether; DBDPO


Highly parallel acoustic assembly of microparticles into well-ordered colloidal crystallites.
The precise arrangement of microscopic objects is critical to the development of functional materials and ornately patterned surfaces. Here, we present an acoustics-based method for the rapid arrangement of microscopic particles into organized and programmable architectures, which are periodically spaced within a square assembly chamber. This macroscale device employs two-dimensional bulk acoustic standing waves to propel particles along the base of the chamber toward pressure nodes or antinodes, depending on the acoustic contrast factor of the particle, and is capable of simultaneously creating thousands of size-limited, isotropic and anisotropic assemblies within minutes. We pair experiments with Brownian dynamics simulations to model the migration kinetics and assembly patterns of spherical microparticles. We use these insights to predict and subsequently validate the onset of buckling of the assemblies into three-dimensional clusters by experiments upon increasing the acoustic pressure amplitude and the particle concentration. The simulations are also used to inform our experiments for the assembly of non-spherical particles, which are then recovered via fluid evaporation and directly inspected by electron microscopy. This method for assembly of particles offers several notable advantages over other approaches (e.g., magnetics, electrokinetics and optical tweezing) including simplicity, speed and scalability and can also be used in concert with other such approaches for enhancing the types of assemblies achievable.


LIMT is a novel metastasis inhibiting lncRNA suppressed by EGF and downregulated in aggressive breast cancer.
Long noncoding RNAs (lncRNAs) are emerging as regulators of gene expression in pathogenesis, including cancer. Recently, lncRNAs have been implicated in progression of specific subtypes of breast cancer. One aggressive, basal-like subtype associates with increased EGFR signaling, while another, the HER2-enriched subtype, engages a kin of EGFR Based on the premise that EGFR-regulated lncRNAs might control the aggressiveness of basal-like tumors, we identified multiple EGFR-inducible lncRNAs in basal-like normal cells and overlaid them with the transcriptomes of over 3,000 breast cancer patients. This led to the identification of 11 prognostic lncRNAs. Functional analyses of this group uncovered LINC01089 (here renamed LncRNA Inhibiting Metastasis; LIMT), a highly conserved lncRNA, which is depleted in basal-like and in HER2-positive tumors, and the low expression of which predicts poor patient prognosis. Interestingly, EGF rapidly downregulates LIMT expression by enhancing histone deacetylation at the respective promoter. We also find that LIMT inhibits extracellular matrix invasion of mammary cells in vitro and tumor metastasis in vivo In conclusion, lncRNAs dynamically regulated by growth factors might act as novel drivers of cancer progression and serve as prognostic biomarkers.


Serial time-encoded amplified microscopy (STEAM) based on a stabilized picosecond supercontinuum source.
Temporal stability of the broadband source, such as supercontinuum (SC), is the key enabling factor for realizing high performance ultrafast serial time-encoded amplified microscopy (STEAM). Owing to that the long-pulse SC (picosecond to nanosecond) generation generally results in an ultrabroadband spectrum with significant pulse-to-pulse fluctuation, only the ultrashort-pulse (femtosecond) SC sources, which offer better temporal stability, have been employed in STEAM so far. Here we report a simple approach to achieve active control of picosecond SC stability and to help extend the applicability of SC in STEAM from the femtosecond to the picosecond or even nanosecond regimes. We experimentally demonstrate stable single-shot STEAM imaging at a frame rate of 4.9 MHz using the CW-triggered picosecond SC source. Such CW-stabilized SC can greatly reduce the shot-to-shot fluctuation, and thus improves the STEAM image quality significantly.


Cricoid chondronecrosis: a complication of endotracheal intubation.
Stenosis of the subglottic area is a common complication of endotracheal intubation and external blunt trauma. Chondronecrosis of the cricoid cartilage is a rare but known complication of neck radiotherapy for laryngeal carcinoma. It has also been reported as a complication of prolonged endotracheal intubation. The clinical and bronchoscopic findings are non-specific and the diagnosis can not be accurately established without surgical evidence or computed tomographic (CT) findings. In addition to technical issues related intubation, multiple anatomic and host factors can contribute to the pathogenesis of this uncommon entity. In this report, we describe the clinical and radiographic findings of a recent case and review the literature. To our knowledge, this is the second case of cricoid chondronecrosis in an adult patient occurring after only a few hours of intubation.


Proven intra and interobserver reliability in the echographic assessments of body fat changes related to HIV associated Adipose Redistribution Syndrome (HARS).
To prove intra- and inter-observer's reliability of ultrasound (US) in the assessment of lipoatrophic findings related to the HIV associated Adipose Redistribution Syndrome (HARS). In two separated sessions, 2 consecutive measurements of subcutaneous fat thickness (SFT) were performed by each observer at the deepest point of Bichat pad, the dorsal face of arm and the mid thigh for the assessment of facial, brachial and crural lipoatrophy, respectively. We enrolled 20 HIV patients, rotating an experienced and untrained sonologist. The assessments were performed avoiding any stand off pads in the skin and excluding artefacts due to the too abundant quantity of gel to obtaining, with minimal transducer pressure, the best resolution of the reference points. Means of facial, brachial and crural SFT showed no significant differences between the workers. Coefficients of variability (SD/mean x100) were similar for facial (ranges: 4.7-5.2% vs 4.9-5.6%, respectively), brachial (ranges: 5.8-8.4% vs 9.7-11.2%) and crural SFTs (ranges: 5.9-6% vs 6.2-8.7%). There was greater consistency in the measurements performed by the experienced vs the untrained worker. Inter-observer agreement, assessed through kappa statistic (k) analysis, confirmed increased measurement's agreement in the facial (k ranged from 0.40 to 0.60), brachial (k: 0.23-0.63) and crural SFT assessments (k: 0.58-0.70) from the 1(st) to 2(nd) session. US shows low intra observer variability and good inter observer reliability in the assessment of body fat changes related to the HARS. The different degree of consistency by the workers and the improvement of interobserver agreement, suggest to stating a well defined period of training to obtain better US reliability.


The burden of overweight and obesity-related ill health in the UK.
This paper reviews previous cost studies of overweight and obesity in the UK. It proposes a method for estimating the economic and health costs of overweight and obesity in the UK which could also be used in other countries. Costs of obesity studies were identified via a systematic search of electronic databases. Information from the WHO Burden of Disease Project was used to calculate the mortality and morbidity cost of overweight and obesity. Population attributable fractions for diseases attributable to overweight and obesity were applied to National Health Service (NHS) cost data to estimate direct financial costs. We estimate the direct cost of overweight and obesity to the NHS at pound 3.2 billion. Other estimates of the cost of obesity range between pound 480 million in 1998 and pound 1.1 billion in 2004 [Correction added after online publication 11 June 2007: 'of the cost of obesity' added after 'Other estimates']. There is wide variation in methods and estimates for the cost of overweight and obesity to the health systems of developed countries. The method presented here could be used to calculate the costs of overweight and obesity in other countries. Public health initiatives are required to address the increasing prevalence of overweight and obesity and reduce associated healthcare costs.


Bone marrow transplantation and cataract development.
To evaluate risk factors for the development of posterior subcapsular cataract following bone marrow transplantation (BMT) and the results of patients undergoing cataract extraction. Retrospective case-control study. Tertiary referral center. Three hundred sixty-six patients (59% male, 41% female) undergoing BMT at one institution who survived for at least 1 month and underwent full ophthalmologic examination. Risk factors were then compared between patients who developed posterior subcapsular cataract and those who did not. Cataract surgery in six eyes of four patients. Formation of posterior subcapsular cataract. Data were obtained on all patients for type of BMT, pretransplantation regimen, underlying malignancy, demographic background, complications of BMT, and medications. Forty (10.9%) of 366 patients developed posterior subcapsular cataract. By univariate analysis, cataract formation was associated with total body irradiation, chronic graft-vs-host disease, the use of allogeneic bone marrow, and the total dose and duration of corticosteroid therapy. Multivariate analysis revealed that the total dose and duration of corticosteroid therapy were the most important risk factors, while total body irradiation was not a statistically significant risk factor. Cataract surgery was performed in six eyes of four patients, all of whom developed visual acuities of 20/40 or better. Posterior subcapsular cataract following BMT is uncommon and rarely requires surgery. Total dose and duration of corticosteroid therapy are the most important risk factors for development of cataract, but total body irradiation is not a statistically significant risk factor.


Grape seed as a functional food ingredient in bread-making.
The objective of this study was to determine the effects of grape seed (GS) on the rheological and bread-making properties, antioxidant activity and phenolic composition of bread. Wheat flour was replaced with GS at levels of 2.5%, 5.0% and 7.5%. GS increased the dough development time at a level of 5.0% but did not change it at levels of 2.5% and 7.5%. The dough stability value increased from 6.4 to 12.3 min with the increase of GS content from 0% to 7.5%. Mixing tolerance index decreased from 41.1 to 6.4 Brabender Units Equivalent. Extensibility of dough containing GS was higher than that of the control dough. The antioxidant activities of the bread increased significantly with the increased GS substitution. Gallic acid and catechin content increased in the bread containing GS. It was concluded that GS could be added to the formulae to improve functionality of the bread.


Value of hepatic elastography and Doppler indexes for predictions of esophageal varices in liver cirrhosis.
Non-invasive methods are required to diagnose presence and grading of esophageal varices in patients with hepatic cirrhosis and in this respect we have evaluated the role of transient elastography and abdominal ultrasound parameters. Cirrhotic patients were prospectively evaluated by transient elastography and Doppler ultrasound for diagnosis of presence and grading of esophageal varices, the results being compared with the findings of the esophagogastroduodenoscopy. Sixty patients with hepatic cirrhosis were analysed. The parameters that reached statistical significance for diagnosis of esophageal varices were: liver stiffness (LSM) > 15 kPa, hemodynamic liver index (PVr1) >/= 0.66, portal vascular resistance (PVR) > 17.66 and splenoportal index (SPI) > 4.77. The only parameter that reached statistical power for the diagnosis of large esophageal varices was LSM at a cut-off value of 28.8 kPa. Assessment of LSM in patients with liver cirrhosis can predict both the presence of esophageal varices and of large esophageal varices. The PVr1, PVR and SPI Doppler indexes can be used to diagnose the presence of esophageal varices but have no role in the prediction of large esophageal varices. Further studies are required to confirm these results and offer a stronger clinical significance.


Neuromagnetic responses to binaural beat in human cerebral cortex.
The dichotic presentation of two sinusoids with a slight difference in frequency elicits subjective fluctuations called binaural beat (BB). BBs provide a classic example of binaural interaction considered to result from neural interaction in the central auditory pathway that receives input from both ears. To explore the cortical representation of the fluctuation of BB, we recorded magnetic fields evoked by slow BB of 4.00 or 6.66 Hz in nine normal subjects. The fields showed small amplitudes; however, they were strong enough to be distinguished from the noise accompanying the recordings. Spectral analyses of the magnetic fields recorded on single channels revealed that the responses evoked by BBs contained a specific spectral component of BB frequency, and the magnetic fields were confirmed to represent an auditory steady-state response (ASSR) to BB. The analyses of spatial distribution of BB-synchronized responses and minimum-norm current estimates revealed multiple BB ASSR sources in the parietal and frontal cortices in addition to the temporal areas, including auditory cortices. The phase of synchronized waveforms showed great variability, suggesting that BB ASSR does not represent changing interaural phase differences (IPD) per se, but instead it reflects a higher-order cognitive process corresponding to subjective fluctuations of BB. Our findings confirm that the activity of the human cerebral cortex can be synchronized with slow BB by using information on the IPD.


A new approach to management of intravenous infiltration in pediatric patients: pathophysiology, classification, and treatment.
Intravenous (IV) infiltrations are problematic complications associated with hospitalization. Treatment methods vary greatly on the basis of physician judgment and institutional protocol, and uniform methods for effective prevention and economical treatment of IV infiltrations are necessary. Common in neonatal and infant patients, infiltration is frequently associated with cosmetic and functional complications. Medicolegal issues for physicians and institutions also accompany many cases of infiltration. This article discusses the pathophysiology of IV infiltrations. It also presents a new scale for IV infiltrations that more accurately reflects issues common to neonatal and pediatric patients and describes a novel, noninvasive treatment. A quantitative study of the decrease in morbidity after implementing this protocol will be conducted pending institutional approval.


The FLT3 ligand potently and directly stimulates the growth and expansion of primitive murine bone marrow progenitor cells in vitro: synergistic interactions with interleukin (IL) 11, IL-12, and other hematopoietic growth factors.
The recently cloned murine flt3 ligand (FL) was studied for its ability to stimulate the growth of primitive (Lin-Sca-1+) and more committed (Lin-Sca-1-) murine bone marrow progenitor cells, alone and in combination with other hematopoietic growth factors (HGFs). Whereas FL was a weak proliferative stimulator alone, it potently synergized with a number of other HGFs, including all four colony-stimulating factor (CSF), interleukin (IL) 6, IL-11, IL-12, and stem cell factor (SCF), to promote the colony formation of Lin-Sca-1+, but not Lin-Sca-1- or erythroid progenitor cells. The synergistic activity of FL was concentration dependent, with maximum stimulation occurring at 250 ng/ml, and was observed when cells were plated at a concentration of one cell per culture, suggesting that its effects are directly mediated. 2 wk of treatment with FL in combination with IL-3 or SCF resulted in the production of a high proportion of mature myeloid cells (granulocytes and macrophages), whereas the combination of FL with G-CSF, IL-11, or IL-12 resulted predominantly in the formation of cells with an immature blast cell appearance. Accordingly, FL in combination with G-CSF or IL-11 expanded the number of progenitors more than 40-fold after 2 wk incubation. Thus, FL emerges as a potent synergistic HGF, that in combination with numerous other HGFs, can directly stimulate the proliferation, myeloid differentiation, and expansion of primitive hematopoietic progenitor cells.


Revealing the signature of dipolar interactions in dynamic spectra of polydisperse magnetic nanoparticles.
We investigate, via a modified mean field approach, the dynamic magnetic response of a polydisperse dipolar suspension to a weak, linearly polarised, AC field. We introduce an additional term into the Fokker-Planck equation, which takes into account dipole-dipole interaction in the form of the first order perturbation, and allows for particle polydispersity. The analytical expressions, obtained for the real and imaginary dynamic susceptibilities, predict three measurable effects: the increase of the real part low-frequency plateaux; the enhanced growth of the imaginary part in the low-frequency range; and the shift of the imaginary part maximum. Our theoretical predictions find an experimental confirmation and explain the changes in the spectrum.


Comparison between Defence Healthcare Engagement and humanitarian assistance.
Humanitarian assistance and Defence Healthcare Engagement have traditionally both been taught on the Medical Humanitarian Stabilisation Operations Course. However, the two activities are distinct. This paper outlines the critical differences between them, focusing on their specific purposes, scope, timescales and ethics. Humanitarian assistance will remain a distinct activity with a focus on the relief of suffering, guided by international norms, while Defence Healthcare Engagement will encompass a broader range of activities, less constrained by internationally agreed principles. This presents an opportunity for the Defence Medical Services to directly contribute to projecting UK influence, preventing conflict and building stability. However, it requires the Defence Medical Services to take responsibility for the ethical issues that Defence Healthcare Engagement raises. This paper recommends the development of an ethical framework that reconciles the strategic aims of Defence Healthcare Engagement with maximising patient welfare at the tactical level. This is a paper commissioned as a part of the Humanitarian and Disaster Relief Operations special issue of BMJ Military Health.


A practical checklist for return of results from genomic research in the European context.
An increasing number of European research projects return, or plan to return, individual genomic research results (IRR) to participants. While data access is a data subject's right under the General Data Protection Regulation (GDPR), and many legal and ethical guidelines allow or require participants to receive personal data generated in research, the practice of returning results is not straightforward and raises several practical and ethical issues. Existing guidelines focusing on return of IRR are mostly project-specific, only discuss which results to return, or were developed outside Europe. To address this gap, we analysed existing normative documents identified online using inductive content analysis. We used this analysis to develop a checklist of steps to assist European researchers considering whether to return IRR to participants. We then sought feedback on the checklist from an interdisciplinary panel of European experts (clinicians, clinical researchers, population-based researchers, biobank managers, ethicists, lawyers and policy makers) to refine the checklist. The checklist outlines seven major components researchers should consider when determining whether, and how, to return results to adult research participants: 1) Decide which results to return; 2) Develop a plan for return of results; 3) Obtain participant informed consent; 4) Collect and analyse data; 5) Confirm results; 6) Disclose research results; 7) Follow-up and monitor. Our checklist provides a clear outline of the steps European researchers can follow to develop ethical and sustainable result return pathways within their own research projects. Further legal analysis is required to ensure this checklist complies with relevant domestic laws.


Effects of state-level medicaid policies and patient characteristics on time to breast cancer surgery among medicaid beneficiaries.
Medicaid beneficiaries with cancer are less likely to receive timely and high-quality care. This study examined whether differences in state-level Medicaid policies affect delays in time to surgery (TTS) among women diagnosed with breast cancer. Using 2006-2008 Medicaid data, we identified women aged 18-64 enrolled in Medicaid diagnosed with breast cancer. Analyses examined associations of state-specific Medicaid surgery reimbursements, Medicaid eligibility recertification period (annually vs. shorter) and required patient copayment on time from breast cancer diagnosis to receipt of breast surgery. Patients receiving neoadjuvant therapy were excluded. Separate multivariable regression analyses controlling for patient demographic characteristics and clustering by state were performed for breast conserving surgery (BCS), inpatient mastectomy, and outpatient mastectomy. The study included 7542 Medicaid beneficiaries with breast cancer: 3272 received BCS, 2156 outpatient mastectomy, and 2115 inpatient mastectomy. Higher Medicaid reimbursements for BCS were associated with decreased time from diagnosis to surgery. A 12-month (vs. <12 month) Medicaid eligibility recertification period was associated with decreased TTS for BCS and outpatient mastectomy. Black Medicaid beneficiaries (compared with non-Hispanic White beneficiaries) were more likely to experience delays for all three types of surgery, while Hispanic beneficiaries were more likely to experience delays only for outpatient mastectomy. State-level Medicaid policies and patient characteristics can affect receipt of timely surgery among Medicaid beneficiaries with breast cancer. As delays in surgery can increase morbidity and mortality, changes to state Medicaid policies and health system programs are needed to improve access to care for this vulnerable population.


Internet-based cognitive-behavioral self help for depression.
Depression is a common condition that can be treated in many different ways. Accumulating evidence suggests that self help, based on cognitive-behavioral principles, is an evidence-based treatment for mild-to-moderate depression. Self help commonly requires some form of guidance, but can still be cost effective and the results are often similar to what can be observed in face-to-face therapy. Recently, the possibility of administering cognitive-behavioral treatment via the internet has been explored. There are several advantages to using the internet, the main one being that it bridges distances and is readily available for an increasing number of people in the world. While few controlled studies have examined the effects of internet-delivered self help for depression, the results are promising for applications that involve brief therapist input. Future possible applications of internet-based self help are discussed.


Maturation of spinal motor neurons derived from human embryonic stem cells.
Our understanding of motor neuron biology in humans is derived mainly from investigation of human postmortem tissue and more indirectly from live animal models such as rodents. Thus generation of motor neurons from human embryonic stem cells and human induced pluripotent stem cells is an important new approach to model motor neuron function. To be useful models of human motor neuron function, cells generated in vitro should develop mature properties that are the hallmarks of motor neurons in vivo such as elaborated neuronal processes and mature electrophysiological characteristics. Here we have investigated changes in morphological and electrophysiological properties associated with maturation of neurons differentiated from human embryonic stem cells expressing GFP driven by a motor neuron specific reporter (Hb9::GFP) in culture. We observed maturation in cellular morphology seen as more complex neurite outgrowth and increased soma area over time. Electrophysiological changes included decreasing input resistance and increasing action potential firing frequency over 13 days in vitro. Furthermore, these human embryonic stem cell derived motor neurons acquired two physiological characteristics that are thought to underpin motor neuron integrated function in motor circuits; spike frequency adaptation and rebound action potential firing. These findings show that human embryonic stem cell derived motor neurons develop functional characteristics typical of spinal motor neurons in vivo and suggest that they are a relevant and useful platform for studying motor neuron development and function and for modeling motor neuron diseases.


Rotator cuff tears reparability index based on pre-operative MRI: our experience.
It is recognised that a significant percetage of large and massive rotator cuff tears (RCT) cannot be anatomically repaired and this correlates with a worste outcome in terms of pain, active range of motion, increased incidence of retair. The aim of our work is to find reliable index on preoperative MRI shoulder image to assist orthopaedist in surgical planning of rotatator cuff tears repair. We performed a retrospective study on a population on 131 patients undergoing arthroscopic cuff repair by a single expert surgeon. Pre-operative MRI images were evaluated by a single orthopaedist, trained on MRI shoulder images ad blinded to surgical outcome. For each magnetic resonance we evaluated the following 9 parameters: fatty Infiltration (FI), Patte Stage (PS), tear size measured in medial-lateral (ML) and anterior- posterior (AP) dimension, Tangent Sign (TS), Occupation Grade (OG), Acromion-Humeral Distance (AHD), Inferior Gleno-Humeral Distance (IGHD), Glenoid Version Angle (GVA). We divided population into two groups: patients who obtained a complete repair of RCT (n=110) and patients who obtained only a partial repair of RCT (n=21). For each MRI index we conducted statistical analysis (Student's t test, Mann- Whitney U test, Shapiro-Wilk test, Chi-square test, Fisher exact test, ROC curves and maximum Youden index) to find a Cut Off value useful to predict partial repair. We have found statistical significance in predicting partial repair on MRI mesurements of Fatty Infiltration (FI grade ≥3; test di Fisher p<0.001), Patte Stage (grade= 3; test di Fisher p<0.001), Tear size measured in ML (>36 mm; Mann-Whitney p<0.001), Positive Tangent Sign (Chi-quadro p<0.001; sensitivity 95,3%, specificity 83,6%), Occupation Grade (OG <0,46; t-test p<0.001). Acromion-Humeral Distance (AHD <7 mm), Inferior Gleno-Humeral Distance (IGHD >5 mm). Tear size measured in AP (>21 mm; Mann-Whitney p<0.001) seems to be dependent on the contextual size of the lesion in ML. We haven't found statistical significance in predicting partial repair of Glenoid Version Angle. A systematic observation of seven independent MRI parameters (FI, PS, tear size ML, TS, OG, AHD, IGHD) can help the surgeon to predict the impossibility to obtain complete repair of RCT and to consider different surgical approach.


Imaging predictive factors and exercise training in CRT patients.
Cardiac resynchronization therapy (CRT) is an established treatment for patients with moderate-to-severe chronic heart failure (CHF) and intraventricular conduction delay, which is identified by a QRS interval of 120msec or more on a 12-lead electrocardiogram (ECG). CRT improved functional capacity, reduced hospitalizations for worsening CHF and increased survival. However, about 30-40% of patients who underwent CRT were non-responders with no clinical or echocardiographic improvement. Imaging parameters for prediction of CRT response have been reviewed. Cardiac magnetic resonance (CMR), recognized as the gold standard to assess viability, has shown to obtain good results regarding quantification of scar burden. CMR-derived measures of mechanical dyssynchrony appear to predict the outcome of CRT, however they have not been externally validated. Nuclear imaging techniques, namely single-photon emission cardiac tomography (SPECT) provide data on scar burden and location, left ventricular (LV) function, LV contraction and mechanical dyssynchrony from a single scan. The presence, location and burden of myocardial scar have been shown to affect response to CRT. However, compared to CMR, the low spatial resolution of scintigraphy might overestimate the scar extent. This problem can be overcome by positron emission tomography (PET). SPECT has also been used to quantify dyssynchrony, using phase analysis. Imaging investigation is ongoing, trying to better identifying CRT non-responders. The combination of ExT in CRT has not been well investigated; however some data show different aerobic exercise modes and intensities can further improve CRT benefits. Data available on the effects of ExT in patients with CRT have been reviewed.


Differences in adult and foetal human cytochrome P-450 forms recognized by monoclonal antibodies with specificity for the P450III family.
Six murine monoclonal antibodies raised against a major human adult liver cytochrome P-450 (P-450) of the PCN family (P450III) detected a protein in human foetal liver microsomes (microsomal fractions) which had an approx. 1 kDa higher molecular mass on SDS/polyacrylamide-gel electrophoresis than the protein recognized in human adult liver microsomes. Although each of the antibodies recognized both the adult and the foetal forms, antibody HL4 showed higher affinity for the foetal form. Recognition by the monoclonal antibodies of peptides generated by proteolytic cleavage of microsomal proteins showed different patterns for the adult and foetal forms. It is concluded that the foetal P-450 form recognized by antibodies to the major human adult liver form P450hA7, although structurally similar, is either a distinct P-450 isoenzyme or that the adult and foetal proteins have different covalent modification. Immunoquantification experiments showed comparable levels of the P-450 forms in adult and foetal liver, although there appeared to be less inter-individual variation in foetal livers.


Anthrax toxin: the long and winding road that leads to the kill.
The past five years have led to a tremendous increase in our molecular understanding of the mode of action of the anthrax toxin, one of the two main virulence factors produced by Bacillus anthracis. The structures of each of the three components of the toxin--lethal factor (LF), edema factor (EF) and protective antigen (PA)--have been solved not only in their monomeric forms but, depending on the subunit, in a heptameric form, bound to their substrate, co-factor or receptor. The endocytic route followed by the toxin has also been unraveled and the enzymatic mechanisms of EF and LF elucidated.


Periapical implant pathology.
Periapical implant pathology, a distinct dental lesion, is the coalescence of adjacent periapical pathology with the apical segment of a dental implant that results in a common lesion. I present four cases to document two proposed case types: type 1, implant to tooth, which occurs during osteotomy preparation either by direct trauma or through indirect damage and causes adjacent pulp to undergo devitalization; and type 2, tooth to implant, which occurs shortly after placement of the implant when an adjacent tooth develops periapical pathology, either by operative damage to the pulp or through reactivation of a prior apical lesion. In both types, the resulting periapical pathology contaminates the fixture and inhibits osseointegration of the implant during stage 1 healing. These two case types are presented to help clarify the use of etiology as the basis of a classification system.


Musculoskeletal findings and disability in alkaptonuria.
To describe the musculoskeletal (MSK) findings in patients with alkaptonuria and to show which of these factors are associated with disability in this population. This is a prospective cross-sectional MSK assessment of subjects. Participants included 53 patients with alkaptonuria across the life span, 22 female and 31 male, mean age 43.6 years (10-80 yrs), participating in a natural history study supported by the National Human Genome Research Institute (NHGRI). Assessments included objective measures of the MSK system (range of motion, radiographic assessment of joints and spine, etc.) and questionnaires including the Human Activity Profile (HAP), Health Assessment Questionnaire (HAQ), SF-36 health survey, and the Fatigue Assessment Instrument. There were 18 patients with kyphosis, 16 with scoliosis, 16 with marked reduction in range of motion of at least one major joint, 15 with joint replacements of major joints, 11 with tendon ruptures. A positive Schober's test was highly correlated with substantial functional loss and associated with disability as measured by the HAP (p < or = 0.0001), HAQ (p < or = 0.0001), and the physical component summary (p < or = 0.0001) of the SF-36 health survey. Severity of lumbar spine involvement had the greatest correlation with disability measures (p < or = 0.0001). All objective and subjective physical measures worsened with age. Disability is common and severe in patients with alkaptonuria and correlates well with physical findings. Disability does not correlate with self-reports of mental competencies. Aging with alkaptonuria is associated with progressive disability.


Paradoxical effect of spatially homogenous transparent fields on simultaneous contrast illusions.
In simultaneous brightness contrast (SBC) demonstrations, identical mid-luminance disks appear different from each other when one is placed on a black background while the other is placed on a white background. The strength of SBC effects can be enhanced by placing a semi-transparent layer on top of the display (Meyer's effect). Here, we try to separate the causes of Meyer's effect by placing a spatially homogenous transparent layer over a standard SBC display, and systematically varying the transmission level (alpha=0, clear; alpha=1, opaque) and color (black, gray, white) of the semi-transparent layer. Spatially homogenous transparent layers, which lack spatial cues, cannot be unambiguously interpreted as transparent fields. We measure SBC strength with both matching and ranking procedures. Paradoxically, with black layers, increasing alpha level weakens SBC when measured with a ranking procedure (no Meyer's effect) and strengthens SBC when measured with a matching procedure (Meyer's effect). With white and gray layers, neither procedure produces Meyer's effect. We account for the differences between white and black layers by positing that the visual system separates luminance from contrast. The results suggest that observers attend to different information in the matching and ranking procedures.


Patrick Geddes and the politics of evolution.
Ever since they began to be widely discussed during the early nineteenth century, evolutionary ideas have played a controversial role in debates about politics and social reform. Understanding the political commitments of those who have sought to integrate politics and evolution is a complex challenge, though; not least because memories of mid-twentieth-century eugenic policies have frequently shaped how we talk about biosocial science. However, as the case of the Scottish biologist-turned-town-planner Patrick Geddes highlights, while we need to be aware of the broad appeal that biosocial science has historically held, we also need to recognise that current political categories can be misleading when thinking about those of who have put evolution and politics together.


Forces during cellular uptake of viruses and nanoparticles at the ventral side.
Many intracellular pathogens, such as mammalian reovirus, mimic extracellular matrix motifs to specifically interact with the host membrane. Whether and how cell-matrix interactions influence virus particle uptake is unknown, as it is usually studied from the dorsal side. Here we show that the forces exerted at the ventral side of adherent cells during reovirus uptake exceed the binding strength of biotin-neutravidin anchoring viruses to a biofunctionalized substrate. Analysis of virus dissociation kinetics using the Bell model revealed mean forces higher than 30 pN per virus, preferentially applied in the cell periphery where close matrix contacts form. Utilizing 100 nm-sized nanoparticles decorated with integrin adhesion motifs, we demonstrate that the uptake forces scale with the adhesion energy, while actin/myosin inhibitions strongly reduce the uptake frequency, but not uptake kinetics. We hypothesize that particle adhesion and the push by the substrate provide the main driving forces for uptake.


Microbial relatives of the seed storage proteins of higher plants: conservation of structure and diversification of function during evolution of the cupin superfamily.
This review summarizes the recent discovery of the cupin superfamily (from the Latin term "cupa," a small barrel) of functionally diverse proteins that initially were limited to several higher plant proteins such as seed storage proteins, germin (an oxalate oxidase), germin-like proteins, and auxin-binding protein. Knowledge of the three-dimensional structure of two vicilins, seed proteins with a characteristic beta-barrel core, led to the identification of a small number of conserved residues and thence to the discovery of several microbial proteins which share these key amino acids. In particular, there is a highly conserved pattern of two histidine-containing motifs with a varied intermotif spacing. This cupin signature is found as a central component of many microbial proteins including certain types of phosphomannose isomerase, polyketide synthase, epimerase, and dioxygenase. In addition, the signature has been identified within the N-terminal effector domain in a subgroup of bacterial AraC transcription factors. As well as these single-domain cupins, this survey has identified other classes of two-domain bicupins including bacterial gentisate 1, 2-dioxygenases and 1-hydroxy-2-naphthoate dioxygenases, fungal oxalate decarboxylases, and legume sucrose-binding proteins. Cupin evolution is discussed from the perspective of the structure-function relationships, using data from the genomes of several prokaryotes, especially Bacillus subtilis. Many of these functions involve aspects of sugar metabolism and cell wall synthesis and are concerned with responses to abiotic stress such as heat, desiccation, or starvation. Particular emphasis is also given to the oxalate-degrading enzymes from microbes, their biological significance, and their value in a range of medical and other applications.


Overcoming difficulties with equipoise to enable recruitment to a randomised controlled trial of partial ablation vs radical prostatectomy for unilateral localised prostate cancer.
To describe how clinicians conceptualised equipoise in the PART (Partial prostate Ablation vs Radical prosTatectomy in intermediate-risk unilateral clinically localised prostate cancer) feasibility study and how this affected recruitment. PART included a QuinteT Recruitment Intervention (QRI) to optimise recruitment. Phase I aimed to understand recruitment, and included: scrutinising recruitment data, interviewing the trial management group and recruiters (n = 13), and audio-recording recruitment consultations (n = 64). Data were analysed using qualitative content and thematic analysis methods. In Phase II, strategies to improve recruitment were developed and delivered. Initially many recruiters found it difficult to maintain a position of equipoise and held preconceptions about which treatment was best for particular patients. They did not feel comfortable about approaching all eligible patients, and when the study was discussed, biases were conveyed through the use of terminology, poorly balanced information, and direct treatment recommendations. Individual and group feedback led to presentations to patients becoming clearer and enabled recruiters to reconsider their sense of equipoise. Although the precise impact of the QRI alone cannot be determined, recruitment increased (from a mean [range] of 1.4 [0-4] to 4.5 [0-12] patients/month) and the feasibility study reached its recruitment target. Although clinicians find it challenging to recruit patients to a trial comparing different contemporary treatments for prostate cancer, training and support can enable recruiters to become more comfortable with conveying equipoise and providing clearer information to patients.


Gomez-Lopez-Hernandez syndrome: an easily missed diagnosis.
Gomez-Lopez-Hernandez syndrome (GLHS) is a rare syndrome comprising the triad rhombencephalosynapsis (RS), parietal alopecia, and trigeminal anesthesia. Other typical findings are skull abnormalities, craniofacial dysmorphic signs, and short stature. Intellectual impairment is typical but cases with normal cognitive functions have also been reported. Only 15 cases of GLHS have been described so far, all sporadic. We report four further patients with GLHS: one neonate, two children and a middle aged man. In all cases the diagnosis was made only in retrospect; one child died as neonate due to esophageal atresia. All patients presented RS and parietal alopecia, three intermittent head stereotypies, two had obvious trigeminal anesthesia, and one normal cognition. Alopecia and also trigeminal anesthesia can be very mild and can be easily missed. However, the dysmorphic signs including bilateral alopecia are already present in the neonatal period and are highly suggestive of GLHS. RS should be looked for in this situation. It is important to mention that neuroimaging does not allow distinguishing between isolated RS and GLHS. If RS is diagnosed the clinical signs of GLHS should be sought. The diagnosis of GLHS can only be made by the combination of the typical dysmorphic signs and neuroimaging in the neonatal period, but not prenatally.


Development of a differentiated microtubule structure: formation of the chicken erythrocyte marginal band in vivo.
The microtubules of mature nucleated erythrocytes are organized into a marginal band that is confined to a single plane at the periphery and that contains essentially the same number of microtubule profiles in each individual cell. Developing erythrocytes can be isolated in homogeneous and synchronously developing populations from chicken embryos. For these reasons, these cells offer a particularly accessible system for study of the pathway leading to a specific microtubule structure in a normal, terminally differentiated animal cell. Along this developmental course, striking changes occur in the properties of the microtubules. Between the postmitotic cell and the formation of the band, a novel arrangement is found: bundles of laterally associated microtubules in each cell, coursing through the cytoplasm but not confined to the periphery. The microtubule organizing centers evident at early stages disappear by the time the band forms. The microtubules in early cells are readily depolymerized by drugs, but that drug sensitivity is lost in the mature cells. The microtubule arrangement of mature cells is faithfully recapitulated after reversible depolymerization, while that of the immature cells is not. Finally, as the band forms, the microtubules and microfilaments increasingly become coaligned. In sum, the microtubules of immature cells have many properties in common with those of cultured cells, but during maturation those properties change. The results suggest that lateral interactions become increasingly important in stabilizing and organizing the microtubules. The properties of marginal band microtubules, and comparable properties of axonal microtubules, may reflect differences between the requirements for cytoskeletal structures of cycling cells and terminally differentiated cells.


Developing a Reliable Core Stability Assessment Battery for Patients with Nonspecific Low Back Pain.
Test-retest design. The objective was to examine the intrarater (test-retest) reliability of the core stability related tests and to develop a reliable core stability assessment battery. Studies suggest that core stability exercises may improve function and decrease pain in patients with nonspecific low back pain (LBP). Reliable clinical tests are required to implement adequate rehabilitation and to evaluate results of these interventions. The study had a test-retest design. Thirty-three different tests that might relate to core stability were identified with their mostly used protocols. Five different components of core stability including endurance, flexibility, strength, functional performance, and motor control were assessed in 38 patients with nonspecific LBP. The same testing procedure was performed again after 48 to 72 hours. Intraclass correlation coefficients (ICCs), standard error of measurement, and minimal detectable change were calculated to assess the intrarater reliability. The intrarater reliability of the tests ranged from little to very high (ICC = 0.08-0.98). Partial curl-up (ICC = 0.90), lateral bridge (ICC = 0.95-0.96), trunk flexor endurance (ICC = 0.97), sit and reach (ICC = 0.98), single-legged hop (ICC = 0.98-0.97), lateral step-down (ICC = 0.93-0.92), eyes open right and left leg unilateral stance (ICC = 0.97 and 0.91) tests had the highest intrarater reliability for each core stability component. The results indicated that the partial curl-up test (strength), side bridge and trunk flexor tests (endurance), sit-and-reach test (flexibility), single-legged hop, and lateral step-down (functional), unilateral stance test with eyes open (motor control) had very high intrarater reliability. A core stability assessment battery involving these tests can be used in patients with nonspecific LBP to assess all components of core stability. 3.


Instrumental aspects of synchrotron XUV spectroscopy.
Electron synchrotrons are becoming increasingly important as sources of extreme uv radiation for physical experiments. The NBS 180-MeV machine has been utilized for gas absorption studies over a four-year period, during which a 3-m grazing incidence spectrograph and monochromator have been designed, constructed and put into operation. The instruments are extremely stable to vibration and temperature variation, and are operating with a slit limited resolution of the order of 0.06 A. The design principles and features of these instruments are described, and a highly successful prealignment procedure for grazing incidence spectrometers is outlined. The effect of the unusual characteristics of this light source on the illumination and performance of the spectroscopic instruments is discussed.


Binary polarization modulator: a simple device for switching light polarization between orthogonal states.
A simple binary polarization modulator is described that periodically switches the polarization of a monochromatic light beam between orthogonal linear, circular, or elliptical states. It consists of a synchronously rotating disk whose planar surface is divided into annuli. Each annulus is segmented by radial lines into sectors, and each sector is coated by a thin film that reflects light of only one of two orthogonal states. Multiple annuli may be used for multiple-wavelength operation. Although a single layer is adequate to achieve the desired effect, multilayers would be required for higher performance standards.