Cigarette use and the estimation of lung cancer attributable to radon in the United States.
Residential exposure to radioactive radon and its decay products has been estimated to account for 10-12% of all lung cancer deaths in the U.S. It has been difficult to evaluate fully the impact of cigarette smoking, the most important cause of lung cancer, on this estimate, because factors for patterns of tobacco use have not been included in the risk models, since risk models are derived from studies of underground miners exposed to radon and detailed data on smoking are limited. Lung cancer risk estimates for exposure to radon progeny in smoker and non-smoker populations are obtained by applying the same risk model to each population group, thereby assuming the joint effects of smoking and exposure to radon progeny are multiplicative. However, in miners, joint relative risks (RR) for the two exposures are most consistent with an intermediate relationship between multiplicative and additive, so that the present approach likely results in an overestimate of risk in smokers and an underestimate of risk in nonsmokers. Lubin et al. (National Institutes of Health Publication No. 94-3644, 1994) present an ad hoc approach for adjusting risk models to incorporate smoking status. The approach is based on the relative magnitude of the effects of radon progeny in smokers and nonsmokers and therefore may not be applicable to non-miner populations if the proportion of smokers and the RR for smoking differ. We show that the modification can be derived explicitly by assuming an arithmetic mixture model for the joint RR for smoking and exposure to radon progeny. In this way, smoking parameters in the population of interest (the proportion of smokers and the RR of smoking) can be used directly to adjust radon progeny risk models and obtain risk estimates that are specific for smokers and nonsmokers. With an intermediate RR relationship for smoking and radon progeny, the attributable percentage of lung cancer deaths from residential radon may be twofold greater in non-smokers than in smokers.


Neuropathy following bariatric surgery.
Bariatric surgery is an increasingly common procedure for weight control and is associated with neurologic complications, including disorders of the peripheral nerve. The clinical features of these disorders, steps to take to prevent them, and their prognosis are discussed in this article.


Biosynthesis of the 09 antigen of Escherichia coli. Core structure of rfe mutant as indication of assembly mechanism.
The chemical structure of the outer (hexose) regions of the core oligosaccharide from Escherichia coli 09 with the complete R1 core, and from a R1-derived rfe mutant were analyzed using compositional analysis, methylation and gas chromatography/mass spectrometry. It was found that, in contrast to the branched outer region of the R1 core, the outer region of the core from the rfe mutant lacked terminal glucose and was linear. These results are in agreement with recent findings on the biosynthesis of the 09 antigen. They suggest a cotransfer of glucose with the 09-specific mannan to a 'pre-core' lacking terminal glucose, as the assembly (translocation) step in the 09 antigen synthesis. Thus it is suggested that the initiation of O-chain synthesis (by the formation of an acceptor glucolipid ) and the termination of core synthesis are closely correlated. In conjunction with previous biochemical data, the analytical results presented here indicate a novel core synthesis.


Conducting research into hidden or hard-to-reach populations.
To explore the problems involved in conducting research with populations that are hidden or hard to reach, and to suggest strategies to recruit participants. Conducting research with populations that are hidden or hard to reach can pose problems. Recruitment is, by definition, difficult and it is impossible to determine if participants are representative of these populations. Nevertheless, it is important to extend research strategies to include such groups, particularly when developing targeted services. This methodological paper draws on a research study undertaken as part of the author's doctoral studies, in which seven men aged 16-20 years old took part in semi-structured interviews. Several factors make research with populations that are hidden and hard to reach difficult, yet information from such populations is essential in identifying strategies that address the needs of the population as a whole. Researchers should adopt methods that allow them to engage with, rather than exclude, these populations, but this requires a critical acknowledgement and evaluation of the potential limitations of the chosen strategies. Problems with sampling must be examined and discussed. Well-evaluated but limited research data are preferable to no information from groups that are hidden and hard to reach. IMPLICATIONS FOR RESEARCH OR PRACTICE: Engaging these populations in research can further professionals' understanding of service provision.


The role of computed tomography in the management of testicular teratoma.
CT scans of the lungs, mediastinum and abdomen have been performed in 65 patients with malignant teratoma between August 1977 and June 1978. CT is superior to conventional radiology in detecting pulmonary metastases and mediastinal lymphadenopathy. It is a valuable technique for defining the full extent of para-aortic nodal disease and provides more information than lymphography alone. In this series sequential CT scans have been used to monitor treatment response to detect relapse and to assess operability of demonstrable residual disease.


The spontaneous clearance of hepatitis E virus (HEV) and emergence of HEV antibodies in a transfusion-transmitted chronic hepatitis E case after completion of chemotherapy for acute myeloid leukemia.
A 64-year-old woman was infected with hepatitis E virus (HEV) during chemotherapy for leukemia. By retrospective analyses of stored serum from the blood products and the patient, the source of the infection was determined to be platelet concentration (PC) transfused during chemotherapy. The partial nucleotide sequence of the HEV strain isolated from the donated PC and that from the patient's sera was identical and was subgenotype 3b. Clinical indicators such as alanine aminotransferase, HEV RNA titer, and anti-HEV antibodies in the serum were investigated from the beginning of the infection until 1 year after the termination of HEV infection. HEV RNA had propagated over 6 months and then cleared spontaneously after the completion of chemotherapy. Anti-HEV antibodies appeared in the serum just before the clearance of HEV RNA. Interestingly, HEV RNA was detected in the patient's urine, spinal fluid, and saliva. The HEV RNA titers in those samples were much lower than in the serum and feces. No renal, neurological, or salivary gland disorders appeared during the follow-up. We observed virological and biochemical progress and cure of transfusion-transmitted chronic hepatitis E in the patient despite an immunosuppressive status during and after chemotherapy against hematological malignancy.


Search for long-lived particles decaying into electron or photon pairs with the D0 detector.
In this Letter we report on a search for long-lived particles that decay into final states with two electrons or photons. Such long-lived particles arise in a variety of theoretical models, such as hidden valleys and supersymmetry with gauge-mediated breaking. By precisely reconstructing the direction of the electromagnetic shower we are able to probe much longer lifetimes than previously explored. We see no evidence of the existence of such long-lived particles and interpret this search as a quasi model-independent limit on their production cross section, as well as a limit on a long-lived fourth generation quark.


A conserved membrane-spanning amino acid motif drives homomeric and supports heteromeric assembly of presynaptic SNARE proteins.
Assembly of the SNARE proteins synaptobrevin/VAMP, syntaxin, and SNAP-25 to binary and ternary complexes is important for docking and/or fusion of presynaptic vesicles to the neuronal plasma membrane prior to regulated neurotransmitter release. Despite the well characterized structure of their cytoplasmic assembly domains, little is known about the role of the transmembrane segments in SNARE protein assembly and function. Here, we identified conserved amino acid motifs within the transmembrane segments that are required for homodimerization of synaptobrevin II and syntaxin 1A. Minimal motifs of 6-8 residues grafted onto an otherwise monomeric oligoalanine host sequence were sufficient for self-interaction of both transmembrane segments in detergent solution or membranes. These motifs constitute contiguous areas of interfacial residues assuming alpha-helical secondary structures. Since the motifs are conserved, they also contributed to heterodimerization of synaptobrevin II and syntaxin 1A and therefore appear to constitute interaction domains independent of the cytoplasmic coiled coil regions. Interactions between the transmembrane segments may stabilize the SNARE complex, cause its multimerization to previously observed multimeric superstructures, and/or be required for the fusogenic activity of SNARE proteins.


The biological and clinical impact of inhibition of NF-κB-initiated apoptosis in diffuse large B cell lymphoma (DLBCL).
NF-κB is frequently over-expressed in a variety of non-Hodgkin's lymphomas (NHLs) and has been implicated in lymphomagenesis; however, its role in diffuse large B cell lymphoma (DLBCL) as a prognostic biomarker has not been fully elucidated. Therefore, we investigated the role of NF-κB and its association with clinicopathological features in a tissue microarray cohort of 230 DLBCL patient samples. We then elucidated the role of NF-κB inhibition on cell viability and apoptosis in vitro, using DLBCL cell lines. Using immunohistochemistry, NF-κB was detected in 25.6% (52/203) DLBCL tumours, was associated with activated B cell (ABC) phenotype (p = 0.0054), Epstein-Barr virus (EBV; p = 0.0080) and over-expression of the anti-apoptotic marker XIAP (p = 0.0013). DLBCL cases with nuclear expression of NF-κB showed a significantly poorer overall survival as compared to those without NF-κB expression (p = 0.0236). In a multivariate analysis using a Cox proportional hazard model for IPI and NF-κB expression, the relative risk was 2.97 for high NF-κB expression (95% CI 1.27-6.94; p = 0.0113) and 7.55 for the high-IPI group (95% CI 3.34-18.35; p < 0.0001). In vitro, Bay 11-7085 inhibited constitutively active NF-κB expression in a dose-dependent manner and inhibition of NF-κB also down-regulated expression of the downstream target gene products Bcl-2, Bcl-XL (BCL2L1), XIAP and Survivin, leading to apoptosis via activation of the mitochondrial apoptotic pathway. NF-κB over-expression was found to be an independent prognostic marker for poor survival in DLBCL. Altogether, these results suggest that NF-κB may be a useful prognostic biomarker and a potential target for therapeutic intervention in DLBCL.


Exposure to antiepileptic drugs in pregnancy: The need for a family factor framework.
Children exposed to antiepileptic drugs (AEDs) in utero are at risk for developmental problems. Maternal epilepsy, its impact on the family system, and other family factors may also contribute. We reviewed the possible associations between family factors and developmental outcome in children who had been exposed to AED during pregnancy. We conducted a narrative review and searched MEDLINE, Embase, Google Scholar, and PsycINFO on the following terms: in utero exposure, pregnancy outcome, and AEDs. A family factor framework (the ABCX model) served as the basis to review distinct family factors in children who were exposed to AEDs in pregnancy. Few studies have investigated these factors. Mothers with epilepsy have problems caring for themselves and for the child and experience more parenting stress. There is a paucity of studies of the possible impact of family factors on the neurocognitive and behavioral development of children of mothers with epilepsy. Further work is required to ascertain which family factors are associated with child development in addition to the effects of AED exposure and their potential interaction. As epilepsy may have considerable impact on intrafamily factors and as children are especially vulnerable to such effects, study designs incorporating family factors should be encouraged.


Inter-individual difference in pupil size correlates to suppression of melatonin by exposure to light.
There are large inter-individual differences in pupil size and suppression of melatonin by exposure to light. It has been reported that melatonin suppression by exposure to light increases when pupils are pharmacologically dilated. However, the correlation between normal inter-individual difference in pupil size and melatonin suppression by exposure to light is not clear. Twenty-three healthy male subjects (22.6+/-2.7 years old) were exposed to light (1000 lx) for 2 h at night. The starting time of exposure to light was set to the ascending phase of melatonin concentration of each subject. Pupil area and saliva melatonin concentration were measured before exposure to light under dim light (15 lx) and during exposure to light. There were large inter-individual differences in melatonin suppression and pupil area. The mean and standard deviation of percentage of melatonin suppression 2 h after exposure to light was 57.2+/-22.1%. The mean and standard deviation of pupil areas before and 2 h after exposure to light were 30.7+/-7.9 mm2 and 15.9+/-4.8 mm2, respectively. The percentage of melatonin suppression by light was positively correlated with pupil area during light exposure (r=0.525, p<0.02). Interestingly, it was also correlated with pupil area measured before exposure to light, under dim light (15 lx) (r=0.658, p<0.001). These results suggest that inter-individual difference in pupil area positively correlates with melatonin suppression by light and that pupil area under dim light is a predictor of inter-individual differences in melatonin suppression by light.


[Flunitrazepam-fentanyl for the intracavitary placement of pacemakers].
Eight hundred pacemaker have been placed under general anaesthesia associating flunitrazepam-fentanyl, with a good comfort and safety for those patients old and often weak.


A pilot study to identify developmental delay in children in underserved urban community child care settings.
Children in underserved community child care were examined to determine the frequency of and a method to identify developmental delay. Initially, during daily experiential observations, child care providers at four urban community centers identified children with or at-risk-for developmental delay. Through the administration of the Denver II screening tool the project directors, an occupational therapist and a physical therapist, confirmed or rejected child care providers' concerns. The frequency of developmental concerns in this sample of 95 children was higher than reported in the general population. The reliability between child care providers' at-risk identification of children and therapists' "Suspect" results of children on the Denver II was remarkably high. This pilot study examines a method that can be implemented in community settings to support the early identification of children with possible developmental delay and to increase access to early intervention and early childhood services.


Transurethral resection syndrome from extravascular absorption of irrigating fluid.
An analysis was made of the clinical course of 20 transurethral resections of the prostate performed under epidural analgesia in which between 676 and 3,600 ml of irrigating fluid containing glycine had been absorbed by the extravascular route. Symptoms consisted in arterial hypotension (n = 14), postoperative oliguria (n = 11), nausea (n = 10), bradycardia (n = 7), abdominal discomfort (n = 5) and visual disturbances (n = 2). There was a significant correlation between hypotension and postoperative oliguria. The hyponatraemia at the end of the operation was only one third of the values obtained if the same amount of irrigating fluid had been absorbed by the intravascular route. Suprapubic drainage of the absorbed fluid (n = 8) did not reduce the hyponatraemia and prolonged the postoperative stay in hospital. Diuretics is an alternative to surgical drainage in all but the most severe cases of extravasation, but should be postponed until normovolaemia is restored and the circulation is stable.


Periodontal status of buccally and palatally impacted maxillary canines after surgical-orthodontic treatment with open technique.
This study investigated differences in periodontal health variables between buccally impacted maxillary canines (BIMC) and palatally impacted maxillary canines (PIMC) after surgical-orthodontic treatment with open technique. Nineteen patients were enrolled: 10 with unilateral BIMC (5 men, 5 women; mean age 18.50 ± 1.96 years) and 9 with unilateral PIMC (4 men, 5 women; mean age 19.44 ± 2.40 years). Probing depth and keratinized tissue were recorded 12 months after surgical-orthodontic treatment, and the differences between the 2 sides were analyzed as primary outcomes. In addition, data for BIMC and PIMC were directly compared. In the BIMC group, probing depths were significantly higher for lateral incisors than for the untreated side (P = 0.044), and keratinized tissue values were significantly lower for canines than for the untreated side (P = 0.006). No significant differences were observed in the PIMC group. In BIMC, surgical-orthodontic treatment with open technique resulted in loss of periodontal keratinized tissue in the treated tooth and periodontal attachment loss in adjacent lateral incisors. However, the periodontal status of PIMC was not affected by surgical-orthodontic treatment with open technique.


Induction of CD8+ regulatory T cells in the intestine by Heligmosomoides polygyrus infection.
This study determined whether Heligmosomoides polygyrus induces intestinal regulatory T cells. Splenic T cells proliferate strongly when cultured with anti-CD3 and antigen-presenting cells (APC). Lamina propria T cells from mice with H. polygyrus mixed with normal splenic T cells from uninfected mice inhibited proliferation over 90%. Lamina propria T cells from mice without H. polygyrus only modestly affected T cell proliferation. The worm-induced regulatory T cell was CD8+ and required splenic T cell contact to inhibit proliferation. The regulation also was IL-10 independent, but TAP-dependent, suggesting that it requires major histocompatibility complex (MHC) class I interaction. Additional studies employed mice with transgenic T cells that did not express functional TGF-beta receptors. The lamina propria T regulator inhibited proliferation of these transgenic T cells nearly 100%, suggesting that TGF-beta signaling via the T cell was not required. CD8+ T cells were needed for worms to reverse piroxicam-induced colitis in Rag mice (T and B cell deficient) reconstituted with IL-10-/- T cells. Thus H. polygyrus induces a regulatory CD8+ lamina propria T cell that inhibits T cell proliferation and that appears to have a role in control of colitis.


Advances in anterior cruciate ligament surgery.
The anterior cruciate ligament is the most frequently torn ligament in the knee. Diagnosis of cruciate ligament tears is often a difficult task. Tests typically used in diagnosis are the anterior drawer test, Lachman's test, pivot shift test, and the flexion rotation drawer. Arthroscopy has increasingly become the standard for the diagnosis of anterior cruciate ligament tears. Management of these tears has been controversial. The diagnostic techniques are discussed and a surgical technique is described for anterior cruciate ligament reconstruction as an outpatient procedure. The middle one-third of the patellar tendon is used as a graft, harvested subcutaneously, and fixed with interference fit screws. The postoperative function of anterior cruciate ligament deficient knees has been quite satisfactory. Morbidity is decreased relative to open surgical inpatient procedures. Finally, overall cost to the patient has been significantly reduced.


Methodological issues in the identification of hip fractures using routine hospital data: a database study.
The proportion of the population over the age of retirement has risen in many countries, and this means there is a corresponding rise in the incidence of hip fractures. However, in order to reliably investigate the ability of interventions to prevent fracture, there needs to be a reliable measure of the incidence of hip fracture. The purpose of this study was to examine the inclusion and exclusion criteria used to identify hip fracture from hospital admission data and to examine the impact that these criteria have on estimated incidence of hip fracture. We examine the influence of: individual compared to consultant episode data; primary data compared to any diagnosis of hip fracture; emergency compared to elective admissions; and the influence of type and rate of surgery on incidence estimates. The results showed that classifying hip fractures by use of consultant episodes overestimated the rate of hip fracture by 6-31%, and this overestimation has increased in recent years. The use of primary diagnosis as opposed to any diagnosis underestimates hip fracture by 5%. Two percent (2%) of the people studied had an operation for a hip fracture but did not have a hip fracture diagnosis (many had a multiple fracture diagnosis), and 5.5% of the people studied had an elective admission for the hip fracture (perhaps falling in hospital during an elective admission). We conclude that the selection criteria can have a great influence on the number of hip fractures identified using routine data. There should be a standardized selection procedure for the identification of hip fracture, as this would enable interventions and preventive measures to be evaluated over time and facilitate comparisons of rates in different regions and countries, in order to examine factors associated with hip fracture.


Identification of estrogenic/anti-estrogenic compounds in diesel exhaust particulate extract.
Diesel exhaust particulate extract (DEPE) was obtained from diesel exhaust particulates with Soxhlet extraction using dichloromethane. After separating DEPE into 11 fractions by liquid-liquid extraction, the neutral fraction (N) showed anti-estrogenic activity and the weak acid (phenol) fraction (WA(P)) showed estrogenic and anti-estrogenic activities by a yeast two-hybrid assay system expressing human estrogen receptor alpha. Both fractions were thoroughly fractionated by silica gel column chromatography and reversed-phase HPLC. In the WA(P) fraction, 3-methyl-4-nitrophenol and 2,6-dimethyl-4-nitrophenol were identified by LC-MS/MS as estrogenic compounds. This is the first study to identify 2,6-dimethyl-4-nitrophenol in DEPE and the first study to show that it is an estrogenic compound. In the N fraction, 1-hydroxypyrene was also identified by LC-MS/MS as an anti-estrogenic compound.


Regulators of G-protein signaling 2 and 4 differentially regulate cocaine-induced rewarding effects.
There is a need to identify new therapeutic targets for the treatment of cocaine addiction due to the rise in cocaine abuse and deaths due to cocaine overdose. Regulator of G protein signaling (RGS) proteins such as RGS2 and RGS4 are widely distributed in brain regions that play a role in drug reward. Importantly, RGS2 and RGS4 negatively regulate G-protein coupled receptor signaling pathways of monoaminergic neurotransmitters that play a role in the rewarding effects of cocaine by enhancing the rate of hydrolysis of Gα-bound guanine nucleotide triphosphate. Thus, the objective of this study was to investigate the effects of cocaine on conditioned place preference (CPP) and locomotor activity in mice that lacked either RGS2 or RGS4 (i.e. knockout (KO) mice) and their wildtype (WT) littermates. Moreover recent studies have reported influence of sex on RGS functioning and hence studies were conducted in both male and female mice. Cocaine-induced CPP was attenuated in male, but not female RGS4 KO mice compared to respective RGS4 WT mice. Cocaine-induced CPP was not influenced by deletion of RGS2 in either male or female mice. Similarly, cocaine-induced locomotor activity was not influenced by deletion of either RGS2 or RGS4 irrespective of sex. Together, the data indicate that the rewarding effects of cocaine were attenuated in the absence of RGS4 expression, but not in the absence of RGS2 expression in a sex-dependent manner. Importantly, these data suggest that RGS4 can serve as a potential target for medications that can be used to treat cocaine addiction.


Anti-apolipoprotein A-1 autoantibodies are associated with immunodeficiency and systemic inflammation in HIV patients.
To determine the existence of autoantibodies against apolipoprotein A-1 (anti-apoA-1 IgG) in HIV patients and explore their association with biological features of HIV infection and different inflammatory biomarkers. We also evaluated their impact on CD4+ lymphocytes survival. Anti-apoA-1 IgG plasma levels were assessed by ELISA in 237 HIV positive patients from a national prospective cohort with no current lipid-lowering therapy. 58% of patients were found positive for anti-apoA-1 IgG and were associated with lower CD4+ counts, but higher viremia and systemic inflammation. Logistic regression analyses indicated that high anti-apoA-1 IgG levels were associated with a 16-fold increased risk of displaying low CD4+ levels, independent of HIV RNA levels and treatment (adjusted Odds ratio [OR]:16.1, 95% Confidence Interval [95%CI]:1.80-143.6; p = 0.01), and a 6-fold increased risk of having a detectable viremia, independent of antiretroviral treatment (OR:5.47; 95% CI:1.63-18.36; p = 0.006). In vitro, anti-apoA-1 IgG induced dose and time-dependent CD4+ apoptosis that was increased by exposure to HIV RNA. In HIV patients, anti-apoA-1 IgG levels are associated with low CD4+ counts, high viremia and a pro-inflammatory systemic profile. Anti-apoA-1 IgG can promote CD4+ lymphocyte apoptosis via undefined pathways.


Coronary, peripheral and cerebrovascular disease: a complex relationship.
Atherosclerosis is a diffuse process that may affect different vascular beds with considerable overlap between coronary, cerebrovascular and peripheral arterial disease. These conditions are related to similar predisposing risk factors and genetic predisposition. Presence of atherosclerosis at one arterial site should prompt the clinician to assess for an involvement, symptomatic or asymptomatic, at other arterial distributions. Patients with peripheral or cerebrovascular disease often receive less than optimal secondary preventive therapy than those with coronary artery disease. It is imperative that these individuals with noncoronary atherosclerotic disease be also treated aggressively to reduce the high adverse cardiovascular event rate reported in these patients.


[Herd immunity and effectiveness of vaccination].
The effectiveness of vaccinations is discussed in relation to vaccine efficacy and effectiveness of vaccination programs. The types of epidemiological studies used in the assessment of vaccine effectiveness are presented, and most common sources of bias in such studies are listed. Basic formulas for calculation of vaccine effectiveness are given as applied for cohort and case-control studies. The definitions and ways of estimation of indicators of herd immunity as applied to the analysis of the effectiveness of vaccinations are presented.


The spectrum of systemic immune alterations after murine focal ischemia: immunodepression versus immunomodulation.
Therapeutic modification of the postischemic immune processes is a key target of current experimental stroke research. For successful translation into the clinical setting, experimental studies must account for the impact of different strokes on the immune system including susceptibility to infection. Herein, we characterize the impact of 3 ischemia models on systemic immunological and microbiological parameters. In C57Bl/6 mice (n=235), the middle cerebral artery was occluded (MCAO) either permanently by distal coagulation or transiently by an intraluminal filament for 30 minutes or 90 minutes. Differential leukocyte counts were performed in blood and lymphatic organs. Lymphocyte subpopulations and apoptotic cells were characterized by flow cytometry. Blood cytokine concentrations were measured by ELISA. Microbiological cultures were grown from blood and lung samples. Only extensive infarcts induced leukopenia 24 hours, 3 days and 7 days after MCAO and decreased lymphocyte counts in spleen, lymph nodes and thymus. In contrast, small infarcts led to no significant changes in differential blood count or reduction of overall cell counts in lymphatic organs. Splenic lymphocyte apoptosis and blood cytokine production was significantly increased after extensive lesions compared to mild ischemia. Hypothermia and weight loss occurred only in mice with large infarcts which also suffered from pneumonia and sepsis. In contrast to infarct size, location and side of the infarct did not affect physiological parameters and immune cell alterations. Postischemic systemic immunomodulation and infectious complications differ substantially among stroke models. Translational studies of immunomodulatory therapies for stroke must account for this heterogeneity.


Guaiol--a naturally occurring insecticidal sesquiterpene.
The dichloromethane fraction of Ferula ferulaeoides was analyzed by GC and GC-MS, and thirty-four compounds were identified. The main component in the fraction, guaiol (37.0%) was separated by chromatographic methods and identified from spectroscopic data, including 1H and 13C NMR, and X-ray crystallographic diffraction. Guaiol showed significant inhibition of aphids at a concentration of 70 mg/L. It also showed good contact activities against the 4th instar larvae of Mythimna separate and 3rd instar larvae of Plutella xylostella, with LD50 values of 0.07 and 8.9 mg/larva, as well as fumigation activity against the 4th instar larvae ofM. separata and adult Musca domestica, with LC50 values of 3.5 microL/L and 16.9 microL/L, respectively.


The premature infant's respiratory response to mechanical ventilation.
Comparisons of the components of ventilator waveform were made in two groups of preterm infants ventilated for the respiratory distress syndrome. Infants actively expiring against positive pressure inflation were compared to infants not showing this interaction. The actively expiring infants were ventilated with a higher peak inspiratory pressure (P less than 0.01) and a significantly greater duration of positive pressure plateau (P less than 0.05) than the control group. The two groups were well matched for gestational and postnatal age and there were no other significant differences in the components of ventilator waveform. Adoption of a ventilator waveform with a shorter positive pressure plateau and less steep rise in positive pressure might reduce the incidence of active expiration and hence pneumothoraces.


Physical models of size-dependent nanofilament formation and rupture in NiO resistive switching memories.
NiO films display unipolar resistance switching characteristics, due to the electrically induced formation and rupture of nanofilaments. While the applicative interest for possible use in highly dense resistance switching memory (RRAM) is extremely high, switching phenomena pose strong fundamental challenges in understanding the physical mechanisms and models. This work addresses the set and reset mechanisms for the formation and rupture of nanofilaments in NiO RRAM devices. Reset is described in terms of thermally-accelerated diffusion and oxidation processes, and its resistance dependence is explained by size-dependent Joule heating and oxidation. The filament is described as a region with locally-enhanced doping, resulting in an insulator-metal transition driven by structural and chemical defects. The set mechanism is explained by a threshold switching effect, triggering chemical reduction and a consequent local increase of metallic doping. The possible use of the observed resistance-dependent reset and set parameters to improve the memory array operation and variability is finally discussed.


Formation and resolution of brain edema associated with brain tumors. A comprehensive theoretical model and clinical analysis.
The purpose of this study is to quantify the relative contribution of the mechanisms in the absorption of edema fluid. The convection/diffusion and the comprehensive bulk flow model were applied for the finite element analysis of peritumoral brain edema. For clinical analysis, 90 meningiomas studied by MRI were selected. Serial CT scan and MRI were performed at 0, 2, 4, 6 hours after injection of Iopamidol or Gadpenteic acid respectively. Then the tracer distributions in the edematous brain was analyzed. The tracer movement in the brain is well represented by the convection/diffusion equation. The absence of the preferential fluid flow directing toward the ventricle indicates that a limited role of CSF sink action into the ventricle. From capillary surface area (240 cm2/g brain), capillary hydraulic conductivity (1.8 x 10(-8) ml/cmH2O/cm2/min) and the simulated average tissue pressure of 9.8 mmHg, maximum absorption rate into capillaries was estimated to be 0.003 ml/h/cm3 brain tissue. Considering the limited role of edema fluid clearance into the ventricle, the results indicate a possible role of subarachnoid CSF space for the clearance of edema fluid. The clearance of edema fluid into subarachnoid CSF space should be studied quantitatively. Finally, unification of the convection/diffusion and the comprehensive bulk flow model will provide a more quantitative analysis of edema formation and resolution by using MRI and tracer studies.


Extent and content of data for regulatory submissions: First-in-human and marketing authorization--Viewpoint of US industry.
The amount and type of data in regulatory submissions increases dramatically from the first-in-human clinical trials application through to the extensive dossier that is required for marketing authorization. The Pharmaceuticals and Biotechnology industries are very familiar with the requirements and expectations of Health Authorities for small molecule and biologics, but have limited experience for cell-based therapies. Fortunately, the United States Food and Drug Administration (FDA) and European Medicines agency (EMA) Committee for Advanced Therapies (CAT) have considerable experience in regulating cell therapies and have provided extensive Guidance documents for developers. The Agencies offers advice to Sponsors through a variety of meetings. However, it is incumbent on the Sponsor to understand the regulations, interpret the Guidance documents and formulate clear company positions to enable the Agency to provide clear feedback. It is important for Sponsors to understand the factors that are critical for the safety and efficacy of their product and to demonstrate to the Health Authorities that they have a control strategy that ensures safety and efficacy during all stages of development. The focus of this paper is to describe some of the challenges for the chemistry manufacturing and controls (CMC) for cell therapies being development internationally.


Seizure susceptibility to various convulsant stimuli of knockout interleukin-6 mice.
In the present study, the susceptibility of knockout interleukin-6 (IL-6(-/-)) mice to various convulsant stimuli has been evaluated and compared with other three related mice strains. Animals were treated with chemical convulsants impairing the gamma-aminobutyric acid neurotransmission [pentylenetetrazole (PTZ), picrotoxin, bicuculline, methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM), methyl-beta-carboline-3-carboxylate (beta-CCM)], enhancing glutamatergic neurotransmission [N-methyl-d-aspartate (NMDA), alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionate (AMPA) and kainic acid (KA)] or a K(+)channel blocker [4-aminopyridine (4-AP)]. The behavioural changes of such convulsant stimuli on IL-6(-/-) were observed and compared with those observed in C57, IL-6(+/+) and DBA/2 mice. The occurrence of clonic and/or tonic seizures was scored and statistically analysed to observe possible differences on seizure susceptibility. The IL-6(-/-) mice exhibited significantly higher seizure susceptibility to PTZ, beta-CCM, DMCM, NMDA, AMPA and KA than did the other mice strains, with the exception of DBA/2 mice. This study demonstrates that IL-6(-/-) mice possess an increased susceptibility to some convulsant stimuli. In particular, the major convulsant effects produced by NMDA, AMPA and KA suggest that the excitatory amino acid system is more active in the central nervous system (CNS) of IL-6(-/-) mice. The present data suggest that IL-6(-/-) mice might be a valid novel epileptic model for the study of pathophysiology and pharmacology of epileptic seizures.


Comparison of Bevacizumab and Ranibizumab in the Treatment of Type 1 Retinopathy of Prematurity Affecting Zone 1.
To investigate the effects of bevacizumab and ranibizumab in the treatment of type 1 retinopathy of prematurity (ROP) affecting zone 1. Files of the patients who received intravitreal bevacizumab (IVB) or ranibizumab (IVR) treatment for ROP affecting zone 1 were evaluated retrospectively. Spherical equivalent (SE) and axial length (AXL) measurements were performed at 1 year of adjusted age. Sixty-eight eyes of 37 patients were included in the study. All patients had initial disease regression but 6 patients (4 in the IVB, 2 in the IVR group) showed reactivation (p = 0.679). The number of eyes with incomplete vascularization were 15 and 12 in the IVB and IVR groups, respectively (p = 0.725). Mean AXL was 20.50 ± 0.99 mm in the IVB group and 19.30 ± 0.48 mm in the IVR group (p < 0.001). Mean SE was -1.49 ± 2.38 dpt in the IVB group and 0.98 ± 2.18 dpt in the IVR group (p < 0.001). Bevacizumab and ranibizumab showed similar effectiveness in the treatment of type 1 ROP affecting zone 1. The AXL was longer and SE was more myopic in eyes treated with IVB. This difference might be caused by the longer intravitreal half-life of bevacizumab than ranibizumab.


Public opinion about AIDS policies. The role of misinformation and attitudes toward homosexuals.
In an effort to better understand the cognitive and attitudinal factors underlying public opinion on AIDS-related issues, this article proposes and empirically tests a model of the relationships between (1) knowledge of HIV transmission, specifically the misinformation that AIDS can be transmitted easily through casual contact with HIV-infected persons; (2) attitudes toward homosexuals, the most prominent of the social groups presently affected by the AIDS crisis; and (3) support for restrictive public policies aimed at HIV-infected persons. Data from two nationally representative surveys conducted in December of 1985 (N = 2,308) and in July of 1987 (N = 2,095) provide evidence that misinformation about AIDS transmission and negative attitudes toward homosexuals are strong predictors of support for stringent restrictions of persons with AIDS. The findings also suggest that several background factors, in particular, education and political liberalism, may also play decisive roles in influencing levels of support for restricting those infected with the AIDS virus.


Assessment of the scope of practice of physicians participating in the Mais Médicos (More Doctors) Program, and associated factors.
The purpose of this study was to characterize the scope of practice of physicians working in primary healthcare participating in the Mais Médicos (More Doctors) Program ('PMM') and investigate the factors associated with execution of a larger number of clinical activities. It is an exploratory study carried over January to March 2016, through a self-applied questionnaire containing a list of 49 procedures, activities and actions carried out in primary healthcare. A total of 1,241 physicians took part in the study, most of them female, between age 40 and 49, and of Cuban nationality. The physicians carried out an average of 22.8 ± 8.2 procedures; they reported knowing how to carry out a larger number of procedures. Factors associated with executing a larger number of procedures were: being male, having graduated more recently, two years or less practicing in their primary healthcare unit, practicing in the North or South geographical regions, in small towns and more distant from the regional health headquarters. The main reason for not carrying out the procedures and activities that they reported knowing how to do was the lack of materials and inadequate infrastructure. The results show that the scope of practice of the physicians of the PMM is lower than their capacities, and that interventions with the intention of widening their scope are necessary.


Function and regulation of plant invertases: sweet sensations.
The disaccharide sucrose and the cleavage products glucose and fructose are the central molecules for carbohydrate translocation, metabolism and sensing in higher plants. Invertases mediate the hydrolytic cleavage of sucrose into the hexose monomers. Plants possess three types of invertases, which are located in the apoplast, the cytoplasm and the vacuole, respectively. It has become evident that extracellular and vacuolar invertase isoenzymes are key metabolic enzymes that are involved in various aspects of the plant life cycle and the response of the plant to environmental stimuli because their substrates and reaction products are both nutrients and signal molecules. Invertases, alone or in combination with plant hormones, can regulate many aspects of the growth and development of plants from gene expression to long-distance nutrient allocation and are involved in regulating carbohydrate partitioning, developmental processes, hormone responses and biotic and abiotic interactions.


Antiviral activity of some beta-diketones. 4. Benzyl diketones. In vitro activity against both RNA and DNA viruses.
The synthesis and in vitro antiviral evaluation of a series of substituted benzyl beta-diketones are described. The introduction of a styryl group onto the phenyl ring enhanced activity against herpesvirus type 2. The 4-methoxystyryl homologue 8 was evaluated extensively in vitro and was found to be effective against both RNA and DNA viruses. Compound 8 was evaluated in the mouse vagina against herpes simplex type 1 and produced a significant increase in survival rate as well as in survival time.


[Diagnostics and comprehensive treatment of patients with odontogenic lymphadenitis complicated by phlegmons].
The duthor detected special changes in oral liquid of macro and trace substances concentrations and their ratio in dynamics of convalescence for 24 patients with odontogenic lymphadenitis complicated by phlegmon. It was established that termination of inflammatory process on earlier terms at addition in complex treatment of this pathology of polyvitaminic complex considerably lowering strontium concentration in oral liquid (Patent RU 2210378 from 20.08.2003).


Solitary parathyroid adenoma: a rare cause of primary hyperparathyroidism in children.
Solitary parathyroid adenoma is a rare cause of primary hyperparathyroidism in children. We report the cases of four children, aged 7 to 14 years old, who presented with a variety of symptoms (growth retardation, glomerulonephritis, pathological fracture, mood swings). Diagnosis was based on clinical examination, imaging, and biochemical analysis. Treatment consisted of surgical excision of the adenoma. As diagnosis was delayed in all four patients, we recommend systematically checking serum calcium levels in children with certain nonspecific symptoms. Adenoma resection usually restores normal serum calcium levels and, hence, avoids further complications.


A cross-comparison of retrospective notes extraction and combined notes extraction and patient interview in the completion of a comorbidity index (ACE-27) in a cohort of United Kingdom patients with head and neck cancer.
Co-existent comorbidity is a major determinant of treatment outcome in head and neck cancer. Most of the work pertaining to this topic has been done in the United States, where the standard practice is for trained cancer registrars to grade comorbidity using validated indexes by retrospective notes review. The adult comorbidity evaluation-27 index (ACE-27) is a validated instrument that has been widely used in head and neck cancer. Although the required clinical data may be available in the notes, a significant amount of historical information is required to grade comorbidity. The aim of this study was to assess the accuracy and inter-rater reliability of the retrospective notes review process, in a typical setting in the United Kingdom (UK), by comparing the information obtained on notes review alone by a physician to that available after a structured patient interview. The study concludes that the retrospective notes review is an accurate and reliable technique for grading comorbidity whose completeness can be improved by the use of patient questionnaire as part of a structured interview.


Role of Stem Cells Transplantation in Tissue Regeneration After Acute or Chronic Acetaminophen Induced Liver Injury.
Acetaminophen-induced liver injury (APAP) is recognized as a frequent etiologic factor responsible for hepatic damage in the developed world. Management remains still elusive as treatment options are limited and their results are inconclusive. Consequently new strategies are explored at the experimental level. Mesenchymal stem cells (MSCs) present a promising modality as they can promote liver regeneration (LG) and compensate acute liver injury (ALI). Our research was focused on articles related to drug-induced liver injury, mechanisms of liver regeneration (LG) after Acute Liver Injury (ALI) and recent experimental protocols of Mesenchymal Stem Cells (MSCs) transplantation after chemical insult. All these studies are cited on Pubmed and MedLine. This review has three distinct sections. First recent developments in ALI pathogenesis are presented. The second section covers cellular pathways and histological findings relevant to liver regeneration. The final chapter analyzes MSCs transplantation protocols after ALI and interrelation between liver regeneration and hepatic differentiation of MSCs. Adipose tissue stem cells (ADSCs) and (MSCs) transplantation represents a promising modality in severe ALI management although many aspects remain to be clarified.


Potentially Inappropriate Antihypertensive Prescriptions to Elderly Patients: Results of a Prospective, Observational Study.
Previous studies of antihypertensive treatment of older patients have focused on blood pressure control, cardiovascular risk or adherence, whereas data on inappropriate antihypertensive prescriptions to older patients are scarce. The aim of the study was to assess inappropriate antihypertensive prescriptions to older patients. An observational, prospective multicentric study was conducted to assess potentially inappropriate prescription of antihypertensive drugs, in patients aged 75 years and older with arterial hypertension (HTN), in the month prior to hospital admission, using four instruments: Beers, Screening Tool of Older Person's Prescriptions (STOPP), Screening Tool to Alert Doctors to the Right Treatment (START) and Assessing Care of Vulnerable Elders 3 (ACOVE-3). Primary care and hospital electronic records were reviewed for HTN diagnoses, antihypertensive treatment and blood pressure readings. Of 672 patients, 532 (median age 85 years, 56% female) had HTN. 21.6% received antihypertensive monotherapy, 4.7% received no hypertensive treatment, and the remainder received a combination of antihypertensive therapies. The most frequently prescribed antihypertensive drugs were diuretics (53.5%), angiotensin-converting enzyme inhibitors (ACEIs) (41%), calcium antagonists (32.2%), angiotensin receptor blockers (29.7%) and beta-blockers (29.7%). Potentially inappropriate prescription was observed in 51.3% of patients (27.8% overprescription and 35% underprescription). The most frequent inappropriately prescribed drugs were calcium antagonists (overprescribed), ACEIs and beta-blockers (underprescribed). ACEI and beta-blocker underprescriptions were independently associated with heart failure admissions [beta-blockers odds ratio (OR) 0.53, 95% confidence interval (CI) 0.39-0.71, p < 0.001; ACEIs OR 0.50, 95% CI 0.36-0.70, p < 0.001]. Potentially inappropriate prescription was detected in more than half of patients receiving antihypertensive treatment. Underprescription was more frequent than overprescription. ACEIs and beta-blockers were frequently underprescribed and were associated with heart failure admissions.


Polarization-based and specular-reflection-based noncontact latent fingerprint imaging and lifting.
In forensic science the finger marks left unintentionally by people at a crime scene are referred to as latent fingerprints. Most existing techniques to detect and lift latent fingerprints require application of a certain material directly onto the exhibit. The chemical and physical processing applied to the fingerprint potentially degrades or prevents further forensic testing on the same evidence sample. Many existing methods also have deleterious side effects. We introduce a method to detect and extract latent fingerprint images without applying any powder or chemicals on the object. Our method is based on the optical phenomena of polarization and specular reflection together with the physiology of fingerprint formation. The recovered image quality is comparable to existing methods. In some cases, such as the sticky side of tape, our method shows unique advantages.


Glucagon fibril polymorphism reflects differences in protofilament backbone structure.
Amyloid fibrils formed by the 29-residue peptide hormone glucagon at different concentrations have strikingly different morphologies when observed by transmission electron microscopy. Fibrils formed at low concentration (0.25 mg/mL) consist of two or more protofilaments with a regular twist, while fibrils at high concentration (8 mg/mL) consist of two straight protofilaments. Here, we explore the structural differences underlying glucagon polymorphism using proteolytic degradation, linear and circular dichroism, Fourier transform infrared spectroscopy (FTIR), and X-ray fiber diffraction. Morphological differences are perpetuated at all structural levels, indicating that the two fibril classes differ in terms of protofilament backbone regions, secondary structure, chromophore alignment along the fibril axis, and fibril superstructure. Straight fibrils show a conventional beta-sheet-rich far-UV circular dichroism spectrum whereas that of twisted fibrils is dominated by contributions from beta-turns. Fourier transform infrared spectroscopy confirms this and also indicates a more dense backbone with weaker hydrogen bonding for the twisted morphology. According to linear dichroism, the secondary structural elements and the aromatic side chains in the straight fibrils are more highly ordered with respect to the alignment axis than the twisted fibrils. A series of highly periodical reflections in the diffractogram of the straight fibrils can be fitted to the diffraction pattern expected from a cylinder. Thus, the highly integrated structural organization in the straight fibril leads to a compact and highly uniform fibril with a well-defined edge. Prolonged proteolytic digestion confirmed that the straight fibrils are very compact and stable, while parts of the twisted fibril backbone are much more readily degraded. Differences in the digest patterns of the two morphologies correlate with predictions from two algorithms, suggesting that the polymorphism is inherent in the glucagon sequence. Glucagon provides a striking illustration of how the same short sequence can be folded into two remarkably different fibrillar structures.


Effect of alkalinisation of lignocaine for propofol injection pain: a prospective, randomised, double-blind study.
The aim of this study was to determine whether pretreatment with alkalinised lignocaine reduced the incidence and severity of pain during propofol injection. This prospective, randomised, double-blind study included 300 adult, American Society of Anesthesiologists physcial status I to II patients undergoing elective surgery. Patients were randomly allocated to one of three groups: Group L received 0.05 ml/kg of 1% lignocaine (5 ml normal saline + 5 ml 2% lignocaine), Group A received 0.05 ml/kg alkalinised lignocaine (5 ml 2% lignocaine + 1 ml 8.4% NaHCO3 + 4 ml normal saline), and Group S, the control group, was given the same amount of normal saline (NaCl 0.9%). All drugs were given as a bolus over 20 seconds before propofol administration. A blinded researcher assessed the patient's pain level using a four-point scale. The pain score [median (range)] and the incidence of pain in Group A (6%) was significantly lower than in groups L (41%) and S (88%, P <0.001). In addition, the pain score and the incidence of pain were found to be significantly different between Group L and Group S (P <0.001). The incidence of moderate and severe pain were greater in Group S when compared with groups A and L (P <0.001). Intravenous pretreatment with alkalinised lignocaine appears to be effective in reducing the pain during propofol injection.


[Postural changes in patients with visual deficits].
Balance is an active system allowing the body to maintain individual stability despite external stimuli. It relies on many senses which provide data to compensate for external variations such as visual information. It is thus necessary that the senses be in good condition and transmit accurate data. We wished to study postural adaptations made by visually impaired people. We performed a prospective study of patients with macular degeneration with visual acuity less than 20/40, glaucoma with a mean visual field defect less 12 decibels, and a control population. All subjects underwent a dynamic equilibrium test on a stabilometric platform with Win-Posturo software. We assessed their postural profile in various situations : eyes open, eyes closed, balance, anteroposterior displacement and lateral displacement. The first group consisted of 16 patients with age macular degeneration (AMD), the second of 17 patients with glaucoma and the third of 18 control subjects. In static equilibrium, for the parameter "length vs. surface area," all groups had an improvement in their performance with eyes open (P=0.05). There was a significant difference between the subject and control groups (P<0.01). In addition, subjects in the group with peripheral visual impairment had significantly greater tendency to lean forward. In dynamic equilibrium, we did not demonstrate any significant difference between the groups. In static equilibrium, patients with poor peripheral vision have better quality somatosensory compensation, but they have a tendency to lean forward, which increases the risk of falling forward. For the three groups, the tests showed that the subjects are vision-dependent, which implies that somatosensory compensation could be developed to limit this dependency. In dynamic equilibrium, the subjects in the disease groups perform significantly worse than the controls. All the visually impaired have a more developed somatosensory mechanism than the controls. The subjects in the first and third groups have the same postural profile, they are vision-dependent. Subjects in the second group have an instability and change in their postural strategy, increasing the risk of falling. Visual acuity has a lesser impact on the risk of falling than the visual field. Comparing postural responses in these different situations, it appears that postural profiles are modified in the case of visual disability, although the postural profile of the group with central visual loss is similar to that of the controls. Retinal involvement, whether central or peripheral, leads to postural imbalance that may result in falls in certain cases. To limit the prevalence of these falls, it would be interesting to address visually impaired patients by examination and postural rehabilitation to decrease the effects of this visual impairment.


How to study political activists: A petition survey approach.
A major challenge for social movement and political campaign studies is generating large, representative samples of political activists. This paper outlines a strategy of surveying those who participate in a common, baseline form of political action: signing petitions. Similar to protest surveys, signing a petition constitutes a more baseline low cost/low risk form of political activism. In 26 states in the U.S. petition lists are public record and, with modest effort, can be used to study a wide variety of issues, groups and campaigns. We outline the steps and costs involved in such a petition survey and how to improve response rate. To assess response bias, we compare demographic and political affiliation measures acquired from a marketing analytics company (Experian) for respondents and non-respondents to our survey of petition signers for two state-level initiative elections, finding only modest and interpretable response bias. The methods presented here have broader implications for survey research in general.


Establishment and characterization of conditionally immortalized astrocytes to study their interaction with ts1, a neuropathogenic mutant of Moloney murine leukemia virus.
The cytopathic infection of primary astrocytes with ts1, a neuroimmunopathogenic mutant of Moloney murine leukemia virus (MuLV), has been correlated to intracellular accumulation of viral precursor envelope protein gPr80env. To further study this specific virus-astrocyte interaction in a homogenous population, several immortal astrocyte lines were established from neonatal FVB/N mice using the temperature-sensitive SV40 tsA58 T antigen. These cells expressed glial fibrillary acidic protein, vimentin and T antigen; appeared nontransformed; were star-shape with long processes. They were susceptible to ts1 infection and suffered a cytopathic effect similar to that caused by ts1 infection of primary astrocytes. This cytopathic effect was characterized by growth inhibition, loss of cell processes and syncytium formation. Some cells also rounded up, formed mini cells and became detached from the culture dish. As in primary astrocytes, the processing of gPr80env in the immortalized astrocytes was inefficient. Since the envelope proteins interact with the ecotropic MuLV receptor both intracellularly and on the cell surface and since the receptor has been shown to be an arginine transporter, we attempted to determine the effect of ts1 on arginine uptake by these cells. Our results showed that in both immortalized and primary astrocytes, ts1 infection reduced the uptake of arginine more than did wild-type virus infection. Since arginine localizes predominantly in astrocytes in the CNS and has diverse functions, the decrease of arginine uptake in ts1-infected astrocytes may alter the metabolism of these cells, leading to impairment of their functions.


Mesenchymal stromal cell therapy for steroid-refractory acute and chronic graft versus host disease: a phase 1 study.
Steroid-refractory acute graft versus host disease (AGVHD) and chronic graft versus host disease (CGVHD) after allogeneic haematopoietic stem cell transplantation are major causes of morbidity and mortality. We undertook a phase I trial in patients with steroid-refractory AGVHD and CGVHD utilising bone marrow-derived mesenchymal stromal cells (MSC). Additionally, all refractory patients were treated with etanercept concomitantly. The primary end point was safety, and secondary end points were best response achieved and overall survival. A median of two infusions per patient were administered. The response rate overall for AGVHD was complete in seven, partial in four and no response in one patient. Of the seven patients who achieved a complete response, six are alive. The actuarial survival for the overall group of AGVHD was 55% at 30 months. Two patients with CGVHD achieved complete response with two partial responses and three with no response. The survival for those with AGVHD who achieved a complete response compared with those who did not was significant (p = 0.03). We identified no early or late safety issues in the nineteen patients. In view of the poor outlook for steroid-refractory AGVHD, further trials are warranted of MSC with steroid therapy, at the onset of AGVHD before steroid resistance.


The concurrence of Klinefelter syndrome and fragile X syndrome.
In this paper we report on a third patient with Klinefelter syndrome and fragile X. In the Leuven experience the simultaneous occurrence of both conditions is 1:155 (3 fra(X) positive Klinefelter patients in a total number of 465 fra(X) positive males), a concurrence much higher than expected by chance considering the frequency of both conditions.


Anesthesia Strategies and Perioperative Optimization for Patients with Ankylosing Spondylitis Undergoing Total Hip Replacement Surgery.
Objective To identify the characteristics of anesthesia and perioperative management for ankylosing spondylitis (AS) patients undergoing total hip arthroplasty (THA). Methods Totally 63 patients scheduled for single THA in PUMC Hospital from January 1st 2013 to June 1st 2015 were included in this retrospective analysis,among whom 21 patients were diagnosed of AS. The perioperative clinical data included:demographic data,American Society of Anesthesiologists (ASA) classification,medical history,airway assessment,preoperative laboratory examinations,electrocardiogram,pulmonary function tests,intubation information,operation time,intraoperative intake and output volume,postoperative hospital stay,and postoperative complications. Results Significantly fewer AS patients undergoing THA were evaluated as ASA classification I than non-AS patients (9.5% vs. 33.3%,P=0.041). AS patients had significantly higher level of preoperative high-sensitivity C-reactive protein [(17.0±14.8)mg/L vs.(4.3±7.1)mg/L,P<0.001],platelets [(275.0±71.3)×10(9)/L vs. (237.7±68.0)×10(9)/L,P=0.048] and neutrophils [(4.7±1.7)×10(9)/L vs. (3.9±1.4)×10(9)/L,P=0.044] and higher incidence of pulmonary function abnormality (42.9% vs.16.7%,P=0.024).More AS patients were induced with scoline (14.3% vs.0,P=0.012). More AS patients underwent THA with Mallampati classification 3 (28.6% vs.7.1%,P=0.022),reduced neck extension(47.6% vs.2.4%,P<0.001),Cormack-Lehane classification2(56.3% vs.15.4%,P=0.002)and 3 (18.8% vs.0,P=0.005),while much fewer AS patients had Cormack-Lehane classification1 (25.0% vs.84.6%,P<0.001).A variety of difficult airway tools were used in intubation (AS group:Macintosh laryngoscope:14%,Macintosh laryngoscope with stylet:38%,visualization laryngoscope:24%,visualization stylet:10% and fiber bronchoscope:14%;non-AS group:57%,24%,12%,5% and 2%,respectively). The use of intraoperative autologous blood transfusion (33.3% vs.11.9%,P=0.041) and postoperative 24 h drainage (61.9% vs.31.0%,P=0.019) were more common in AS group. However,no statistical difference existed in the success rate of first intubation,postoperative hemoglobin,postoperative hematocrit,and postoperative hospitalization(all P>0.05). Conclusions AS patients undergoing THA have elevated preoperative inflammatory markers,with high incidence of pulmonary function abnormality and difficult airway. In consideration of high risk of surgery and anesthesia,adequate airway evaluation and optimization of perioperative management are needed to ensure the patients' safety.


Impact of bulk cardiac motion on right coronary MR angiography and vessel wall imaging.
The purpose of this study was to investigate the impact of in-plane coronary artery motion on coronary magnetic resonance angiography (MRA) and coronary MR vessel wall imaging. Free-breathing, navigator-gated, 3D-segmented k-space turbo field echo ((TFE)/echo-planar imaging (EPI)) coronary MRA and 2D fast spin-echo coronary vessel wall imaging of the right coronary artery (RCA) were performed in 15 healthy adult subjects. Images were acquired at two different diastolic time periods in each subject: 1) during a subject-specific diastasis period (in-plane velocity <4 cm/second) identified from analysis of in-plane coronary artery motion, and 2) using a diastolic trigger delay based on a previously implemented heart-rate-dependent empirical formula. RCA vessel wall imaging was only feasible with subject-specific middiastolic acquisition, while the coronary wall could not be identified with the heart-rate-dependent formula. For coronary MRA, RCA border definition was improved by 13% (P < 0.001) with the use of subject-specific trigger delay (vs. heart-rate-dependent delay). Subject-specific middiastolic image acquisition improves 3D TFE/EPI coronary MRA, and is critical for RCA vessel wall imaging.


Uncoupling the functions of a multifunctional protein: the isolation of a DNA pilot protein mutant that affects particle morphogenesis.
Defective øX174 H protein-mediated DNA piloting indirectly influences the entire viral lifecycle. Faulty piloting can mask the H protein's other functions or inefficient penetration may be used to explain defects in post-piloting phenomena. For example, optimal synthesis of other viral proteins requires de novo H protein biosynthesis. As low protein concentrations affect morphogenesis, protein H's assembly functions remain obscure. An H protein mutant was isolated that allowed morphogenetic effects to be characterized independent of its other functions. The mutant protein aggregates assembly intermediates. Although excess internal scaffolding protein restores capsid assembly, the resulting mutant H protein-containing particles are less infectious. In addition, nonviable phenotypes of am(H) mutants in Su+ hosts, which insert non-wild-type amino acids, do not always correlate with a lack of missense protein function. Phenotypes are highly influenced by host and phage physiology. This phenomenon was unique to am(H) mutants, not observed with amber mutants in other genes.


[Perioperative parenteral nutrition. For whom? How?].
Preoperative artificial feeding (for 7 to 15 days) through an enteral or parenteral route is justified only in a subgroup of patients suffering form severe denutrition, who are scheduled for surgery with high morbidity or mortality. Postoperatively, the field of indication is broader, and it includes any patients who cannot soon feed themselves enough to catch their resting energy expenditure plus 20%. The administration route should use the technique with the lowest morbidity (enteral feeding) and the lowest costs. The role of new substrates (structured lipids, glutamine, trace elements) on immunity should be specified.


Management of refractory chylous ascites with peritoneovenous shunts.
The purpose of this study was to define outcome of treatments of refractory chylous ascites using peritoneovenous shunts (PVSs). Clinical data of patients with refractory chylous ascites treated with PVSs between 1992 and 2015 were retrospectively reviewed. The primary end point was clinical benefit, defined as cured, improved, or poor results; secondary end points were complications and reinterventions. Seventeen patients (eight female [47%]; median age, 47 years [range, 19-78 years]) with refractory chylous ascites were studied. This group represented 6% of 284 patients treated for chylous ascites during the study period. The etiology was primary lymphangiectasia in 10 patients (59%) and secondary chylous ascites due to previous surgery, lymphatic obstruction with associated portal hypertension, or malignant tumor in 7 (41%). Eleven patients were treated with LeVeen shunts and six with Denver shunts. Thirty-day mortality, morbidity, and reintervention rates were 5.9%, 18%, and 12%, respectively. Reintervention rate at 6 months was 9.1% with LeVeen shunt, significantly lower than 100% with Denver shunt (P = .001). During a mean follow-up of 5.1 years (range, 17 days-22.7 years), 7 of 11 patients with LeVeen shunt and all 6 patients with Denver shunt required shunt replacement. Median duration of patency was 215 days (range, 2 days-9.0 years) of a total of 25 LeVeen shunts placed in 11 patients and 44 days (range, 6-91 days) of 20 Denver shunts placed in 6 patients. At last follow-up, patency of the LeVeen shunt was 36% (4/11); symptoms improved in 64% of the patients (7/11). Patency rate of Denver shunts was 33% (2/6), and symptoms improved in 33% (2/6). Treatment of refractory chylous ascites continues to be a major challenge. The only currently available PVS, the Denver shunt, had a median patency period of <2 months; it required frequent replacements and resulted in intermittent short-term clinical benefit in one-third of the patients. Improvements in technology to design new shunts, to develop new therapies, or to adopt new techniques to treat chylous ascites are urgently needed.


Oxidized derivatives of dihydrobrassicasterol: cytotoxic and apoptotic potential in U937 and HepG2 cells.
The ability of phytosterol compounds to reduce plasma serum cholesterol levels in humans is well investigated. However, phytosterols are structurally similar to cholesterol with a double bond at the C5-6 position and are therefore susceptible to oxidation. Much research has been carried out on the biological effects of cholesterol oxidation products (COPs) in vitro. In contrast, there is less known about phytosterol oxidation products (POPs). From previous studies, it is apparent that oxidized derivatives of the phytosterols, β-sitosterol and stigmasterol, are cytotoxic in vitro but are less potent than their COP counterparts. In the present study, the cytotoxic and apoptotic potential of oxidized derivatives of dihydrobrassicasterol (DHB) including 5α,6α-epoxyergostan-3β-ol (α-epoxide), 5β,6β-epoxyergostan-3β-ol (β-epoxide), ergost-5-en-7-on-3β-ol (7-keto), ergost-5-ene-3β,7β-diol (7-β-OH), and ergostane-3β,5α,6β-triol (triol) were evaluated in the U937 and HepG2 cell lines. In general, 7-keto, 7-β-OH, and triol derivatives had a significant cytotoxic impact on U937 and HepG2 cells. The oxides appear to be more toxic toward U937 cells. In line with previous findings, the POPs investigated in this study were less potent than the equivalent COPs. The results add to the body of data on the toxicity of individual POPs.


Predictors of posttraumatic stress symptoms in childhood cancer survivors.
The diagnosis and treatment of childhood cancer are extremely stressful experiences, with psychological sequelae which can persist many years after the end of treatment. This study investigated the relative contributions of general anxiety, treatment intensity, medical sequelae of treatment, and the subjective appraisal of life threat and treatment intensity to later posttraumatic stress symptoms, such as intrusive memories, avoidance, and hypervigilance. One hundred eighty-six childhood cancer survivors ages 8 through 20 years, off of treatment for more than 1 year, and their parents completed questionnaires. Medical sequelae of treatment and intensity of treatment were rated by a pediatric oncologist. Significant, independent predictors of persistent posttraumatic stress symptoms included: 1) the survivor's retrospective subjective appraisal of life threat at the time of treatment, and the degree to which the survivor experienced the treatment as "hard" or "scary"; 2) the child's general level of anxiety; 3) history of other stressful experiences; 4) time since the termination of treatment (negative association); 5) female gender; and 6) family and social support. Mother's perception of treatment and life threat contributed to anxiety and subjective appraisal for the survivor, but did not independently contribute to posttraumatic stress symptoms. Symptoms of posttraumatic stress seem to decrease with time, but are persistent in a subset of childhood cancer survivors. Other than time and gender, the predictors of posttraumatic stress symptoms are primarily subjective factors (ie, anxiety and subjective appraisal) rather than objective stressors of treatment and medical sequelae.


CD8+ T cells rapidly acquire NK1.1 and NK cell-associated molecules upon stimulation in vitro and in vivo.
NKT cells express both NK cell-associated markers and TCR. Classically, these NK1.1+TCRalphabeta+ cells have been described as being either CD4+CD8- or CD4-CD8-. Most NKT cells interact with the nonclassical MHC class I molecule CD1 through a largely invariant Valpha14-Jalpha281 TCR chain in conjunction with either a Vbeta2, -7, or -8 TCR chain. In the present study, we describe the presence of significant numbers of NK1.1+TCRalphabeta+ cells within lymphokine-activated killer cell cultures from wild-type C57BL/6, CD1d1-/-, and Jalpha281-/- mice that lack classical NKT cells. Unlike classical NKT cells, 50-60% of these NK1.1+TCRalphabeta+ cells express CD8 and have a diverse TCR Vbeta repertoire. Purified NK1.1-CD8alpha+ T cells from the spleens of B6 mice, upon stimulation with IL-2, IL-4, or IL-15 in vitro, rapidly acquire surface expression of NK1.1. Many NK1.1+CD8+ T cells had also acquired expression of Ly-49 receptors and other NK cell-associated molecules. The acquisition of NK1.1 expression on CD8+ T cells was a particular property of the IL-2Rbeta+ subpopulation of the CD8+ T cells. Efficient NK1.1 expression on CD8+ T cells required Lck but not Fyn. The induction of NK1.1 on CD8+ T cells was not just an in vitro phenomenon as we observed a 5-fold increase of NK1.1+CD8+ T cells in the lungs of influenza virus-infected mice. These data suggest that CD8+ T cells can acquire NK1.1 and other NK cell-associated molecules upon appropriate stimulation in vitro and in vivo.


Enhanced detection of beta-galactosidase reporter activation is achieved by a reduction of hemoglobin content in tissue lysates.
beta-galactosidase (beta-gal), the product of the E. coli LacZ gene, has been used extensively as a reporter in numerous systems. Until recently, the most commonly used method of detecting beta-gal reporter enzymatic activity was a colormetric assay based on the cleavage of the beta-gal substrate 5-bromo-4-chloro-3-indolyl beta-D-galactopyranoside (X-gal) to form a blue precipitate. However, when increased sensitivity is needed, many investigators now turn to alternate substrates that produce fluorescent or luminescent products upon cleavage by beta-gal. These products are much more easily quantified than X-gal. The luminescent and fluorometric assays work very well in cultured cells but are often less sensitive in whole tissue lysates. In this study, we have evaluated the sensitivity of a fluorescent and a luminescent substrate in whole tissue lysates cleared of red blood cells or washed with PBS only. We have found that both assays show increased low-end sensitivity in tissues with reduced levels of hemoglobin (Hb). Hb is apparently able to quench luminescent and, to a lesser degree, fluorescent reporter light emission. Therefore, steps should be taken to reduce Hb levels either by lysis, perfusion, or both to enhance the sensitivity of these assays.


Developmental changes in mouse brain polyamine metabolism.
Mouse brain ornithine decarboxylase (ODC) activity is high at the time of birth, whereas S-adenosyl-L-methionine decarboxylase (SAM-DC) activity is low. ODC activity, and putrescine, spermidine and spermine concentrations decline rapidly during postnatal development to the low level characteristic of mature brains, while SAM-DC activity behaves in the opposite manner. The fluctuations in mouse brain polyamine metabolism are in accord with those found in the rat. The apparent Km values of ODC and SAM-DC for their substrates decline parallel with the decrease of substrate and product concentrations during ontogeny suggesting substrate and/or product dependent regulation of polyamine synthesis in the developing brain.


Regional requirements for Dishevelled signaling during Xenopus gastrulation: separable effects on blastopore closure, mesendoderm internalization and archenteron formation.
During amphibian gastrulation, the embryo is transformed by the combined actions of several different tissues. Paradoxically, many of these morphogenetic processes can occur autonomously in tissue explants, yet the tissues in intact embryos must interact and be coordinated with one another in order to accomplish the major goals of gastrulation: closure of the blastopore to bring the endoderm and mesoderm fully inside the ectoderm, and generation of the archenteron. Here, we present high-resolution 3D digital datasets of frog gastrulae, and morphometrics that allow simultaneous assessment of the progress of convergent extension, blastopore closure and archenteron formation in a single embryo. To examine how the diverse morphogenetic engines work together to accomplish gastrulation, we combined these tools with time-lapse analysis of gastrulation, and examined both wild-type embryos and embryos in which gastrulation was disrupted by the manipulation of Dishevelled (Xdsh) signaling. Remarkably, although inhibition of Xdsh signaling disrupted both convergent extension and blastopore closure, mesendoderm internalization proceeded very effectively in these embryos. In addition, much of archenteron elongation was found to be independent of Xdsh signaling, especially during the second half of gastrulation. Finally, even in normal embryos, we found a surprising degree of dissociability between the various morphogenetic processes that occur during gastrulation. Together, these data highlight the central role of PCP signaling in governing distinct events of Xenopus gastrulation, and suggest that the loose relationship between morphogenetic processes may have facilitated the evolution of the wide variety of gastrulation mechanisms seen in different amphibian species.


Rotationally induced fingering patterns in a two-dimensional heterogeneous porous medium.
Rotating fluid flows under two-dimensional homogeneous porous media conditions (or in a rotating Hele-Shaw cell) reveal the development of complex interfacial fingering patterns. These pattern-forming structures are characterized by the occurrence of finger competition events, finger pinch-off episodes, as well as by the production of satellite droplets. In this work, we use intensive numerical simulations to investigate how these fully nonlinear pattern growth phenomena are altered by the presence of permeability heterogeneities in the rotating porous medium. This is done by employing a diffuse-interface Darcy-Cahn-Hilliard description of the problem and considering a permeability field presenting a log-Gaussian distribution, characterized by a variance s and a correlation length l. We study how the heterogeneity measures s and l couple to the governing hydrodynamic dimensionless parameters of the problem and introduce important changes on the pattern formation dynamics of the system.


[Marfan syndrome and related connective tissue disorders].
Marfan syndrome is an autosomal dominantly inherited connective tissue disorder with a prevalence of approximately 1:5000 people. Typical manifestations affect the cardiovascular system, eyes, skeleton, lungs, skin and dura mater. Most patients have a so-called marfanoid habitus with tall stature, long and narrow limbs, a long and narrow head shape and other skeletal abnormalities. Of particular medical importance are the possible complications such as severe scoliosis or pectus excavatum, spontaneous pneumothorax, retinal detachment, or an acute glaucoma evoked by lens luxation. However, the most dangerous complication is acute dissection of the ascending aorta, which is usually the result of a slowly progressive aortic dilatation. With the introduction of therapies the average life expectancy of previously just 32 years could be raised to above 60 years.


Multifunctional magnetic hairbot for untethered osteogenesis, ultrasound contrast imaging and drug delivery.
To explore novel materials graded for biological functions is one of the grand challenges and ambitions of robotics. In this study, the design, development, and external guidance of micron-sized hair-derived robots (hairbots) are shown as autologous cargo carriers for guided drug delivery, untethered osteogenesis, and sonographic contrast agents. Having biogenic origin, the hairbots show excellent biocompatibility, as demonstrated with cell adhesion, spreading and proliferation. External magnetic fields are used to enhance differentiation of mesenchymal stem cells (MSCs) into bone like cells, which can be used as magnetic therapy for bone healing. Effect of external magnetic forces was simulated by COMSOL Multiphysics® modelling software. The action of hairbots as osteoconductive material triggering osteogenic differentiations of MSCs is studied via calcium signaling by fluorescence microscopy. Further, by exploiting the hollow medullary region, the proposed hairbots are designed to perform theranostic dual functions (therapy + diagnostic) - as Doxorubicin drug delivery vehicle, and for Ultrasound contrast imaging. Harnessing sensing and actuation due to magnetic capabilities of hairbots, for enhanced biological functionality shown herein, provides a novel material in the search of new multifunctional microrobots.


[The functional efficiency of cardiac pacemakers as affected by ionizing radiation].
Influence of functions of cardiac pace-makers by ionizing radiation are represented, that is characterized in praxis relevant parameters as pulse duration and sensitivity in a special clear manner. For these parameters dose limits were defined in a phantom where tolerance ranges of pace-makers, guaranteed by producer, were over or underdosed. These dose values were different in dependence of installed electronic wiring diagrams. The radioresistance of pace-makers with Lewicki-wiring diagram (MCP 211 L) was higher than those with wiring diagram U 115. Measurings showed that the upper dose limits were greater than the known values with 60Co- and 9-MV-roentgen braking radiation and with that the complete programming and functional capacity of the pace-makers were conserved. The close cooperation of radiologists, physicists, cardiologists and technicians in the implantation clinic guarantees a good care for patients with pace-makers during radiotherapy without complications.


Changes in crevicular fluid levels of interleukin-1 beta, leukotriene B4, prostaglandin E2, thromboxane B2 and tumour necrosis factor alpha in experimental gingivitis in humans.
We conducted a study to determine the sequence of cytokine and lipid mediator activation within the periodontium during the development of experimental gingivitis in humans. Crevicular fluid samples were collected from 7 previously cleaned, healthy patients at baseline, 1, 2, 3 and 4 weeks following the cessation of all oral hygiene measures. Gingival and plaque scores were taken at each visit to follow the development of gingivitis and plaque retention. Crevicular fluid samples were assayed in quadruplicate for prostaglandin E2 (PGE2), thromboxane B2 (TxB2), leukotriene B4, interleukin-1 beta (IL-1 beta) and tumour necrosis factor alpha (TNF alpha) by RIAs or ELISAs, maintaining site pairing to examine temporal changes. Redness scores (expressed as mean percentage of sites with redness present) increased almost linearly from a baseline value of zero to approximately 40% at 1 week, 59% at 2 weeks, 83% at 3 weeks and 100% at 4 weeks. The mean % of sites with bleeding on probing increased gradually from zero at baseline to 5% at 3 weeks and then rose abruptly to 25% at 4 weeks. CF-PGE2 and CF-TxB2 levels remained fairly stable at baseline levels for the first 3 weeks then rose sharply by 2.5- and 2-fold, respectively, at 4 weeks. CF-LTB4 levels increased 2-fold by 1 week and 4-fold by 4 weeks. The CF levels of IL-1 beta increased abruptly from mean baseline values of 16.5 +/- 9.3 ng/ml to 131 +/- 76.0 ng/ml at 1 week and remained at this level for the duration of the experiment.(ABSTRACT TRUNCATED AT 250 WORDS)


Human endometrial interleukin-6 (IL-6): in vivo messenger ribonucleic acid expression, in vitro protein production, and stimulation thereof by IL-1 beta.
To investigate human endometrial interleukin-6 (IL-6) expression and effects thereon by IL-1 beta. Prospective. Academic medical center. Endometrial biopsy specimens from normal volunteers (n = 20) at four specific menstrual stages were used for in vivo study. Endometrial specimens for in vitro study were obtained from patients (n = 19) undergoing gynecologic surgery. Time and dose-response treatment of endometria with IL-1 beta in tissue culture. In vivo IL-6 messenger RNA expression by Northern analysis and in vitro endometrial IL-6 protein production by assay of the conditioned media. Midsecretory and late secretory phase endometria expressed more IL-6 messenger RNA than late proliferative phase endometria in vivo. Similarly in vitro, in pg/mg endometrium per hour secretory endometria IL-6 protein production, 25.7 +/- 7.1 (mean +/- SEM), exceeded that of proliferative endometria, 4.7 +/- 1.0. With IL-1 beta treatment, secretory endometria IL-6 protein production exceeded that of proliferative endometria. Interleukin-1 beta stimulated endometrial IL-6 protein production in time- and dose-dependent manners. Human endometrial IL-6 expression varies with the menstrual cycle, occurs more highly in secretory endometria, and in vitro is stimulated by interleukin-1 beta. Human endometrial IL-6 may therefore mediate some actions of IL-1 beta involving the endometrium and trophoblast.


Estrogen receptor beta: the antimechanostat?
We have known for sometime that sex hormones influence the growth, preservation, and loss of bone tissue in the skeleton. However, we are only beginning to recognize how estrogen influences the responsiveness of the skeleton to exercise. Frost's mechanostat theory proposes that estrogen reduces the mechanical strain required to initiate an osteogenic response, but this may only occur at the endocortical and trabecular bone surfaces. The discovery of estrogen receptors alpha and beta may help us to understand the bone surface-specific effects of exercise. Findings from estrogen receptor knockout mice suggest that the activity of ERalpha may explain the positive interaction between estrogen and exercise on bone formation near marrow, that is, endocortical and trabecular bone surfaces. Estrogen inhibits the anabolic exercise response at the periosteal surface, and this we propose is due to the activation of ERbeta. Signaling through this receptor retards periosteal bone formation and suppresses gains in bone size and bone strength, and for these reasons it behaves as an antimechanostat.


Characteristic spectral features of the polarized fluorescence of human breast cancer in the wavelet domain.
Wavelet transform of polarized fluorescence spectra of human breast tissues is found to localize spectral features that can reliably differentiate normal and malignant tissue types. The intensity differences of parallel and perpendicularly polarized fluorescence spectra are subjected to investigation, since they are relatively free of diffusive background. A number of parameters, capturing spectral variations and subtle changes in the diseased tissues in the visible wavelength regime, are clearly identifiable in the wavelet domain. These manifest both in the average low-pass and high frequency high-pass wavelet coefficients.


Three-dimensional structure of adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase from Salmonella typhimurium determined to 2.3 A resolution,.
The X-ray structure of adenosylcobinamide kinase/adenosylcobinamide phosphate guanylyltransferase (CobU) from Salmonella typhimurium has been determined to 2.3 A resolution. This enzyme of subunit molecular weight 19 770 plays a central role in the assembly of the nucleotide loop for adenosylcobalamin where it catalyzes both the phosphorylation of the 1-amino-2-propanol side chain of the corrin ring and the subsequent attachment of GMP to form the product adenosylcobinamide-GDP. The kinase activity is believed to be associated with a P-loop motif, whereas the transferase activity proceeds at a different site on the enzyme via a guanylyl intermediate. The enzyme was crystallized in the space group C2221 with unit cell dimensions of a = 96.4 A, b = 114.4 A, and c = 106.7 A, with three subunits per asymmetric unit. The structure reveals that the enzyme is a molecular trimer and appears somewhat like a propeller with overall molecular dimensions of approximately 64 A x 77 A x 131 A. Each subunit consists of a single domain that is dominated by a seven-stranded mixed beta-sheet flanked on either side by a total of five alpha-helices and one helical turn. Six of the seven beta-strands run parallel. The C-terminal strand lies at the edge of the sheet and runs antiparallel to the others. Interestingly, CobU displays a remarkable structural and topological similarity to the central domain of the RecA protein, although the reason for this observation is unclear. The structure contains a P-loop motif located at the base of a prominent cleft formed by the association of two subunits and is most likely the kinase active site. Each subunit of CobU contains a cis peptide bond between Glu80 and Cys81 where Glu80 faces the P-loop and might serve to coordinate the magnesium ion of the triphosphate substrate. Interestingly, His46, which is the putative site for guanylylation, lies approximately 21 A from the P-loop and is solvent-exposed. This suggests that the enzyme undergoes a conformational change when the substrates bind to bring these two active sites into closer proximity.


Reproductive health effects and teratogenicity of antiepileptic drugs.
Women with epilepsy are less likely to bear children than women in the general population, and although this reduced fertility can be attributed in part to effects of the disease itself, the effects of antiepileptic drugs (AEDs), including changes in reproductive endocrine function, are also a factor. Conversely, some AEDs interact with oral contraceptives and can increase the risk for contraceptive failure and unplanned pregnancy. Women with epilepsy also have elevated rates of congenital anomalies and major malformations in their offspring, for which exposure of the developing fetus to AEDs taken by the mother appears to be responsible. In utero exposure to some AEDs may also be associated with increased risk for impaired cognitive function in the growing child. Clearly, possible long-term effects on reproductive health and pregnancy outcomes require careful attention when AED therapy is being considered for a patient with childbearing potential. Moreover, because AEDs are increasingly being used in therapy for other conditions such as migraine, bipolar disorder, and pain, it is not only the treatment of women with epilepsy that will be affected by these concerns.


Oral iron absorption in infantile protein-energy malnutrition.
The ability of infants with protein-energy malnutrition to absorb iron was assessed using the serum iron response to a dose of ferrous sulfate providing 3 mg elemental iron per kg body weight. Responses were grouped as flat (delta serum Fe less than 30 microgram/dl), intermediate (30 to 100 microgram/dl), and normal (greater the 100 microgram/dl). Of 25 consecutively admitted children studied, seven had a flat, five an intermediate, and 13 a normal curve (mean delta serum Fe: 10 microgram/dl, 66 microgram/dl, and 175 microgram/dl, respectively). There were no differences among the three groups in hematocrit, fasting serum iron or transferrin saturation, severity of malnutrition, or evidence of other malabsorption sufficient to explain these differences. Although hematocrits, fasting serum iron, and transferrin saturations did not change appreciably during nutritional rehabilitation, all children with initially abnormal responses subsequently had normal tests.


Recurrent urticaria as a rare manifestation of familial Mediterranean fever.
Familial Mediterranean fever (FMF) is a genetic disorder characterized by acute episodes of fever with some combination of severe abdominal pain, pleurisy, arthritis, and skin rash. The case of a patient with recurrent urticaria referred for study of drug allergy is presented. After allergy had been ruled out, the urticaria was attributed to previously undiagnosed symptoms of an underlying systemic disease: FME. Urticaria is the least frequent cutaneous manifestation of this disease, and genetic analysis was required to confirm the diagnosis.


A study of cognitive vulnerability-stress model of depressive symptoms among Chinese adolescents.
The objective of the present study is to test the validity of the integrated cognitive model of depression proposed by Kwon and Oei (1994) with a Chinese adolescent sample. A two-wave panel design was used. We hypothesized that the interaction between dysfunctional attitudes measured at time 1 and adolescents' negative life events experienced between times 1 and 2 would predict changes in the frequency of automatic thoughts between times 1 and 2. We further hypothesized that changes in the frequency of automatic thoughts would, in turn, predict changes in the severity of depressive symptoms. Participants were 329 Chinese adolescents. As a comparison, we tested three other competing models: linear mediation, alternative aetiologies and symptom models. All participants completed the Adolescent Self-Rating Life Events Checklist, Dysfunctional Attitudes Scale, Automatic Thoughts Questionnaire and Center for Epidemiological Studies Depression Scale on two occasions-5 months apart. Path analysis was used to test all models. Results of the path analysis indicated that the integrated cognitive model showed an adequate fit for the Chinese adolescent data. During phases of increased depression, dysfunctional attitudes were common cognitive moderators of depression, whereas automatic thoughts were specific cognitive mediators of depression.


What lies beneath? An evaluation of lower molar trigonid crest patterns based on both dentine and enamel expression.
The nearly ubiquitous presence of a continuous crest connecting the protoconid and metaconid of the lower molars (often referred to as the middle trigonid crest), is one of several dental traits that distinguish Homo neanderthalensis from Homo sapiens. This study examined variation in trigonid crest patterns on the enamel and dentine surfaces to (1) evaluate the concordance between the morphology of trigonid crests at the inner dentine and the outer enamel surfaces; (2) examine their developmental origin(s); and (3) examine trait polarity through comparison with Australopithecus africanus and Pan. The sample included 73 H. neanderthalensis, 67 contemporary H. sapiens, 5 A. africanus, and 24 Pan lower molars. Results indicate general agreement in the morphology observed on the dentine and enamel surfaces. All but one H. neanderthalensis molar shows some trigonid crest development, whereas trigonid crests occur in low frequency in contemporary humans. Pan and A. africanus both also show high frequencies of a continuous trigonid crest. However, the origin of the trigonid crest differs among groups. H. neanderthalensis uniquely possesses a 'middle' trigonid crest that originates from the mesial accessory ridge of one or both cusps. Based on our results we suggest that presence of a continuous middle trigonid crest at the dentine surface is primitive and the lack of any trigonid crest is derived. Genetic drift may explain the high frequency of trigonid crests in H.neanderthalensis. However, H. neanderthalensis still appears to be derived relative to Pan and A. africanus in its high frequency of the mesial-mesial trigonid crestconfiguration.


Prevention of myocardial injury by pretreatment with verapamil hydrochloride prior to experimental brain death: efficacy in a baboon model.
Systemic and pulmonary hemodynamics were studied in two groups of Chacma baboons following the induction of brain death. Group A was a control group of 11 animals who underwent brain death. They showed significant increments of mean systemic arterial, left atrial, and pulmonary arterial pressures; of systemic vascular resistance, heart rate, and pulmonary artery blood flow; and a reduction in aortic blood flow during the induction of brain death. As a result of increased sympathetic nervous system activity, areas of myocardial cell necrosis occurred in 73% of the animals and pulmonary edema in 36%. Group B consisted of five animals that were pretreated with verapamil hydrochloride infused over a period of 30 minutes prior to the induction of brain death (mean dosage, 0.26 mg/kg). Except for a rise in heart rate, no significant changes occurred in systemic or pulmonary hemodynamics, and no myocardial or pulmonary histopathological changes were seen. These findings would indicate that verapamil hydrochloride prevents both the peripheral and central hemodynamic changes that result from increased sympathetic activity associated with the induction of brain death, and thus prevents myocardial structural damage, which may be associated with increased calcium uptake by the myocyte.


Antenatal diagnosis of renal pelvic dilatation--the natural history of conservative management.
Seventy children with an antenatal diagnosis of unilateral renal pelvic dilatation underwent Tc 99 m DTPA diuretic renograms. There were 16 kidneys with moderate function, and 54 with good function, 31 underwent pyeloplasty, all had a renal pelvis greater than 12 mm diameter on ultrasound. Thirty nine children with good function were treated conservatively. Long term follow up has demonstrated that conservative management for PUJ dilatation with a good functioning kidney may be justified but a randomised control study is required.