Idarubicin and standard-dose cytosine arabinoside in adults with recurrent and refractory acute lymphocytic leukemia.
Drug resistance and early disease recurrence were major contributing factors in the limited survival of patients with acute lymphocytic leukemia (ALL). New chemotherapeutic agents and drug combinations were employed in refractory patients to overcome drug resistance. The current study evaluated the efficacy of a regimen comprising intravenous bolus injections of idarubicin, 12 mg/m2 daily x 3, and a continuous 7-day infusion of cytosine arabinoside (ara-C), 100 mg/m2 daily, in adults with refractory or recurrent ALL. Twenty patients aged 14-75 years were treated. Six patients (30%) achieved complete remission (CR), 5 (25%) had a partial response (PR), and 9 (45%) did not respond. Recovery of blood counts occurred at a median of 20 days. One patient who achieved CR and one who achieved PR survived 1.5 and 2 years, respectively, after receiving this treatment. The median response and overall survival periods were 2.75 and 6.3 months, respectively. There was no relation between remission duration and previous chemotherapy. Neither leukocyte count at study entry nor patient karyotype was associated with attainment of CR. All patients experienced profound myelosuppression. Gastrointestinal toxicity was mild to moderate, with the exception of one case of World Health Organization Grade 3 mucositis. The regimen of idarubicin and ara-C achieved a 55% overall response rate in patients with recurrent or refractory ALL. This response rate compared favorably with other regimens and was achieved with acceptable toxicity. Response duration was disappointing, however.


The Nuka System of Care: improving health through ownership and relationships.
Southcentral Foundation's Nuka System of Care, based in Anchorage, Alaska, is a result of a customer-driven overhaul of what was previously a bureaucratic system centrally controlled by the Indian Health Service. Alaska Native people are in control as the "customer-owners" of this health care system. The vision and mission focus on physical, mental, emotional, and spiritual wellness and working together as a Native Community. Coupled with operational principles based on relationships, core concepts and key points, this framework has fostered an environment for creativity, innovation and continuous quality improvement. Alaska Native people have received national and international recognition for their work and have set high standards for performance excellence, community engagement, and overall impact on population health. In this article, the health care transformation led by Alaska Native people is described and the benefits and results of customer ownership and the relationship-based Nuka System of Care are discussed.


The impact of cognitive performance on quality of life in individuals with Parkinson's disease.
Evidence points to the occurrence of cognitive impairment in all stages of PD, constituting a frequent and debilitating symptom, due to high impact on quality of life and mortality of patients. To correlate cognitive performance with quality of life in PD. The sample was drawn from a Movement Disorders Clinic of a reference hospital in Porto Alegre. Inclusion criteria were: PD diagnosis, according to the United Kingdom Parkinson's Disease Society Brain Bank criteria for idiopathic PD (Hughes et al. 1992) and patient consent to participate. Patients with other neurological pathologies and those submitted to deep brain stimulation were excluded. The evaluation consisted of a cognitive testing battery (composed of eight tests for assessing cognitive performance), and a questionnaire on quality of life (PDQ-39) and depression (BDI). The sample comprised 85 individuals with PD, with a mean age of 62.9 years (±10.7), mean disease duration of 10.4 years (±5.7), and mean educational level of four years (±4.3). There was a significant relationship between total score on the PDQ and all cognitive tests, showing that poor cognitive performance was correlated with poor quality of life. Moreover, a significant correlation was observed between cognitive tests and depression, H&Y, education level, and age. It may be concluded that the individuals with PD in this sample showed a correlation between poorer quality of life and worse cognitive performance. Poor performance was also correlated with more advanced stage, older age, low level of education and depression.


The impact of web-based and face-to-face simulation on patient deterioration and patient safety: protocol for a multi-site multi-method design.
There are international concerns in relation to the management of patient deterioration which has led to a body of evidence known as the 'failure to rescue' literature. Nursing staff are known to miss cues of deterioration and often fail to call for assistance. Medical Emergency Teams (Rapid Response Teams) do improve the management of acutely deteriorating patients, but first responders need the requisite skills to impact on patient safety. In this study we aim to address these issues in a mixed methods interventional trial with the objective of measuring and comparing the cost and clinical impact of face-to-face and web-based simulation programs on the management of patient deterioration and related patient outcomes. The education programs, known as 'FIRST(2)ACT', have been found to have an impact on education and will be tested in four hospitals in the State of Victoria, Australia. Nursing staff will be trained in primary (the first 8 min) responses to emergencies in two medical wards using a face-to-face approach and in two medical wards using a web-based version FIRST(2)ACTWeb. The impact of these interventions will be determined through quantitative and qualitative approaches, cost analyses and patient notes review (time series analyses) to measure quality of care and patient outcomes. In this 18 month study it is hypothesised that both simulation programs will improve the detection and management of deteriorating patients but that the web-based program will have lower total costs. The study will also add to our overall understanding of the utility of simulation approaches in the preparation of nurses working in hospital wards. (ACTRN12616000468426, retrospectively registered 8.4.2016).


Characterization of scatter in cone-beam CT breast imaging: comparison of experimental measurements and Monte Carlo simulation.
It is commonly understood that scattered radiation in x-ray computed tomography (CT) degrades the reconstructed image. As a precursor to developing scatter compensation methods, it is important to characterize this scatter using both empirical measurements and Monte Carlo simulations. Previous studies characterizing scatter using both experimental measurements and Monte Carlo simulations have been reported in diagnostic radiology and conventional mammography. The emerging technology of cone-beam CT breast imaging (CTBI) differs significantly from conventional mammography in the breast shape and imaging geometry, aspects that are important factors impacting the measured scatter. This study used a bench-top cone-beam CTBI system with an indirect flat-panel detector. A cylindrical phantom with equivalent composition of 50% fibroglandular and 50% adipose tissues was used, and scatter distributions were measured by beam stop and aperture methods. The GEANT4-based simulation package GATE was used to model x-ray photon interactions in the phantom and detector. Scatter to primary ratio (SPR) measurements using both the beam stop and aperture methods were consistent within 5% after subtraction of nonbreast scatter contributions and agree with the low energy electromagnetic model simulation in GATE. The validated simulation model was used to characterize the SPR in different CTBI conditions. In addition, a realistic, digital breast phantom was simulated to determine the characteristics of various scatter components that cannot be separated in measurements. The simulation showed that the scatter distribution from multiple Compton and Rayleigh scatterings, as well as from the single Compton scattering, has predominantly low-frequency characteristics. The single Rayleigh scatter was observed to be the primary contribution to the spatially variant scatter component.


Lymphomatoid granulomatosis: A case series from South India.
Lymphomatoid granulomatosis (LYG) is a rare B-lymphoproliferative disorder characterised by an angiocentric and angiodestructive pattern along with Epstein - Barr virus (EBV) association. It is one of the diagnostic challenges in lymphoma pathology. Deregulation of EBV immune surveillance is one of the narrated hypotheses in the literature. Extrapulmonary manifestations are rare with LYG. Morphological grading is done based on the number of EBV-positive B cells, which is useful to strategize treatment protocol. We report here a series of nine cases of LYG to discuss the clinical, histological, and immunohistochemistry findings. This is the first case series from India in published literature. We reviewed cases of LYG diagnosed at our center for the past 11 years (2006-2016). A total of nine cases were included in this study. Histomorphology was studied in conjunction with immunohistochemistry and clinical details. Cases without classical morphology and negative for EBV immunostain were excluded from the study. There were nine patients in our study (7 males and 2 female; M:F ratio 3.5:1). The age of these patients ranged from 4 years to 57 years (mean age: 30 years). The most common site involved was the lung (4, 44%), followed by the skin (2, 22%), central nervous system (2, 22%) and lymph node (1, 11%). One patient had primary immunodeficiency. Another patient had undergone renal transplant 11 years before the development of the lesion. Angiocentricity and angioinvasion were appreciated in all nine cases (9/9) with necrosis in four cases (44%) and ill-defined histiocytic aggregates in three cases (33%). The histological features were as follows: Grade 1(4 cases, 44%), Grade 2(2 cases, 22%), and Grade 3(3 cases, 33%). LYG is a rare EBV driven angiodestructive disease with predominantly lung involvement as well as isolated extrapulmonary sites as seen in our study. It is often progressive and ultimately fatal in the absence of appropriate treatment. Grading of the lesion helps to initiate the appropriate treatment of choice.


Assignment of the gene for dyskeratosis congenita to Xq28.
Dyskeratosis congenita is an X-linked recessive disorder with diagnostic dermatological features, bone marrow hypofunction, and a predisposition to neoplasia in early adult life. Linkage analysis was undertaken in an extensive family with the condition using the Xg blood group and 17 cloned X chromosomal DNA sequences which recognise restriction fragment length polymorphisms (RFLPs). No recombination was observed between the locus for dyskeratosis congenita (DKC) and the RFLPs identified by DXS52 (St14-1) (Zmax = 3.33 at theta max = 0 with 95% confidence limits of 0 to 14cM). Similarly no recombination was observed for the disease locus and F8 (Zmax = 1.23 at theta max = 0) nor for DXS15 (Zmax = 1.62 at theta max = 0), but both of these markers were only informative in part of the family whereas DXS52 was fully informative. DXS52, DXS15, and F8 are known to be tightly linked and have previously been assigned to Xq28. Thus the gene for dyskeratosis congenita can be assigned to Xq28. These DNA sequence polymorphisms will be of clinical value for carrier detection and prenatal diagnosis.


Transgenic production of cytokinin suppresses bacterially induced hypersensitive response symptoms and increases antioxidative enzyme levels in Nicotiana spp.
Responses of cytokinin overproducing transgenic Nicotiana plants to infections with compatible and incompatible Pseudomonas syringae pathovars were compared. Plants used were transformed with the ipt(isopentenyl transferase) gene that catalyzes the synthesis of cytokinin. In cytokinin overproducing lines that carry the ipt gene fused to the CaMV 35S (Nt+ipt), the wound-inducible proteinase inhibitor II (Ntx+ipt), or the light-inducible Rubisco small subunit protein (Npl+ipt) promoter, development of the hypersensitive response (HR) after infection with incompatible bacteria (P. syringae pv. tomato) was significantly inhibited as compared to the untransformed (Nt) controls. Over a 12 h period following inoculation, P. syrinage pv. tomato populations were slightly reduced in leaves of the cytokinin-overproducing Nt-ipt line compared with the Nt control. When the compatible P. syringae. pv. tabaci was used to infect the ipt transformed lines, slight or no significant differences in necrosis development were observed. Following infection, the titer of P. syringae pv. tabaci increased rapidly in both the transgenic and control lines but was higher in Nt+ipt plants. Leaf superoxide dismutase and catalase enzyme activities were about 60% higher in ipt leaf extracts than in the controls. This augmented antioxidant capacity likely decreased the amount of H(2)O(2) that may be associated with the higher tolerance of plants to pathogen-induced necrosis. In addition, the Nt+ipt lines had a significantly lower molar ratio of free sterols to phospholipids. The more stable membrane lipid composition and the higher antioxidant capacity likely contributed to the suppressed HR symptoms in the cytokinin overproducing Nt+ipt plants. In conclusion, the overproduction of cytokinins in tobacco appears to suppress the HR symptoms induced by incompatible bacteria.


Evaluation of the importance of various operating and sludge property parameters to the fouling of membrane bioreactors.
A single-fibre microfiltration system was employed to investigate the importance of various operating and sludge property parameters to the membrane fouling during sludge filtration. The sludge was obtained from a submerged membrane bioreactor (SMBR). A series of comparative and correlative filtration and fouling tests were conducted on the influence of the operating variables, sludge properties and the liquid-phase organic substances on the membrane fouling development. The test results were analysed statistically with Pearson's correlation coefficients and the stepwise multivariable linear regression. According to the statistical evaluation, the membrane fouling rate has a positive correlation with the biopolymer cluster (BPC) concentration, sludge concentration (mixed liquor suspended solids, MLSS), filtration flux and viscosity, a negative correlation with the cross-flow velocity, and a weak correlation with the extracellular polymeric substances and soluble microbial products. BPC appear to be the most important factor to membrane fouling development during the sludge filtration, followed by the filtration flux and MLSS concentration. The cross-flow rate also is important to the fouling control. It is argued that, during membrane filtration of SMBR sludge, BPC interact with sludge flocs at the membrane surface to facilitate the deposition of the sludge cake layer, leading to serious membrane fouling.


Helicobacter pylori infection in indigenous families of Central America: serostatus and oral and fingernail carriage.
Helicobacter pylori infection remains one of the most common in humans, but the route of transmission of the bacterium is still uncertain. This study was designed to elucidate possible sources of infection in an isolated, rural population in Guatemala. A total of 242 subjects in family units participated in the study. A medical history, including a history of dyspepsia, was taken by a physician and immunoglobulin G antibodies to H. pylori were detected with the QuickVue (Quidel, San Diego, Calif.) onsite serology test. Overall, 58% of subjects were seropositive, with a positive relationship between mother and child (P = 0.02) and a positive correlation between the serostatuses of siblings (intraclass correlation coefficient = 0.63). There was no association between serostatus and gastric symptoms. Oral H. pylori was detected from periodontal pockets of various depths and the dorsum of the tongue by nested PCR. Eighty-seven percent of subjects had at least one oral site positive for H. pylori, with the majority of subjects having multiple positive sites. There was no association between periodontal pocket depth and the detection of H. pylori. Nested PCR was also used to detect H. pylori from beneath the nail of the index finger of each subject's dominant hand. Overall, 58% of subjects had a positive fingernail result, with a significant positive relationship between fingernail and tongue positivity (P = 0.002). In conclusion, the results of this study suggest that oral carriage of H. pylori may play a role in the transmission of infection and that the hand may be instrumental in transmission.


A coordinated relocation strategy for enhancing case management of lead poisoned children: outcomes and costs.
Controlling residential lead hazards is critical for case management of lead poisoned children. To attain this goal, permanent relocation of the family is sometimes necessary or advisable for many reasons, including poor housing conditions; extensive lead hazards; lack of abatement resources, landlord compliance and local enforcement capacity; and family eviction. During 1996-1998, the Kennedy Krieger Institute implemented a unique capitated program for case management of Baltimore City children with blood lead concentrations (PbB) >19 microg/dL. The Program provided financial, housing, and social work assistance to facilitate relocation as a means of providing safer housing. Nearly half of the Program families relocated with direct assistance, and 28% relocated on their own. The Program evaluation examined the costs and benefits of relocation. Average relocation cost per child was relatively inexpensive (<1,500 dollars). Average relocation time of 5 months (range <2 months to >12 months) was less than the 8-month average time to complete lead hazard control work in 14 city and state programs funded by U.S. HUD. Relocation was associated with (1) a statistically significant decrease in dust lead loadings on floors, windowsills and window troughs that persisted for one year, and (2) statistically significantly greater decreases in children's PbB compared to children who did not relocate from untreated homes. Children relocated to housing that met current Federal residential dust lead standards had statistically significant decreases in blood lead levels. Visual inspection did not consistently identify relocation houses with dust lead levels below current Federal standards, indicating that dust testing should be an essential component of future programs. This will require additional resources for dust testing and possibly cleaning and repairs but is expected to yield additional benefits for children. The findings support recent U.S. CDC case management recommendations suggesting that permanent relocation to safer housing is a viable means to reduce children's lead exposure. The benefits of relocation notwithstanding, 40% of families moved at least twice. Research is needed to better understand how to expedite relocation and encourage families to remain in safe housing. Relocation does not negate owners' and health authorities' responsibilities to address lead hazards in the child's original house in order to protect future occupants.


Acute social isolation evokes midbrain craving responses similar to hunger.
When people are forced to be isolated from each other, do they crave social interactions? To address this question, we used functional magnetic resonance imaging to measure neural responses evoked by food and social cues after participants (n = 40) experienced 10 h of mandated fasting or total social isolation. After isolation, people felt lonely and craved social interaction. Midbrain regions showed selective activation to food cues after fasting and to social cues after isolation; these responses were correlated with self-reported craving. By contrast, striatal and cortical regions differentiated between craving food and craving social interaction. Across deprivation sessions, we found that deprivation narrows and focuses the brain's motivational responses to the deprived target. Our results support the intuitive idea that acute isolation causes social craving, similar to the way fasting causes hunger.


Nonshivering thermogenesis induced by repetitive hypothalamic cooling in the rat.
The effect of prolonged and repetitive cooling of the preoptic/anterior hypothalamic area on the sensitivity to the metabolic effect of noradrenaline and on the resistance to cold exposure was studied in the white rat. The preoptic area of 18 unanesthetized animals was cooled 9 h/day 5 days/wk, for a total of 80-150 h. One hour after a noradrenaline test injection (0.4 mg/kg), the experimental animals in which the preoptic area had been cooled to about 24 degrees C increased oxygen uptake by 81%, whereas those in which the preoptic area had been cooled to about 28 degrees C increased oxygen uptake by 48% (the control animals by only 37%). Despite their increased capacity for nonshivering thermogenesis, the experimental animals did not tolerate cold exposure (-10 degrees C) better than the controls. This development of nonshivering thermogenesis is thought to have been mediated by the hypothalamic temperature-sensitive neurons, and the possibility that it could explain the shift from shivering to nonshivering thermogenesis seen during adaptation to cold is discussed.


Polycyclic aromatic hydrocarbons (PAHs) reduce hepatic β-oxidation of fatty acids in chick embryos.
Polycyclic aromatic hydrocarbons (PAHs) are widespread fused-ring contaminants formed during incomplete combustion of almost all kind of organic materials from both natural and anthropogenic sources. Some PAHs have been shown to be carcinogenic to humans, and a wide range of PAHs are found in wildlife all around the globe including avian species. The purpose of this project was to assess the effects of a standard mixture of 16 PAHs (United States Environmental Protection Agency) on the hepatic fatty acid β-oxidation in chicken embryos (Gallus gallus domesticus) exposed in ovo. The hepatic β-oxidation was measured using a tritium release assay with [9,10-(3)H]-palmitic acid (16:0) as substrate. Treated groups were divided into groups of 0.05, 0.1, 0.3, 0.5, and 0.8 mg PAHs/kg egg weight. The hepatic β-oxidation was reduced after exposure in ovo to the 16 PAHs mixture compared to control. The mechanisms causing reduced fatty acid oxidation in the present study are unclear, however may be due to deficient membrane structure, the functionality of enzymes controlling the rate of fatty acid entering into the mitochondria, or complex pathways connected to endocrine disruption. To the best of our knowledge, this is the first time a PAH-caused reduction of hepatic β-oxidation of fatty acids in avian embryos has been observed. The implication of this finding on risk assessment of PAH exposure in avian wildlife remains to be determined.


Mechanisms and advancement of antifading agents for fluorescence microscopy and single-molecule spectroscopy.
Modern fluorescence microscopy applications go along with increasing demands for the employed fluorescent dyes. In this work, we compared antifading formulae utilizing a recently developed reducing and oxidizing system (ROXS) with commercial antifading agents. To systematically test fluorophore performance in fluorescence imaging of biological samples, we carried out photobleaching experiments using fixed cells labeled with various commonly used organic dyes, such as Alexa 488, Alexa 594, Alexa 647, Cy3B, ATTO 550, and ATTO 647N. Quantitative evaluation of (i) photostability, (ii) brightness, and (iii) storage stability of fluorophores in samples mounted in different antifades (AFs) reveal optimal combinations of dyes and AFs. Based on these results we provide guidance on which AF should preferably be used with a specific dye. Finally, we studied the antifading mechanisms of the commercial AFs using single-molecule spectroscopy and reveal that these empirically selected AFs exhibit similar properties to ROXS AFs.


Bronchoconstrictor additives in bronchodilator solutions.
Nebulized bronchodilator solutions are available in the United States as both nonsterile and sterile-filled products. Sulfites, benzalkonium chloride (BAC), or chlorobutanol are added to nonsterile products to prevent bacterial growth, but there have been reports of contaminated solutions containing preservatives. Ethylenediamine tetraacetic acid (EDTA) is added to some products to prevent discoloration of the solution. With the exception of chlorobutanol, all of these additives are capable of inducing bronchospasm in a concentration-dependent manner. However, it is rarely apparent to the patient or health care provider that the additive diminishes the bronchodilator effects. Older products (eg, isoproterenol and isoetharine) contain enough sulfites to produce bronchospasm in most patients with asthma, even in those without a prior history of sulfite sensitivity. Bronchoconstriction from inhaled BAC is cumulative, prolonged, and correlates directly with basal airway responsiveness. The multidose dropper bottle of albuterol contains 50 microg BAC/dose, which is below the threshold for bronchoconstriction whereas the screwcap unit-dose vial contains 300 microg/dose, which is above the threshold for many patients. If the screwcap product is used in the emergency department, a patient could receive as much as 1800 microg of BAC in the first hour. Three sterile-filled unit dose albuterol products contain no additives, whereas a fourth, (manufactured by Dey Laboratories) contains 300 microg of EDTA, which is also below the threshold dose for bronchoconstriction. Only additive-free sterile solutions should be used for hourly or continuous nebulization of albuterol. The multidose dropper bottle or the Dey product can be used when the interval between doses is longer, whereas the screwcap product should not be used for acute therapy. Ipratropium is available only as a sterile, additive-free unit-dose vial, as is levalbuterol.


A critical review of pharmacological significance of Hydrogen Sulfide in hypertension.
In the family of gas transmitters, hydrogen sulfide (H2S) is yet not adequately researched. Known for its rotten egg smell and adverse effects on the brain, lungs, and kidneys for more than 300 years, the vasorelaxant effects of H2S on blood vessel was first observed in 1997. Since then, research continued to explore the possible therapeutic effects of H2S in hypertension, inflammation, pancreatitis, different types of shock, diabetes, and heart failure. However, a considerable amount of efforts are yet needed to elucidate the mechanisms involved in the therapeutic effects of H2S, such as nitric oxide-dependent or independent vasodilation in hypertension and regression of left ventricular hypertrophy. More than a decade of good repute among researchers, H2S research has certain results that need to be clarified or reevaluated. H2S produces its response by multiple modes of action, such as opening the ATP-sensitive potassium channel, angiotensin-converting enzyme inhibition, and calcium channel blockade. H2S is endogenously produced from two sulfur-containing amino acids L-cysteine and L-methionine by the two enzymes cystathionine γ lyase and cystathionine β synthase. Recently, the third enzyme, 3-mercaptopyruvate sulfur transferase, along with cysteine aminotransferase, which is similar to aspartate aminotransferase, has been found to produce H2S in the brain. The H2S has interested researchers, and a great deal of information is being generated every year. This review aims to provide an update on the developments in the research of H2S in hypertension amid the ambiguity in defining the exact role of H2S in hypertension because of insufficient number of research results on this area. This critical review on the role of H2S in hypertension will clarify the gray areas and highlight its future prospects.


Clinical significance of elevated troponin I levels in patients with nontraumatic subarachnoid hemorrhage.
Aneurysmal subarachnoid hemorrhage (SAH) is associated with electrocardiographic abnormalities, regional or focal wall-motion abnormalities on echocardiograms, and/or increased creatine kinase MB isoenzyme (CK-MB) or cardiac troponin I (cTnI). The goal of this prospective study was to compare the sensitivity and specificity of cTnI with those of CK-MB in the prediction of left ventricular dysfunction on echocardiograms in patients with nontraumatic SAH. In addition, those patients with abnormal findings on their echocardiograms and elevated cTnI levels were further evaluated for the presence of coronary artery disease (CAD) by a cardiologist and to determine whether any left ventricular dysfunction that had been detected was reversible. The authors obtained electrocardiograms and echocardiograms, and measured serial levels of cardiac enzymes (CK-MB and cTnI) in 43 patients with nontraumatic SAH. Patients with known CAD were excluded. Those patients found to have elevated enzyme levels and abnormal findings on their echocardiograms underwent additional evaluation for CAD. The sensitivity and specificity of both cTnI and CK-MB for detecting left ventricular function were determined. Twenty-eight percent of patients with SAH in the study had elevated cTnI levels within the first 24 hours after hemorrhage. Seven of the 12 patients had evidence of left ventricular dysfunction on echocardiograms. In all these patients a return to baseline function was found during follow-up examinations. The authors found that cTnI is much more sensitive than CK-MB (100% compared with 29%) in the detection of left ventricular dysfunction in patients with SAH. An elevated level of cTnI is a good indicator of left ventricular dysfunction in patients with SAH. In this study cardiac dysfunction was reversible and should not necessarily preclude these patients from undergoing operative interventions or becoming heart donors. Clinical management may require more aggressive hemodynamic monitoring until cardiac function returns to normal.


A resourceful genome: updating the functional repertoire and evolutionary role of animal mitochondrial DNAs.
Recent data from mitochondrial genomics and proteomics research demonstrate the existence of several atypical mitochondrial protein-coding genes (other than the standard set of 13) and the involvement of mtDNA-encoded proteins in functions other than energy production in several animal species including humans. These results are of considerable importance for evolutionary and cellular biology because they indicate that animal mtDNAs have a larger functional repertoire than previously believed. This review summarizes recent studies on animal species with a non-standard mitochondrial functional repertoire and discusses how these genetic novelties represent promising candidates for studying the role of the mitochondrial genome in speciation.


Congenital muscular dystrophy type 1A with residual merosin expression.
Congenital muscular dystrophy type 1A (MDC1A) is an autosomal recessive disorder characterized by hypotonia, elevated serum creatine kinase level, delayed motor milestones, white matter changes observed by brain magnetic resonance imaging, and normal intelligence. A mutation in the laminin α2 (LAMA2) gene, located at 6q22-23, is a genetic cause of MDC1A. Patients have merosin (laminin α2)-deficient skeletal muscles. However, the degree of merosin expression ranges from total absence to partial reduction. Patients with residual merosin expression have more variable and milder phenotypes than those with absolute merosin deficiency. We observed a Korean girl with MDC1A with residual merosin expression. Clinical presentation of this patient was typical except for late onset of the disease and external capsule involvement. Immunohistochemical staining of muscle fibers including merosin, is important to evaluate patients with hypotonia, delayed motor development, and abnormal white matter changes.


Operating conditions for the continuous bioremediation of free cyanide contaminated wastewater using Aspergillus awamori.
Generation of cyanide-containing wastewater is a growing problem worldwide as numerous cyanide complexes are highly unstable and degrade to form free cyanide (F-CN), the most toxic form of cyanide. Agro-waste materials, such as sweet orange (Citrus sinensis) waste from the citrus industry, are rich in readily metabolisable carbohydrates that can supplement microbial activity and thus support biodegradation of toxic compounds in wastewater. This study reports on optimal operating conditions for the continuous biodegradation of F-CN in wastewater using an Aspergillus awamori isolate in a process supported solely using C. sinensis waste extract. The optimal degradation conditions were pH 8.75 and 37.02 °C with the isolate's F-CN tolerance being observed up to 430 mg F-CN/L. Furthermore, the ammonium produced as a by-product of F-CN degradation was also metabolised by the A. awamori, with negligible residual citric acid and formate being observed in the effluent post treatment. This study demonstrates the feasibility of using agricultural waste as a primary and sole carbon source for the cultivation of a cyanide-degrading A. awamori species for F-CN degradation under alkaline conditions.


Corticosteroid-induced neural remodeling predicts behavioral vulnerability and resilience.
Neurons in distinct brain regions remodel in response to postnatal stressor exposure, and structural plasticity may underlie stress-related modifications in behavioral outcomes. Given the persistence of stress-related diseases such as depression, a critical next step in identifying the contributions of neural structure to psychopathology will be to identify brain circuits and cell types that fail to recover from stressor exposure. We enumerated dendritic spines during and after chronic stress hormone exposure in hippocampal CA1, deep-layer prefrontal cortex, and the basal amygdala and also reconstructed dendritic arbors of CA1 pyramidal neurons. Corticosterone modified dendritic spine density in these regions, but with the exception of the orbitofrontal cortex, densities normalized with a recovery period. Dendritic retraction of hippocampal CA1 neurons and anhedonic-like insensitivity to a sucrose solution also persisted despite a recovery period. Using mice with reduced gene dosage of p190rhogap, a cytoskeletal regulatory protein localized to dendritic spines, we next isolated structural correlates of both behavioral vulnerability (spine elimination) and resilience (spine proliferation) to corticosterone within the orbital cortex. Our findings provide novel empirical support for the perspective that stress-related structural reorganization of certain neuron populations can persist despite a "recovery" period from stressor exposure and that these modifications may lay a structural foundation for stressor vulnerability-or resiliency-across the lifespan.


Gas-phase unfolding and disassembly reveals stability differences in ligand-bound multiprotein complexes.
Mass spectrometry (MS) is widely used to assess the binding of small molecules to proteins and their complexes. In many cases, subtle differences in the stability afforded by binding of ligands to protein assemblies cannot be detected by MS. Here we show that monitoring the unfolding of protein subunits, using ion mobility-MS, allows differentiation of the effects of ligand binding not normally observed by MS alone. Using wild-type and disease-associated variants of tetrameric transthyretin, MS data indicate that populations of the variant protein are less stable than wild-type. Ion mobility-MS, however, is able to show that the natural ligand of transthyretin, thyroxine, provides a larger stability increase to the tetramer composed of variant subunits than to the wild-type protein-ligand complex. Overall, therefore, our results have implications for small-molecule drug design directed at multiprotein targets.


Meningococcal vaccines.
Neisseria meningitidis is one of the leading infectious causes of death in children under five years old in industrialized countries, and most cases can be attributed to five disease-causing serogroups: A, B, C, Y and W135. Meningococcal vaccine development began in the 1930s with killed whole-cell and exotoxin vaccines, but widespread use of polysaccharide vaccines did not begin until the 1970s. Serogroup A, C, Y and W135 polysaccharides are all included in vaccines for travellers, other high risk groups and control of outbreaks, but have limited immunogenicity and effficacy in childhood. Protein-polysaccharide conjugate vaccines overcome this problem and offer the possibility of protection in early childhoodfrom serogroup A, C, Y and W135. An effective serogroup B vaccine remains elusive and the greatest challengefor vaccine developers.


Identifying and explaining vibrational modes of quinacridones via temperature-resolved terahertz spectroscopy: absorption experiments and solid-state density functional theory simulations.
Quinacridone and its substituted analogs are pigments widely used in art and industry. The temperature dependence of the crystal structures of two quinacridone polymorphs (β and γ), along with the common variant 2,9-dimethylquinacridone, were investigated using powder X-ray diffraction and terahertz spectroscopy. These were then compared with solid-state density functional theory simulations of both structures and vibrations. X-ray patterns were collected at eight temperatures in the range 13-298 K and terahertz spectra at fifteen temperatures in the range 20-300 K. Simulations were at absolute zero and at appropriate expansions to model room temperature. It was found that some of the powder X-ray diffraction features in only β-quinacridone (15.7°, 19.7° and 31.2° at 13 K) underwent anomalous shifting with temperature change. We attribute this to the unique coplanar hydrogen bonding pattern of β-quinacridone compared to the other solids, with the unusual diffraction peaks originating from crystallographic planes perpendicular to the a axis intermolecular hydrogen bonds. This observation coincides with a contraction of the a axis with heating and results from its relatively weak N-HO hydrogen bonds and significant C-HH-C repulsions. Associated with this anomalous contraction, for β-quinacridone only spectral peaks are seen to increase in energy with temperature.


Impact of chest X-ray before discharge in asymptomatic children after cardiac surgery--prospective evaluation.
In many paediatric cardiac units chest radiographs are performed routinely before discharge after cardiac surgery. These radiographs contribute to radiation exposure. To evaluate the diagnostic impact of routine chest X-rays before discharge in children undergoing open heart surgery and to analyze certain risk factors predicting pathologic findings. This was a prospective (6 months) single-centre observational clinical study. One hundred twenty-eight consecutive children undergoing heart surgery underwent biplane chest X-ray at a mean of 13 days after surgery. Pathologic findings on chest X-rays were defined as infiltrate, atelectasis, pleural effusion, pneumothorax, or signs of fluid overload. One hundred nine asymptomatic children were included in the final analysis. Risk factors, such as age, corrective versus palliative surgery, reoperation, sternotomy versus lateral thoracotomy, and relevant pulmonary events during postoperative paediatric intensive care unit (PICU) stay, were analysed. In only 5.5 % (6 of 109) of these asymptomatic patients were pathologic findings on routine chest X-ray before discharge found. In only three of these cases (50 %), subsequent noninvasive medical intervention (increasing diuretics) was needed. All six patients had relevant pulmonary events during their PICU stay. Risk factor analysis showed only pulmonary complications during PICU stay to be significantly associated (p = 0.005) with pathologic X-ray findings. Routine chest radiographs before discharge after cardiac surgery can be omitted in asymptomatic children with an uneventful and straightforward perioperative course. Chest radiographs before discharge are warrantable if pulmonary complications did occur during their PICU stay, as this is a risk factor for pathologic findings in chest X-rays before discharge.


Selection at the Y chromosome of the African buffalo driven by rainfall.
Selection coefficients at the mammalian Y chromosome typically do not deviate strongly from neutrality. Here we show that strong balancing selection, maintaining intermediate frequencies of DNA sequence variants, acts on the Y chromosome in two populations of African buffalo (Syncerus caffer). Significant correlations exist between sequence variant frequencies and annual rainfall in the years before conception, with five- to eightfold frequency changes over short time periods. Annual rainfall variation drives the balancing of sequence variant frequencies, probably by affecting parental condition. We conclude that sequence variants confer improved male reproductive success after either dry or wet years, making the population composition and dynamics very sensitive to climate change. The mammalian Y chromosome, interacting with ecological processes, may affect male reproductive success much more strongly than previously thought.


Travel health: a survey of life jacket designs currently in use on commercial aircraft.
Although any travel harbors potential health problems, travel across water poses the additional risk of involuntary contact with water in the event of an emergency. Studies suggest that fatal boat-related accidents have occurred due to the passengers' inability to don their life jackets. With the dramatic increase of long-haul flights, it was decided to investigate if potential safety hazards can be identified leading to similar problems in relation to the life jackets provided onboard aircraft. It was assumed that the variety of designs combined with a possible lack of attention paid to safety instructions could represent such a problem. Safety instruction cards in passengers' seat pockets usually depict the life jacket model used on a particular aircraft. Ninety-eight such safety cards from 53 airlines were analyzed and categorized to identify the range and variety of designs currently in use. Twelve different categories of life jacket models could be distinguished with some airlines using more than one model. It was also found that not all cards show a clear depiction of the models used, the cards of two airlines show two different designs on the same cards, and two other companies chose to change the model halfway through the pictured donning procedure. There is a wide variety of life jacket designs in use with the safety cards not always giving accurate instructions. This variety also has implications for the safety demonstration at the beginning of a flight. Further research is recommended into a range of topics, one being the quality and content of these instructions, and also into other personal floating devices provided for the safety of travelers in the event of an emergency over water.


The core and unique proteins of haloarchaea.
Since the first genome of a halophilic archaeon was sequenced in 2000, biologists have been advancing the understanding of genomic characteristics that allow for survival in the harsh natural environments of these organisms. An increase in protein acidity and GC-bias in the genome have been implicated as factors in tolerance to extreme salinity, desiccation, and high solar radiation. However, few previous attempts have been made to identify novel genes that would permit survival in such extreme conditions. With the recent release of several new complete haloarchaeal genome sequences, we have conducted a comprehensive comparative genomic analysis focusing on the identification of unique haloarchaeal conserved proteins that likely play key roles in environmental adaptation. Using bioinformatic methods, we have clustered 31,312 predicted proteins from nine haloarchaeal genomes into 4,455 haloarchaeal orthologous groups (HOGs). We assigned likely functions by association with established COG and KOG databases in NCBI. After identifying homologs in four additional haloarchaeal genomes, we determined that there were 784 core haloarchaeal protein clusters (cHOGs), of which 83 clusters were found primarily in haloarchaea. Further analysis found that 55 clusters were truly unique (tucHOGs) to haloarchaea and qualify as signature proteins while 28 were nearly unique (nucHOGs), the vast majority of which were coded for on the haloarchaeal chromosomes. Of the signature proteins, only one example with any predicted function, Ral, involved in desiccation/radiation tolerance in Halobacterium sp. NRC-1, was identified. Among the core clusters, 33% was predicted to function in metabolism, 25% in information transfer and storage, 10% in cell processes and signaling, and 22% belong to poorly characterized or general function groups. Our studies have established conserved groups of nearly 800 protein clusters present in all haloarchaea, with a subset of 55 which are predicted to be accessory proteins that may be critical or essential for success in an extreme environment. These studies support core and signature genes and proteins as valuable concepts for understanding phylogenetic and phenotypic characteristics of coherent groups of organisms.


Childhood Socioeconomic Position and Pubertal Onset in a Cohort of Multiethnic Girls: Implications for Breast Cancer.
Background: Higher socioeconomic position (SEP) has been associated with increased risk of breast cancer. Its relationship with earlier age of pubertal onset, a risk factor for breast cancer, is less clear.Methods: We studied the relationship of SEP to pubertal onset in a multiethnic cohort of 1,237 girls ages 6 to 8 years at baseline. Girls in three U.S. cities were followed for 5 to 8 years with annual clinical examinations from 2004 to 2012. SEP measures were examined for associations with pubertal onset, assessed by breast budding (thelarche) and pubic hair development (adrenarche). Analyses were conducted with accelerated failure time models using a Weibull distribution, with left, right, and interval censoring.Results: Higher body mass index percentage at entry to the study and black or Hispanic race/ethnicity were the strongest predictors of age at pubertal onset. An SEP index comprising household family income, mother's education, and home ownership was an independent predictor of thelarche in adjusted models for all girls together and for white and Latina, separately, but not black girls, and the relationship varied by study site. The SEP index was not related to adrenarche in adjusted models. Overall, girls from the lowest quintile of SEP entered puberty on average 6% earlier than girls from the highest quintile (time ratio = 0.94; 95% confidence interval 0.91-0.97) in adjusted models.Conclusions: Our results suggest that early-life SEP may influence the timing of pubertal development.Impact: Factors related to lower SEP in childhood can adversely affect early development in ways that may increase the risk of breast cancer. Cancer Epidemiol Biomarkers Prev; 26(12); 1714-21. ©2017 AACR.


Effects of different forms of chitosan on intercellular junctions of mouse fibroblasts in vitro.
Chitosan is a linear polysaccharide that has many biomedical applications. We compared the effects of chitosan, in both solution and membranous form, on intercellular adhesion of Swiss 3T3 mouse fibroblasts. Cells were grown as spheroidal cell cultures. Some control cell spheroids were cultured without chitosan and two experimental groups were cultured with chitosan. Chitosan in solution was used for one experimental group and chitosan in membranous form was used for the other. For each group, intercellular adhesion was investigated on days 5 and 10 of culture. Transmission electron microscopy revealed well-defined cellular projections that were more prominent in cells exposed to either membranous or solution forms of chitosan than to the chitosan-free control. Immunocytochemical staining of ICAM-1 and e-cadherin was used to determine the development of intercellular junctions. Compared to the weakly stained control, strong reactions were observed in both chitosan exposed groups at both 5 and 10 days. Cells were treated with 5-bromo-2-deoxyuridine (BrdU) and incubated with anti-BrdU primary antibody to assess proliferation. Both the solution and membranous forms of chitosan increased proliferation at both 5 and 10 days. Cellular viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The MTT assay indicated high cell viability; maximum viability was obtained with the solution form of chitosan at day 5. Chitosan exposure increased the number of intercellular junctions and showed a significant proliferative effect on 3T3 mouse fibroblasts.


Mechanism of preconditioning. Ionic alterations.
The mechanism by which preconditioning (brief intermittent periods of ischemia and reflow) improves recovery of function and reduces enzyme release after a subsequent 30-minute period of ischemia was investigated in perfused rat hearts. Specifically, it was hypothesized that ischemia after preconditioning would result in a decreased production of H+ and therefore a smaller rise in [Na+]i and [Ca2+]i via Na(+)-H+ and Na(+)-Ca2+ exchange. To test this hypothesis we measured pHi, [Na+]i, [Ca2+]i, and cell high-energy phosphates during ischemia and reflow, and we correlated this with recovery of contractile function and release of creatine kinase during reflow. 31P nuclear magnetic resonance (NMR) was used to measure pHi and cell phosphates. [Na+]i was measured by 23Na NMR using the shift reagent thulium 1,4,7,10-tetraazacyclododecane-N,N,'N",N"'-tetramethylenephosph onate to distinguish intracellular from extracellular sodium. [Ca2+]i was measured by 19F NMR using hearts loaded with 1,2-bis(2-amino-5-fluorophenoxy)ethane-N,N,N',N'-tetraacetic acid, termed 5F-BAPTA. Basal time-averaged levels of pHi, [Na+]i, and [Ca2+]i were 7.07 +/- 0.08, 9.4 +/- 0.8 mM, and 715 +/- 31 nM, respectively. After 30 minutes of ischemia, in preconditioned hearts, pHi was 6.5 +/- 0.06, [Na+]i was 2.09 +/- 4.4 mM, [Ca2+]i was 2.1 +/- 0.4 microM, and ATP was negligible. In untreated hearts, after 30 minutes of ischemia, pHi was 6.3 +/- 0.08, [Na+]i was 26.7 +/- 3.8 mM, [Ca2+]i was 3.2 +/- 0.6 microM, and ATP was undetectable. During reperfusion after 30 minutes of ischemia, preconditioned hearts had significantly better recovery of contractile function than untreated hearts (71 +/- 9% versus 36 +/- 8% initial left ventricular developed pressure), and after 60 minutes of ischemia, preconditioned hearts had significantly less release of the intracellular enzyme creatine kinase (102 +/- 12 versus 164 +/- 17 IU/g dry wt). We also found that unpreconditioned hearts arrested with 16 mM MgCl2 (to inhibit calcium entry via calcium channels and Na(+)-Ca2+ exchange) before 30 minutes of ischemia recover function on reflow to the same extent as preconditioned hearts with or without magnesium arrest. Thus, preconditioning has no additional benefit in addition to magnesium arrest. In addition, in hearts that received 16 mM MgCl2 just before the 30-minute period of ischemia, preconditioning had no effect on the rise in [Ca2+]i during the 30-minute period of ischemia. These data support the hypothesis that preconditioning attenuates the increase in [Ca2+]i, [Na+]i, and [H+]i during ischemia, most likely because of reduced stimulation of Na(+)-H+ and Na(+)-Ca2+ exchange.(ABSTRACT TRUNCATED AT 400 WORDS)


Systematic review and meta-analysis on the nonsurgical treatment of chronic periodontitis by means of scaling and root planing with or without adjuncts.
Conduct a systematic review and meta-analysis on nonsurgical treatment of patients with chronic periodontitis by means of scaling and root planing (SRP) with or without adjuncts. A panel of experts convened by the American Dental Association Council on Scientific Affairs conducted a search of PubMed (MEDLINE) and Embase for randomized controlled trials of SRP with or without the use of adjuncts with clinical attachment level (CAL) outcomes in trials at least 6 months in duration and published in English through July 2014. The authors assessed individual study bias by using the Cochrane Risk of Bias Tool and conducted meta-analyses to obtain the summary effect estimates and their precision and to assess heterogeneity. The authors used funnel plots and Egger tests to assess publication bias when there were more than 10 studies. The authors used a modified version of the US Preventive Services Task Force methods to assess the overall level of certainty in the evidence. The panel included 72 articles on the effectiveness of SRP with or without the following: systemic antimicrobials, a systemic host modulator (subantimicrobial-dose doxycycline), locally delivered antimicrobials (chlorhexidine chips, doxycycline hyclate gel, and minocycline microspheres), and a variety of nonsurgical lasers (photodynamic therapy with a diode laser, a diode laser, neodymium:yttrium-aluminum-garnet lasers, and erbium lasers). With a moderate level of certainty, the panel found approximately a 0.5-millimeter average improvement in CAL with SRP. Combinations of SRP with assorted adjuncts resulted in a range of average CAL improvements between 0.2 and 0.6 mm over SRP alone. The panel judged the following 4 adjunctive therapies as beneficial with a moderate level of certainty: systemic subantimicrobial-dose doxycycline, systemic antimicrobials, chlorhexidine chips, and photodynamic therapy with a diode laser. There was a low level of certainty in the benefits of the other included adjunctive therapies. The panel provides clinical recommendations in the associated clinical practice guideline.


Betulinic acid restores imatinib sensitivity in BCR-ABL1 kinase-independent, imatinib-resistant chronic myeloid leukemia by increasing HDAC3 ubiquitination and degradation.
Although imatinib (IM) has been demonstrated to be an efficient treatment in chronic myeloid leukemia (CML), some patients still experience IM resistance and disease relapse. Through in vitro studies, we observed that HDAC3 levels were elevated in BCR-ABL1 kinase-independent, IM-resistant primary cells from CML patients and in IM-resistant K562 (K562R) cells and that downregulation of HDAC3 could enhance IM efficacy in K562R cells. Furthermore, betulinic acid (BA), a lupane-type pentacyclic triterpenoid saponin isolated from birch trees, restored IM sensitivity in the BCR-ABL1 kinase-independent, IM-resistant primary cells and in K562R cells, as well as in primary CD34+ bone marrow cells from CML patients. We found that BA restored IM sensitivity through inhibition of HDAC3 accumulation in cells, and that this was mediated by BA-dependent ubiquitination and degradation of HDAC3. BA at low dosage significantly increased IM antitumor effects on murine xenografts bearing K562R cells and inhibited HDAC3 expression in tumor tissue. Our findings demonstrated that HDAC3 is an essential factor in BCR-ABL1 kinase-independent IM resistance, and that BA in combination with IM may be a novel treatment strategy for overcoming IM resistance in CML.


Structured cognition and neural systems: from rats to language.
Much of animal and human cognition is compositional in nature: higher order, complex representations are formed by (rule-governed) combination of more primitive representations. We review here some of the evidence for compositionality in perception and memory, motivating an approach that takes ideas and techniques from computational linguistics to model aspects of structural representation in cognition. We summarize some recent developments in our work that, on the one hand, use algorithms from computational linguistics to model memory consolidation and the formation of semantic memory, and on the other hand use insights from the neurobiology of memory to develop a neurally inspired model of syntactic parsing that improves over existing (not cognitively motivated) models in computational linguistics. These two theoretical studies highlight interesting analogies between language acquisition, semantic memory and memory consolidation, and suggest possible neural mechanisms, implemented in computational algorithms that may underlie memory consolidation.


Gene expression profiling of intestinal epithelial cell maturation along the crypt-villus axis.
To define the genetic reprogramming that drives intestinal epithelial cell maturation along the crypt-villus axis, enterocytes were sequentially isolated from the villus tip to the crypts of mouse small intestine. Changes in gene expression were assessed using 27,405-element complementary DNA microarrays (14,685 unique genes) and specific changes validated by Western blotting. A total of 1113 genes differentially expressed between the crypt and villus were identified. Among these, established markers of absorptive and goblet cell differentiation were up-regulated in villus cells, whereas Paneth cell markers were maximally expressed in crypt cells. The 1113 differentially expressed genes were significantly enriched for genes involved in cell cycle progression, RNA processing, and translation (all predominantly down-regulated during maturation) and genes involved in cytoskeleton assembly and lipid uptake (predominantly up-regulated during maturation). No enrichment for apoptosis-regulating genes was observed. We confirmed that Wnt signaling was maximal in the proliferative compartment and observed a decrease in MYC and an increase in MAD and MAX expression during the maturation program. Consistent with these changes, the 1113 genes were enriched for MYC targets, establishing the importance of this network in intestinal cell maturation. This database serves as a resource for understanding the molecular mechanisms of intestinal cell maturation and for dissection of how perturbations in the maturation process can lead to changes in gastrointestinal physiology and pathology, particularly intestinal tumorigenesis.


Exploring the Potential for Family Carers to Support People With Mental Illness to Stop Smoking.
Cigarette smoking poses significant health burdens for people with mental illness. They die sooner than they should, and smoking is a major contributor to their high rates of morbid chronic physical health conditions and early mortality, compared to the general population. Family carers provide important support to people with mental illness. However, family carers' perspectives of smoking by their family members with mental illness are largely absent from the research literature and from practice, despite smoking rates remaining high and quit rates remaining low for this population. We know little about how family carers are or could be involved in supporting people with mental illness who smoke to stop smoking. This paper aims to provide a discussion of the opportunities for family carers to support their family member's smoking cessation and a discussion of our preliminary research on this topic. From the available literature, it appears that family carers are well placed to support smoking cessation for this population; however, they struggled physically, philosophically, and emotionally with perceived responsibilities involving their family member's smoking and the caring role. They felt isolated and asserted that there was limited support from service providers to assist them. We concluded that family carers are important agents within the person's immediate environment who could help them to improve their smoking cessation success. This suggests also that mental health services and other health service providers could benefit from including family carers in their efforts to support smoking cessation for people with mental illness who smoke.


Photoemission and photoionization time delays and rates.
Ionization and, in particular, ionization through the interaction with light play an important role in fundamental processes in physics, chemistry, and biology. In recent years, we have seen tremendous advances in our ability to measure the dynamics of photo-induced ionization in various systems in the gas, liquid, or solid phase. In this review, we will define the parameters used for quantifying these dynamics. We give a brief overview of some of the most important ionization processes and how to resolve the associated time delays and rates. With regard to time delays, we ask the question: how long does it take to remove an electron from an atom, molecule, or solid? With regard to rates, we ask the question: how many electrons are emitted in a given unit of time? We present state-of-the-art results on ionization and photoemission time delays and rates. Our review starts with the simplest physical systems: the attosecond dynamics of single-photon and tunnel ionization of atoms in the gas phase. We then extend the discussion to molecular gases and ionization of liquid targets. Finally, we present the measurements of ionization delays in femto- and attosecond photoemission from the solid-vacuum interface.


Effects of complex decongestive physiotherapy on the oedema and the quality of life of lower unilateral lymphoedema following treatment for gynecological cancer.
There is increasing interest in the health-related quality of life (QOL) of patients with chronic lymphoedema. The purpose of the present study was to ascertain whether or not complex decongestive physiotherapy (CDP) for 57 gynecological cancer patients with unilateral lymphedema results in a measurable change in the oedema and QOL, and % excess volume correlated with change in QOL. % excess volume was significantly (P<0.05) decreased after CDP. The QOL scores were significantly (P<0.05) higher than the scores at baseline, indicating an improvement in the QOL. The change in % excess volume was associated with a change in physical functioning, social functioning, role-physical, bodily pain and general health at baseline and 1 month (P<0.05). This study suggests that significant improvements are made in the QOL of gynecological cancer patients with unilateral lymphoedema after CDP, which is necessarily correlated with limb reduction.


Eye movements discriminate fatigue due to chronotypical factors and time spent on task--a double dissociation.
Systematic differences in circadian rhythmicity are thought to be a substantial factor determining inter-individual differences in fatigue and cognitive performance. The synchronicity effect (when time of testing coincides with the respective circadian peak period) seems to play an important role. Eye movements have been shown to be a reliable indicator of fatigue due to sleep deprivation or time spent on cognitive tasks. However, eye movements have not been used so far to investigate the circadian synchronicity effect and the resulting differences in fatigue. The aim of the present study was to assess how different oculomotor parameters in a free visual exploration task are influenced by: a) fatigue due to chronotypical factors (being a 'morning type' or an 'evening type'); b) fatigue due to the time spent on task. Eighteen healthy participants performed a free visual exploration task of naturalistic pictures while their eye movements were recorded. The task was performed twice, once at their optimal and once at their non-optimal time of the day. Moreover, participants rated their subjective fatigue. The non-optimal time of the day triggered a significant and stable increase in the mean visual fixation duration during the free visual exploration task for both chronotypes. The increase in the mean visual fixation duration correlated with the difference in subjectively perceived fatigue at optimal and non-optimal times of the day. Conversely, the mean saccadic speed significantly and progressively decreased throughout the duration of the task, but was not influenced by the optimal or non-optimal time of the day for both chronotypes. The results suggest that different oculomotor parameters are discriminative for fatigue due to different sources. A decrease in saccadic speed seems to reflect fatigue due to time spent on task, whereas an increase in mean fixation duration a lack of synchronicity between chronotype and time of the day.


Hatching date influences age at first reproduction in the black-headed gull.
In long-lived colonial birds, age at recruitment is an important life-history character. Variation in this parameter may reflect differences in several factors, including competitive ability and breeding strategies. Further, these differences may be due to timing of hatching (for instance through differences in competitive ability). We investigated the age of first-time breeders in relation to hatching date in a black-headed gull Larus ridibundus colony situated in central France, from 1979 to 1993. Age at first breeding was estimated for four groups of individuals (total n=550) according to their hatching date, using a recent capture-recapture methodology which allowed us to estimate recruitment rate without the limiting assumptions of methods relying on simple return rates. The age at first breeding was negatively correlated with the hatching date of individuals: individuals hatched earlier in the season started breeding at a younger age than individuals born later. Proportionally more 2-year-old late-hatched individuals were seen breeding on small peripheral colonies than young early-hatched individuals. This difference disappeared after age 3 years. These results strongly suggest that individuals hatched late in the season start to breed on peripheral colonies before recruiting to their natal colony. A difference of few weeks in hatching date has consequences which can last for several years.


Measurements of the production cross section of a [Formula: see text] boson in association with jets in pp collisions at [Formula: see text] TeV with the ATLAS detector.
Measurements of the production cross section of a [Formula: see text] boson in association with jets in proton-proton collisions at [Formula: see text] TeV are presented, using data corresponding to an integrated luminosity of 3.16 fb[Formula: see text] collected by the ATLAS experiment at the CERN Large Hadron Collider in 2015. Inclusive and differential cross sections are measured for events containing a [Formula: see text] boson decaying to electrons or muons and produced in association with up to seven jets with [Formula: see text] GeV and [Formula: see text]. Predictions from different Monte Carlo generators based on leading-order and next-to-leading-order matrix elements for up to two additional partons interfaced with parton shower and fixed-order predictions at next-to-leading order and next-to-next-to-leading order are compared with the measured cross sections. Good agreement within the uncertainties is observed for most of the modelled quantities, in particular with the generators which use next-to-leading-order matrix elements and the more recent next-to-next-to-leading-order fixed-order predictions.


Methodology for sampling women at high maternal risk in administrative data.
In population level studies, the conventional practice of categorizing women into low and high maternal risk samples relies upon ascertaining the presence of various comorbid conditions in administrative data. Two problems with the conventional method include variability in the recommended comorbidities to consider and inability to distinguish between maternal and fetal risks. High maternal risk sample selection may be improved by using the Obstetric Comorbidity Index (OCI), a system of risk scoring based on weighting comorbidities associated with maternal end organ damage. The purpose of this study was to compare the net benefit of using OCI risk scoring vs the conventional risk identification method to identify a sample of women at high maternal risk in administrative data. This was a net benefit analysis using linked delivery hospitalization discharge and vital records data for women experiencing singleton births in Georgia from 2008 to 2012. We compared the value identifying a sample of women at high maternal risk using the OCI score to the conventional method of dichotomous identification of any comorbidities. Value was measured by the ability to select a sample of women designated as high maternal risk who experienced severe maternal morbidity or mortality. The high maternal risk sample created with the OCI had a small but positive net benefit (+ 0.6), while the conventionally derived sample had a negative net benefit indicating the sample selection performed worse than identifying no woman as high maternal risk. The OCI can be used to select women at high maternal risk in administrative data. The OCI provides a consistent method of identification for women at risk of maternal morbidity and mortality and avoids confounding all obstetric risk factors with specific maternal risk factors. Using the OCI may help reduce misclassification as high maternal risk and improve the consistency in identifying women at high maternal risk in administrative data.


Natural and experimental infection with an attaching and effacing strain of Escherichia coli in calves.
Gnotobiotic calves were inoculated with an O5:K4:H-, urease-positive strain of Escherichia coli isolated from a 2-day-old calf with diarrhea. The calves developed elevated temperatures and passed loose mucoid feces, with or without blood. The E. coli strain was negative for heat-stable and heat-labile enterotoxins but produced high levels of Shiga-like toxin. Bacteria attached diffusely to the epithelium of the large intestine and multifocally to the epithelium of the ileum. The duodenum and jejunum were not affected. At the sites of bacterial attachment, microvilli were effaced, enterocytes were degenerate, and necrosis and exfoliation had occurred. These results confirm a previous report from England that calves may naturally contract infections similar to those caused by enteropathogenic E. coli strains pathogenic to humans or rabbits. This suggests that the calf bacterial strains, like some enteropathogenic E. coli strains, produce high levels of Shiga-like toxin and cause attachment and effacement lesions in the colonic epithelium of the infected host.


Large magneto-thermopower in MnGe with topological spin texture.
Quantum states characterized by nontrivial topology produce interesting electrodynamics and versatile electronic functionalities. One source for such remarkable phenomena is emergent electromagnetic field, which is the outcome of interplay between topological spin structures with scalar spin chirality and conduction electrons. However, it has scarcely been exploited for emergent function related to heat-electricity conversion. Here we report an unusually enhanced thermopower by application of magnetic field in MnGe hosting topological spin textures. By considering all conceivable origins through quantitative investigations of electronic structures and properties, a possible origin of large magneto-thermopower is assigned to the strong energy dependence of charge-transport lifetime caused by unconventional carrier scattering via the dynamics of emergent magnetic field. Furthermore, high-magnetic-field measurements corroborate the presence of residual magnetic fluctuations even in the nominally ferromagnetic region, leading to a subsisting behavior of field-enhanced thermopower. The present finding may pave a way for thermoelectric function of topological magnets.


Stimulus intensity dependence of cerebral blood volume changes in left frontal lobe by low-frequency rTMS to right frontal lobe: A near-infrared spectroscopy study.
Repetitive transcranial magnetic stimulation (rTMS) has recently been widely employed for the investigation of brain function and treatment of psychiatric and neurological disorders. Although high and low stimulation frequencies are assumed to activate and deactivate brain function, respectively, the optimal parameters of rTMS for treatment of depression have been determined only on the basis of their clinical efficacy. In this study, we administered a 60-s low-frequency rTMS of three grades low intensities over the right dorsolateral prefrontal cortex (DLPFC) in 10 healthy volunteers, and monitored functional changes of the contralateral DLPFC by near-infrared spectroscopy (NIRS) during and immediately after rTMS. Obtained results demonstrated significant [oxy-Hb] decreases during rTMS, and significant differences in the time courses of [oxy-Hb] changes among three stimulus intensities, that is, [oxy-Hb] decreases were most prominent during the latter half of the stimulation and the first 30s of poststimulation only at 15mm condition (58% intensity). These results suggest that monitoring of brain functional changes due to rTMS using NIRS is useful for elucidating the brain mechanisms underlying the clinical effects of rTMS, and the effects of rTMS over contralateral DLPFC are obtained if the stimulus intensities are more than one-half of the motor thresholds.


Distributed Cognition: Understanding Complex Sociotechnical Informatics.
Distributed cognition theory posits that our cognitive tasks are so tightly coupled to the environment that cognition extends into the environment, beyond the skin and the skull. It uses cognitive concepts to describe information processing across external representations, social networks and across different periods of time. Distributed cognition lends itself to exploring how people interact with technology in the workplace, issues to do with communication and coordination, how people's thinking extends into the environment and sociotechnical system architecture and performance more broadly. We provide an overview of early work that established distributed cognition theory, describe more recent work that facilitates its application, and outline how this theory has been used in health informatics. We present two use cases to show how distributed cognition can be used at the formative and summative stages of a project life cycle. In both cases, key determinants that influence performance of the sociotechnical system and/or the technology are identified. We argue that distributed cognition theory can have descriptive, rhetorical, inferential and application power. For evidence-based health informatics it can lead to design changes and hypotheses that can be tested.


Molecular manipulation of keratin 8/18 intermediate filaments: modulators of FAS-mediated death signaling in human ovarian granulosa tumor cells.
Granulosa cell tumors (GCT) are a rare ovarian neoplasm but prognosis is poor following recurrence. Keratin intermediate filaments expressed in these tumors are a diagnostic marker, yet paradoxically, may also constitute a target for therapeutic intervention. In the current study, we evaluated keratin 8/18 (K8/18) filament expression as a mechanism of resistance to apoptosis in GCT, specifically focusing on regulation of the cell surface death receptor, Fas (FAS). The GCT cell line, KGN, was transiently transfected with siRNA to KRT8 and KRT18 to reduce K8/18 filament expression. Expression of K8/18, FAS, and apoptotic proteins (PARP, cleaved PARP) were evaluated by fluorescence microscopy, flow cytometric analysis, and immunoblotting, respectively. The incidence of FAS-mediated apoptosis in KGN cells was measured by caspase 3/7 activity. All experiments were performed independently three to six times, using a fresh aliquot of KGN cells for each experiment. Quantitative data were analyzed by one- or two-way analysis of variance (ANOVA), followed by a Tukey's post-test for multiple comparisons; differences among means were considered statistically significant at P < 0.05. Control cultures of KGN cells exhibited abundant K8/18 filament expression (~90 % of cells), and minimal expression of FAS (<25 % of cells). These cells were resistant to FAS-activating antibody (FasAb)-induced apoptosis, as determined by detection of cleaved PARP and measurement of caspase 3/7 activity. Conversely, siRNA-mediated knock-down of K8/18 filament expression enhanced FAS expression (> 70 % of cells) and facilitated FasAb-induced apoptosis, evident by increased caspase 3/7 activity (P < 0.05). Additional experiments revealed that inhibition of protein synthesis, but not MEK1/2 or PI3K signaling, also prompted FasAb-induced apoptosis. The results demonstrated that K8/18 filaments provide resistance to apoptosis in GCT by impairing FAS expression. The abundance of keratin filaments in these cells and their role in apoptotic resistance provides a greater mechanistic understanding of ovarian tumorgenicity, specifically GCT, as well as a clinically-relevant target for potential therapeutic intervention.


Anatomical and Gene Expression Changes in the Retinal Pigmented Epithelium Atrophy 1 (rpea1) Mouse: A Potential Model of Serous Retinal Detachment.
The purpose of this study was to examine the rpea1 mouse whose retina spontaneously detaches from the underlying RPE as a potential model for studying the cellular effects of serous retinal detachment (SRD). Optical coherence tomography (OCT) was performed immediately prior to euthanasia; retinal tissue was subsequently prepared for Western blotting, microarray analysis, immunocytochemistry, and light and electron microscopy (LM, EM). By postnatal day (P) 30, OCT, LM, and EM revealed the presence of small shallow detachments that increased in number and size over time. By P60 in regions of detachment, there was a dramatic loss of PNA binding around cones in the interphotoreceptor matrix and a concomitant increase in labeling of the outer nuclear layer and rod synaptic terminals. Retinal pigment epithelium wholemounts revealed a patchy loss in immunolabeling for both ezrin and aquaporin 1. Anti-ezrin labeling was lost from small regions of the RPE apical surface underlying detachments at P30. Labeling for tight-junction proteins provided a regular array of profiles outlining the periphery of RPE cells in wild-type tissue, however, this pattern was disrupted in the mutant as early as P30. Microarray analysis revealed a broad range of changes in genes involved in metabolism, signaling, cell polarity, and tight-junction organization. These data indicate changes in this mutant mouse that may provide clues to the underlying mechanisms of SRD in humans. Importantly, these changes include the production of multiple spontaneous detachments without the presence of a retinal tear or significant degeneration of outer segments, changes in the expression of proteins involved in adhesion and fluid transport, and a disrupted organization of RPE tight junctions that may contribute to the formation of focal detachments.


The development of the psychosocial work environment in Denmark from 1997 to 2005.
The aim of the study was to elucidate the development of the psychosocial work environment in Denmark from 1997-2005. The analyses were based on two national questionnaire surveys (N1=1062; N2=3517) of randomly selected employees who completed the Copenhagen Psychosocial Questionnaire. The psychosocial work environment was described by 19 scales and 6 single items. Quality of leadership and social support from supervisors were the only dimensions that saw improvements. The negative developments were: higher work pace, less influence (job control), less possibilities for development (skill discretion), lower level of meaning of work, more role conflicts, decreased role clarity, reduced sense of community, less social support from colleagues, increased conflicts at work, more threats of violence and more slander and gossip. The psychosocial work environment in Denmark has deteriorated during the period 1997-2005. This deterioration was seen not just among certain groups of employees but in all subgroups, incorporating gender, age and socioeconomic status. The negative development of a country's psychosocial work environment is worrying; as such, there is a strong need to change this negative trend.


Breast tomography with synchrotron radiation: preliminary results.
A system for in vivo breast imaging with monochromatic x-rays has been designed and built at the synchrotron radiation facility Elettra in Trieste (Italy) and will be operational in 2004. The system design involves the possibility of performing both planar mammography and breast tomography. In the present work, the first results obtained with a test set-up for breast tomography are shown and discussed. Tomographic images of in vitro breasts were acquired using monochromatic x-ray beams in the energy range 20-28 keV and a linear array silicon pixel detector. Tomograms were reconstructed using standard filtered backprojection algorithms; the effect of different filters was evaluated. The attenuation coefficients of fibroglandular and adipose tissue were measured, and a quantitative comparison of images acquired at different energies was performed by calculating the differential signal-to-noise ratio of fibroglandular details in adipose tissue. All images required a dose comparable to the dose delivered in clinical, conventional mammography and showed a high resolution of the breast structures without the overlapping effects that limit the visibility of the structures in 2D mammography. A quantitative evaluation of the images proves that the image quality at a given dose increases in the considered energy range and for the considered breast sizes.


Tattoo ink darkening of a yellow tattoo after Q-switched laser treatment.
The popularity of tattoos is burgeoning with 20-30 million tattooed individuals in the Western World. Requests for removal can be expected to rise concurrently with increased applications. Laser removal of tattoos is potentially a more cosmetically acceptable method of removing tattoos than surgical excision or dermabrasion. Nevertheless, complications and side-effects can result from laser treatment and include scarring, hypopigmentation, hyperpigmentation, partial removal, infection, bleeding and tattoo ink darkening. The latter has been reported for flesh-toned and red tattoos. Such a complication has never been reported for the laser treatment of a yellow tattoo in the dermatological literature. We describe a case of tattoo ink darkening of a yellow tattoo after treatment with the 532 nm quality-switched Neodymium : Ytrrium-Aluminium Garnet laser to highlight clinicopathological features. The mechanism by which some tattoos darken after laser treatment is not clearly understood. We review darkening of tattoos after laser treatment to raise awareness of this important complication. This paper will help to facilitate discussions with the patient and in obtaining informed consent prior to commencing treatment. Tattoo ink darkening of a yellow tattoo adds to the growing list of complications resulting from attempts at tattoo removal.


Protooncogene expression and the clinical characteristics of acute nonlymphocytic leukemia: A Leukemia Intergroup pilot study.
Northern blot analysis was used to assess the level of expression of five protooncogenes and histone H3 in the bone marrow cells of patients with acute nonlymphocytic leukemia (ANLL). The relationship between the level of gene expression and the clinical characteristics of the disease and response to therapy was studied. The levels of expression of c-myc and c-myb are weakly correlated and are unrelated to French-American-British (FAB) type of ANLL. The levels of expression of c-fms, c-fes, and c-fos are highly correlated with each other and are highest in leukemia with a monocytic component (c-fms v FAB = .71, c-fes v FAB = .75). High levels of c-myc expression are associated with a high probability of not responding to remission induction therapy (P = .004). The converse is true for c-fms expression levels. High levels of expression of c-myc or c-myb are associated with short remissions (P = .059 and .065, respectively), perhaps because they are associated with a high capacity for leukemic cell self-renewal and/or an inability of leukemic cells to differentiate in response to chemotherapy.


Tenofovir disoproxil fumarate versus adefovir dipivoxil for chronic hepatitis B.
Tenofovir disoproxil fumarate (DF) is a nucleotide analogue and a potent inhibitor of human immunodeficiency virus type 1 reverse transcriptase and hepatitis B virus (HBV) polymerase. In two double-blind, phase 3 studies, we randomly assigned patients with hepatitis B e antigen (HBeAg)-negative or HBeAg-positive chronic HBV infection to receive tenofovir DF or adefovir dipivoxil (ratio, 2:1) once daily for 48 weeks. The primary efficacy end point was a plasma HBV DNA level of less than 400 copies per milliliter (69 IU per milliliter) and histologic improvement (i.e., a reduction in the Knodell necroinflammation score of 2 or more points without worsening fibrosis) at week 48. Secondary end points included viral suppression (i.e., an HBV DNA level of <400 copies per milliliter), histologic improvement, serologic response, normalization of alanine aminotransferase levels, and development of resistance mutations. At week 48, in both studies, a significantly higher proportion of patients receiving tenofovir DF than of those receiving adefovir dipivoxil had reached the primary end point (P<0.001). Viral suppression occurred in more HBeAg-negative patients receiving tenofovir DF than patients receiving adefovir dipivoxil (93% vs. 63%, P<0.001) and in more HBeAg-positive patients receiving tenofovir DF than patients receiving adefovir dipivoxil (76% vs. 13%, P<0.001). Significantly more HBeAg-positive patients treated with tenofovir DF than those treated with adefovir dipivoxil had normalized alanine aminotransferase levels (68% vs. 54%, P=0.03) and loss of hepatitis B surface antigen (3% vs. 0%, P=0.02). At week 48, amino acid substitutions within HBV DNA polymerase associated with phenotypic resistance to tenofovir DF or other drugs to treat HBV infection had not developed in any of the patients. Tenofovir DF produced a similar HBV DNA response in patients who had previously received lamivudine and in those who had not. The safety profile was similar for the two treatments in both studies. Among patients with chronic HBV infection, tenofovir DF at a daily dose of 300 mg had superior antiviral efficacy with a similar safety profile as compared with adefovir dipivoxil at a daily dose of 10 mg through week 48. (ClinicalTrials.gov numbers, NCT00116805 and NCT00117676.)


An evaluation of antifungal agents for the treatment of fungal contamination in indoor air environments.
Fungal contamination in indoor environments has been associated with adverse health effects for the inhabitants. Remediation of fungal contamination requires removal of the fungi present and modifying the indoor environment to become less favourable to growth. This may include treatment of indoor environments with an antifungal agent to prevent future growth. However there are limited published data or advice on chemical agents suitable for indoor fungal remediation. The aim of this study was to assess the relative efficacies of five commercially available cleaning agents with published or anecdotal use for indoor fungal remediation. The five agents included two common multi-purpose industrial disinfectants (Cavicide® and Virkon®), 70% ethanol, vinegar (4.0%-4.2% acetic acid), and a plant-derived compound (tea tree (Melaleuca alternifolia) oil) tested in both a liquid and vapour form. Tea tree oil has recently generated interest for its antimicrobial efficacy in clinical settings, but has not been widely employed for fungal remediation. Each antifungal agent was assessed for fungal growth inhibition using a disc diffusion method against a representative species from two common fungal genera, (Aspergillus fumigatus and Penicillium chrysogenum), which were isolated from air samples and are commonly found in indoor air. Tea tree oil demonstrated the greatest inhibitory effect on the growth of both fungi, applied in either a liquid or vapour form. Cavicide® and Virkon® demonstrated similar, although less, growth inhibition of both genera. Vinegar (4.0%-4.2% acetic acid) was found to only inhibit the growth of P. chrysogenum, while 70% ethanol was found to have no inhibitory effect on the growth of either fungi. There was a notable inhibition in sporulation, distinct from growth inhibition after exposure to tea tree oil, Virkon®, Cavicide® and vinegar. Results demonstrate that common cleaning and antifungal agents differ in their capacity to inhibit the growth of fungal genera found in the indoor air environment. The results indicate that tea tree oil was the most effective antifungal agent tested, and may have industrial application for the remediation of fungal contamination in residential and occupational buildings.


Switching of dominant retrotransposon silencing strategies from posttranscriptional to transcriptional mechanisms during male germ-cell development in mice.
Mammalian genomes harbor millions of retrotransposon copies, some of which are transpositionally active. In mouse prospermatogonia, PIWI-interacting small RNAs (piRNAs) combat retrotransposon activity to maintain the genomic integrity. The piRNA system destroys retrotransposon-derived RNAs and guides de novo DNA methylation at some retrotransposon promoters. However, it remains unclear whether DNA methylation contributes to retrotransposon silencing in prospermatogonia. We have performed comprehensive studies of DNA methylation and polyA(+) RNAs (transcriptome) in developing male germ cells from Pld6/Mitopld and Dnmt3l knockout mice, which are defective in piRNA biogenesis and de novo DNA methylation, respectively. The Dnmt3l mutation greatly reduced DNA methylation levels at most retrotransposons, but its impact on their RNA abundance was limited in prospermatogonia. In Pld6 mutant germ cells, although only a few retrotransposons exhibited reduced DNA methylation, many showed increased expression at the RNA level. More detailed analysis of RNA sequencing, nascent RNA quantification, profiling of cleaved RNA ends, and the results obtained from double knockout mice suggest that PLD6 works mainly at the posttranscriptional level. The increase in retrotransposon expression was larger in Pld6 mutants than it was in Dnmt3l mutants, suggesting that RNA degradation by the piRNA system plays a more important role than does DNA methylation in prospermatogonia. However, DNA methylation had a long-term effect: hypomethylation caused by the Pld6 or Dnmt3l mutation resulted in increased retrotransposon expression in meiotic spermatocytes. Thus, posttranscriptional silencing plays an important role in the early stage of germ cell development, then transcriptional silencing becomes important in later stages. In addition, intergenic and intronic retrotransposon sequences, in particular those containing the antisense L1 promoters, drove ectopic expression of nearby genes in both mutant spermatocytes, suggesting that retrotransposon silencing is important for the maintenance of not only genomic integrity but also transcriptomic integrity.


A systematic review of school-based interventions targeting social communication behaviors for students with autism.
Initiating and responding to peers are social communication behaviors which are challenging for students with autism. We reviewed intervention studies set in mainstream elementary schools, which targeted these behaviors and reported on intervention outcomes as well as the resources required for their implementation. A total of 22 studies met the criteria for inclusion. Findings suggest that school-based interventions can increase the frequency and duration of initiating and responding behaviors in elementary school aged students with autism. These interventions were resource-intensive and usually delivered by researchers or teaching assistants away from the classroom. Future research should build on this emerging evidence base to consider interventions which could be implemented by classroom teachers as part of the classroom program.


Tissue zinc status and drug elimination in patients with chronic liver disease.
1. The zinc status and drug-metabolizing ability of 15 patients with histologically diagnosed hepatic cirrhosis were studied. Zinc status was assessed using both serum and leucocyte zinc concentrations, and drug-metabolizing ability was assessed by antipyrine kinetics. 2. Patients with cirrhosis were found to have lower serum and leucocyte zinc concentrations when compared with a healthy control group. 3. Leucocyte zinc content and antipyrine clearance were correlated. Those patients with the lowest leucocyte zinc content had the greatest impairment of drug metabolism. Antipyrine elimination and serum zinc concentrations were not correlated. 4. Leucocyte zinc concentrations and antipyrine clearance were not influenced by the severity of liver dysfunction, as assessed by using the Child Turcotte classification. 5. These results suggest that tissue zinc depletion in some patients with hepatic cirrhosis may explain in part the impaired capacity to metabolize drugs.


The Depression Network (DeNT) Study: methodology and sociodemographic characteristics of the first 470 affected sibling pairs from a large multi-site linkage genetic study.
The Depression Network Study (DeNt) is a multicentre study designed to identify genes and/or loci linked to and/or associated with susceptibility to unipolar depression in Caucasian families. This study presents the method and socio-demographic details of the first 470 affected sibling pairs recruited from 8 different sites in Europe and the United States of America. Probands fulfilling either the Diagnostic and Statistical Manual 4th edition (DSM-IV) or the International Classification of Diseases 10th edition (ICD-10) criteria for recurrent unipolar depression of moderate or severe degree and who had at least one similarly affected sibling were eligible for the study. Detailed clinical and psychological assessments were undertaken on all subjects including an interview using the Schedules for Clinical Assessment in Neuropsychiatry. Blood samples were collected from all participants to extract DNA for linkage analysis. The different sites used different recruitment strategies depending on local health care organisation but despite this there was remarkable similarity across sites for the subjects recruited. Although the Bonn site had significantly older subjects both for age of onset and age at interview, for the sample as a whole, subjects were interviewed in their mid-40s and had experienced the onset of their recurrent depression in their 20s. Preliminary genome screening was able to include 929 out of the 944 subjects (98.4%) typed at 932 autosomal and 544 X chromosome markers. This paper describes the methodology and the characteristics of the subjects from the 414 families included in the first wave of genotyping from the multi-site DeNT study. Ultimately the study aims to collect affected sibling pairs from approximately 1200 families.


Studies on the assay, activity and sedimentation behaviour of acetyl-CoA carboxylase from isolated hepatocytes incubated with insulin or glucagon.
The activity of acetyl-CoA carboxylase, measured in various ways, was studied in 15000g extracts of rat liver hepatocytes and compared with the rate of fatty acid synthesis in intact hepatocytes incubated with insulin or glucagon. Hepatocyte extracts were prepared by disruption of cells with a Dounce homogenizer or by solubilization with 1.5% (v/v) Triton X-100. Sucrose-density-gradient centrifugation demonstrated that the sedimentation coefficient of acetyl-CoA carboxylase from cell extracts was 30-35S, regardless of the conditions of incubation or disruption of hepatocytes. Solubilization of cells with 1.5% Triton X-100 yielded twice as much enzyme activity (measured by [14C]bicarbonate fixation) in the sucrose-gradient fractions as did cell disruption by the Dounce homogenizer. Analysis by high-performance liquid chromatography of acetyl-CoA carboxylase reaction mixtures showed that [14C]malonyl-CoA accounted for 10-60% of the total acid-stable radioactivity, depending on the method for disrupting hepatocytes and on the preincubation of the 15000g extract, with or without citrate, before assay. Under conditions in which incubation of cells with insulin or glucagon caused an activation or inhibition, respectively, of acetyl-CoA carboxylase, only 25% of the acid-stable radioactivity was [14C]malonyl-CoA and enzyme activity was only 13% (control), 16% (insulin), and 57% (glucagon) of the rate of fatty acid synthesis. Under conditions when up to 60% of the acid-stable radioactivity was [14C]malonyl-CoA and acetyl-CoA carboxylase activity was comparable with the rate of fatty acid synthesis, there was no effect of insulin or glucagon on enzyme activity.


Sequential injection chemiluminescence immunoassay for anionic surfactants using magnetic microbeads immobilized with an antibody.
A rapid and sensitive immunoassay for the determination of linear alkylbenzene sulfonates (LAS) is described. The method involves a sequential injection analysis (SIA) system equipped with a chemiluminescence detector and a neodymium magnet. Magnetic beads, to which an anti-LAS monoclonal antibody was immobilized, were used as a solid support in an immunoassay. The introduction, trapping and release of the magnetic beads in the flow cell were controlled by means of a neodymium magnet and adjusting the flow of the carrier solution. The immunoassay was based on an indirect competitive immunoreaction of an anti-LAS monoclonal antibody on the magnetic beads and the LAS sample and horseradish peroxidase (HRP)-labeled LAS, and was based on the subsequent chemiluminscence reaction of HRP with hydrogen peroxide and p-iodophenol, in a luminol solution. The anti-LAS antibody was immobilized on the beads by coupling the antibody with the magnetic beads after activation of a carboxylate moiety on the surface of magnetic beads that had been coated with a polylactic acid film. The antibody immobilized magnetic beads were introduced, and trapped in the flow cell equipped with the neodymium magnet, an LAS solution containing HRP-labeled LAS at constant concentration and the luminol solution were sequentially introduced into the flow cell based on an SIA programmed sequence. Chemiluminescence emission was monitored by means of a photon counting unit located at the upper side of the flow cell by collecting the emitted light with a lens. A typical sigmoid calibration curve was obtained, when the logarithm of the concentration of LAS was plotted against the chemiluminescence intensity using various concentrations of standard LAS samples (0-500ppb) under optimum conditions. The time required for analysis is less than 15min.