Hypertrophic cardiomyopathy due to sarcomeric gene mutations is characterized by impaired energy metabolism irrespective of the degree of hypertrophy.
We investigated cardiac energetics in subjects with mutations in three different familial hypertrophic cardiomyopathy (HCM) disease genes, some of whom were nonpenetrant carriers without hypertrophy, using phosphorus-31 magnetic resonance spectroscopy. Familial hypertrophic cardiomyopathy is caused by mutations in sarcomeric protein genes. The mechanism by which these mutant proteins cause disease is uncertain. A defect of myocyte contractility had been proposed, but in vitro studies of force generation have subsequently shown opposing results in different classes of mutation. An alternative hypothesis of "energy compromise" resulting from inefficient utilization of adenosine triphosphate (ATP) has been suggested, but in vivo data in humans with genotyped HCM are lacking. The cardiac phosphocreatine (PCr) to ATP ratio was determined at rest in 31 patients harboring mutations in the genes for either beta-myosin heavy chain, cardiac troponin T, or myosin-binding protein C, and in 24 controls. Transthoracic echocardiography was used to measure left ventricular (LV) dimensions and maximal wall thickness. The PCr/ATP was reduced in the HCM subjects by 30% relative to controls (1.70 +/- 0.43 vs. 2.44 +/- 0.30; p < 0.001), and the reduction was of a similar magnitude in all three disease-gene groups. The PCr/ATP was equally reduced in subjects with (n = 24) and without (n = 7) LV hypertrophy. Our data provide evidence of a bioenergetic deficit in genotype-confirmed HCM, which is present to a similar degree in three disease-gene groups. The presence of energetic abnormalities, even in those without hypertrophy, supports a proposed link between altered cardiac energetics and development of the disease phenotype.


Elevations in serum muscle enzyme activities in racehorses due to unaccustomed exercise and training.
Hereditary muscular disease is well described in racehorses, yet little is known about traumatic muscle disease associated with unaccustomed exercise or training. The objective of the study was to compare sedentary horses, racehorses undergoing training for the first time (unaccustomed exercise), and experienced racehorses during a training season (accustomed exercise) to investigate the effect of exercise and training on serum muscle enzyme activities and other variables. Horses were sampled prior to exercise for serum activities of aspartate amino transferase (AST), creatine kinase and other variables γ glutamyl transferase (GGT) and serum amyloid A (SAA) in a three-part study. Serum activities of AST and GGT were higher in fit racehorses (n=47) compared with sedentary horses (n=57) at a single time point (P<0.05). The monthly serum activity of AST in two-year-old racehorses (n=10) increased from month 1 to 4 of unaccustomed training (P<0.05). The serum activities of AST and GGT in three-year-old racehorses (n=12) previously accustomed to exercise sampled fortnightly to monthly showed a linear increase (P<0.05) with cumulative training days over the seven months of training, but showed minimal increase during the first four months of accustomed training. SAA was weakly correlated to cumulative training days. In conclusion, AST activity was increased by unaccustomed exercise and cumulative training stress in the racehorse. GGT appeared to be correlated to cumulative training load. Mild to moderate elevations in serum AST in racehorses may be associated with cumulative muscle damage from training or trauma associated with unaccustomed exercise.


The diagnosis of low-grade peripheral B-cell neoplasms in bone marrow trephines.
The aim of this study was to establish how effective is the use of immunohistochemistry on formalin-fixed bone marrow in diagnosing low-grade B-cell neoplasms. We investigated a series of 41 consecutive patients with bone marrow involvement for whom no other diagnostic tissues were available. The sections were stained with the following antibodies: CD3, CD20, CD79a, CD5, CD10, CD23, anti-cyclin D1 and kappa and lambda light chains. Antigen retrieval was performed using either a microwave oven or a pressure cooker. Labelling was performed with an avidin-biotin-peroxidase labelling system. A final diagnosis was reached in 37 out of 41 cases (90%): B-chronic lymphocytic leukaemia (15 cases), follicular lymphoma (10 cases), mantle-cell lymphoma (eight cases) and lymphoplasmacytoid lymphoma/immunocytoma (four cases). In the remaining four cases, a generic diagnosis of low-grade B-cell neoplasm was made. The immunophenotyping of formalin-fixed marrow is a useful technique for diagnosing most of the low-grade B-cell neoplasms.


Group B Streptococcus Induces Neutrophil Recruitment to Gestational Tissues and Elaboration of Extracellular Traps and Nutritional Immunity.
Streptococcus agalactiae, or Group B Streptococcus (GBS), is a gram-positive bacterial pathogen associated with infection during pregnancy and is a major cause of morbidity and mortality in neonates. Infection of the extraplacental membranes surrounding the developing fetus, a condition known as chorioamnionitis, is characterized histopathologically by profound infiltration of polymorphonuclear cells (PMNs, neutrophils) and greatly increases the risk for preterm labor, stillbirth, or neonatal GBS infection. The advent of animal models of chorioamnionitis provides a powerful tool to study host-pathogen relationships in vivo and ex vivo. The purpose of this study was to evaluate the innate immune response elicited by GBS and evaluate how antimicrobial strategies elaborated by these innate immune cells affect bacteria. Our work using a mouse model of GBS ascending vaginal infection during pregnancy reveals that clinically isolated GBS has the capacity to invade reproductive tissues and elicit host immune responses including infiltration of PMNs within the choriodecidua and placenta during infection, mirroring the human condition. Upon interacting with GBS, murine neutrophils elaborate DNA-containing extracellular traps, which immobilize GBS and are studded with antimicrobial molecules including lactoferrin. Exposure of GBS to holo- or apo-forms of lactoferrin reveals that the iron-sequestration activity of lactoferrin represses GBS growth and viability in a dose-dependent manner. Together, these data indicate that the mouse model of ascending infection is a useful tool to recapitulate human models of GBS infection during pregnancy. Furthermore, this work reveals that neutrophil extracellular traps ensnare GBS and repress bacterial growth via deposition of antimicrobial molecules, which drive nutritional immunity via metal sequestration strategies.


Instability of a (CGG)98 repeat in the Fmr1 promoter.
Fragile X syndrome is one of 14 trinucleotide repeat diseases. It arises due to expansion of a CGG repeat which is present in the 5'-untranslated region of the FMR1 gene, disruption of which leads to mental retardation. The mechanisms involved in trinucleotide repeat expansion are poorly understood and to date, transgenic mouse models containing transgenic expanded CGG repeats have failed to reproduce the instability seen in humans. As both cis-acting factors and the genomic context of the CGG repeat are thought to play a role in expansion, we have now generated a knock-in mouse Fmr1 gene in which the murine (CGG)8 repeat has been exchanged with a human (CGG)98 repeat. Unlike other CGG transgenic models, this model shows moderate CGG repeat instability upon both in maternal and paternal transmission. This model will now enable us to study the timing and the mechanism of repeat expansion in mice.


Computational Immune Monitoring Reveals Abnormal Double-Negative T Cells Present across Human Tumor Types.
Advances in single-cell biology have enabled measurements of >40 protein features on millions of immune cells within clinical samples. However, the data analysis steps following cell population identification are susceptible to bias, time-consuming, and challenging to compare across studies. Here, an ensemble of unsupervised tools was developed to evaluate four essential types of immune cell information, incorporate changes over time, and address diverse immune monitoring challenges. The four complementary properties characterized were (i) systemic plasticity, (ii) change in population abundance, (iii) change in signature population features, and (iv) novelty of cellular phenotype. Three systems immune monitoring studies were selected to challenge this ensemble approach. In serial biopsies of melanoma tumors undergoing targeted therapy, the ensemble approach revealed enrichment of double-negative (DN) T cells. Melanoma tumor-resident DN T cells were abnormal and phenotypically distinct from those found in nonmalignant lymphoid tissues, but similar to those found in glioblastoma and renal cell carcinoma. Overall, ensemble systems immune monitoring provided a robust, quantitative view of changes in both the system and cell subsets, allowed for transparent review by human experts, and revealed abnormal immune cells present across multiple human tumor types.


Early Readmission Risk Identification for Hospitalized Older Adults With Decompensated Heart Failure.
The current study evaluated risk factors of early hospital readmission in geriatric patients with acute heart failure (HF) and analyzed 2,279 consecutively hospitalized older adults with decompensated HF from November 2013 to October 2014 across 15 U.S. hospitals. The eTracker-HF was designed to make risk factors known to treating clinicians in electronic health records. Multilevel multivariate logistic regression was applied to examine the association between risk factors and all-cause and HF 30-day readmission rates. All-cause and HF 30-day readmission rates were 22.3% and 9.8%, respectively. Old age, non-White ethnicity, delirium, physical impairment, ejection fraction <40%, advanced chronic kidney disease, and previous myocardial infarction were associated with all-cause and HF readmission. Home health care use was inversely associated with early readmission. In addition to demographic and cardiovascular risk factors, geriatric syndromes were associated with early readmission. Discharge to home health care may reduce early readmission in these patients. [Res Gerontol Nurs. 2018; 11(4):190-197.].


Requirements for reliable worst-case assessment of human exposure to RF electromagnetic fields with known uncertainty.
This paper gives an overview of the current state of science on numerical and experimental assessment of the exposure of the human body to radio frequency electromagnetic fields. Differences of near- and far-field exposure conditions are discussed with respect to the requirements on the correct representation of the human body and on the numerical or experimental technique. The general requirements for the application of these techniques on the assessment of human exposure are defined, and a combined numerical and experimental approach is proposed that allows the evaluation of the worst-case absorption considering the variability of exposure situations and anatomical properties with known uncertainty.


Pharmacogenomics and antidepressant drugs.
While antidepressant pharmacotherapy is an effective treatment of depression, it still is hampered by a delayed time of onset of clinical improvement and a series of side effects. Moreover, a substantial group of patients has only limited response or fails to respond at all. One source accounting for these variations are genetic differences as currently analysed by single nucleotide polymorphisms (SNP) mapping. In recent years a number of pharmacogenetic studies on antidepressant drugs have been published. So far they mostly focused on metabolizing enzymes of the cytochrome P450 (CYP) families and genes within the monoaminergic system with compelling evidence for an effect of CYP2D6 polymorphisms on antidepressant drug plasma levels and of a serotonin transporter promoter polymorphism on clinical response to a specific class of antidepressants, the selective serotonin reuptake inhibitors. It is clear, however, that other candidate systems have to be considered in the pharmacogenetics of antidepressant drugs, such as neuropeptidergic systems, the hypothalamus-pituitary adrenal (HPA) axis and neurotrophic systems. There is recent evidence that polymorphisms in genes regulating the HPA axis have an important impact on response to antidepressants. These studies mark the beginning of an emerging standard SNP profiling system that ultimately allows identifying the right drug for the right patient at the right time.


Contact geometry and mechanics predict friction forces during tactile surface exploration.
When we touch an object, complex frictional forces are produced, aiding us in perceiving surface features that help to identify the object at hand, and also facilitating grasping and manipulation. However, even during controlled tactile exploration, sliding friction forces fluctuate greatly, and it is unclear how they relate to the surface topography or mechanics of contact with the finger. We investigated the sliding contact between the finger and different relief surfaces, using high-speed video and force measurements. Informed by these experiments, we developed a friction force model that accounts for surface shape and contact mechanical effects, and is able to predict sliding friction forces for different surfaces and exploration speeds. We also observed that local regions of disconnection between the finger and surface develop near high relief features, due to the stiffness of the finger tissues. Every tested surface had regions that were never contacted by the finger; we refer to these as "tactile blind spots". The results elucidate friction force production during tactile exploration, may aid efforts to connect sensory and motor function of the hand to properties of touched objects, and provide crucial knowledge to inform the rendering of realistic experiences of touch contact in virtual reality.


Surgical Interventions for Advanced Parameningeal Rhabdomyosarcoma of Children and Adolescents.
Owing to its rarity, rhabdomyosarcoma of the head and neck (HNRMS) has seldom been discussed in the literature. As most of the data is based only on the retrospective experiences of tertiary healthcare centers, there are difficulties in formulating a standard treatment protocol. Moreover, the disease is poorly understood at its pathological, genetic, and molecular levels. For instance, 20% of all histological assessment is inaccurate; even an experienced pathologist can confuse rhabdomyosarcoma (RMS) with neuroblastoma, Ewing's sarcoma, and lymphoma. RMS can occur sporadically or in association with genetic syndromes associated with predisposition to other cancers such as Li-Fraumeni syndrome and neurofibromatosis type 1 (von Recklinghausen disease). Such associations have a potential role in future gene therapies but are yet to be fully confirmed. Currently, chemotherapies are ineffective in advanced or metastatic disease and there is lack of targeted chemotherapy or biological therapy against RMS. Also, reported uses of chemotherapy for RMS have not produced reasonable responses in all cases. Despite numerous molecular and biological studies during the past three decades, the chemotherapeutic regimen remains unchanged. This vincristine, actinomycin, cyclophosphamide (VAC) regime, described in Kilman, et al. (1973) and Koop, et al. (1963), has achieved limited success in controlling the progression of RMS. Thus, the pathogenesis of RMS remains poorly understood despite extensive modern trials and more than 30 years of studies exploring the chemotherapeutic options. This suggests a need to explore surgical options for managing the disease. Surgery is the single most critical therapy for pediatric HNRMS. However, very few studies have explored the surgical management of pediatric HNRMS and there is no standard surgical protocol. The aim of this review is to explore and address such issues in the hope of maximizing the number of options available for young patients with HNRMS.


Development and spontaneous regression of a de novo posterior communicating artery aneurysm in a child following gamma knife stereotactic radiosurgical obliteration of a cerebral AVM: Case report and review of the literature.
Reports of the development of true intracranial aneurysms after radiosurgery are exceedingly rare and unconvincing. We report the case of a young boy who developed a posterior communicating artery aneurysm after the Gamma Knife radiosurgical treatment of a thalamic AVM. This ten year-old presented with left upper extremity tremors. MRI/MRA revealed a right thalamic AVM. No intracranial aneurysms were found on initial angiography. The patient underwent two-stage endovascular embolization of his AVM followed by Gamma Knife radiosurgical treatment (18 Gy delivered to the 50% isodose line). Follow up angiogram at 38 months confirmed obliteration of the AVM, but revealed a new 2.2 x 1.5 mm aneurysm located at the origin of the right posterior communicating artery. A MRA obtained 5 months later (43 months after treatment) demonstrated regression of the aneurysm. This is the first report of the development of an intracranial aneurysm after Gamma Knife radiosurgery in a child and the first description to include pre and post-treatment angiography that clearly demonstrates interval aneurysm development. Although the aneurysm showed subsequent regression during continued follow-up, this report illustrates the critical importance of post-treatment angiography for patients with intracranial AVM treated in this manner.


Fabrication of a Flexible Amperometric Glucose Sensor Using Additive Processes.
This study details the use of printing and other additive processes to fabricate a novel amperometric glucose sensor. The sensor was fabricated using a Au coated 12.7 μm thick polyimide substrate as a starting material, where micro-contact printing, electrochemical plating, chloridization, electrohydrodynamic jet (e-jet) printing, and spin coating were used to pattern, deposit, chloridize, print, and coat functional materials, respectively. We have found that e-jet printing was effective for the deposition and patterning of glucose oxidase inks with lateral feature sizes between ~5 to 1000 μm in width, and that the glucose oxidase was still active after printing. The thickness of the permselective layer was optimized to obtain a linear response for glucose concentrations up to 32 mM and no response to acetaminophen, a common interfering compound, was observed. The use of such thin polyimide substrates allow wrapping of the sensors around catheters with high radius of curvature ~250 μm, where additive and microfabrication methods may allow significant cost reductions.


A longitudinal study of aspects of a hospital's family-centred nursing: changing practice through data translation.
To examine how results and data from multiple Family Centred Nursing Index surveys help the development of family-centred nursing at organizational and ward levels. A critical analysis of survey data. The Family Centred Nursing Index provides a valid and reliable assessment of aspects of nursing, through a comprehensive survey of traditional indicators of practice development and a broader range of aspects of practice. A survey with 113 questions, each to be answered on 7-point Likert scale conducted six times in the last 7 years. Surveys have been in 2006, 2008, 2009, 2010, 2011/2012 and 2012/2013. All nurses employed by the organization can participate. These are reported as means across 19 constructs linked to five key domains and their significance is examined by year and (in the clinical settings) and compared against the organizational (whole population) averages. Ongoing survey and analysis of nurses' views of their work is providing a valuable source of developmental data. The results show unexpected associations between constructs e.g. - a high level of work stress does not correlate with a lower level of job satisfaction (and vice versa). A clear historical picture of many elements of developing family-centred care is emerging at both the organizational and individual-ward levels. This study provides insights into aspects of organizational and wards working environment for nurses and how these aspects of nurses' work interact in unexpected ways. It is appropriate for providing information to organizations and ward teams in relation to their development towards family-centred cultures.


High fidelity and lesion bypass capability of human DNA polymerase delta.
DNA polymerase delta (Pol delta) is one of the main replicative DNA polymerases in human cells and therefore is a critical determinant of the overall accuracy of DNA synthesis. Here we document the fidelity of a human Pol delta holoenzyme and systematically score the types of mutations that the enzyme generates in a forward mutation assay. We find that human Pol delta is highly accurate, catalyzing less than one nucleotide mis-insertion per 220,000 nucleotides polymerized. Inactivation of proofreading or mutation of a conserved active site residue significantly elevates the frequency of incorporation errors, demonstrating the contribution of both the base selection and proofreading domains to the overall accuracy of synthesis by Pol delta. The highly selective nature of the polymerase active site is also indicated by the stalling of Pol delta upon encountering multiple types of DNA lesions. However, DNA damage is not an absolute block to Pol delta progression. We propose that partial lesion bypass by Pol delta represents a balance between stalling to allow for repair of mutagenic lesions by specialized repair proteins and bypass of damage to allow for successful completion of DNA synthesis by Pol delta in the presence of weakly blocking DNA adducts.


Social Responsibility and the State's Duty to provide Healthcare: An Islamic Ethico-Legal Perspective.
The United Nations Educational, Scientific and Cultural Organization's (UNESCO) Declaration on Bioethics and Human Rights asserts that governments are morally obliged to promote health and to provide access to quality healthcare, essential medicines and adequate nutrition and water to all members of society. According to UNESCO, this obligation is grounded in a moral commitment to promoting fundamental human rights and emerges from the principle of social responsibility. Yet in an era of ethical pluralism and contentions over the universality of human rights conventions, the extent to which the UNESCO Declaration can motivate behaviors and policies rests, at least in part, upon accepting the moral arguments it makes. In this essay I reflect on a state's moral obligation to provide healthcare from the perspective of Islamic moral theology and law. I examine how Islamic ethico-legal conceptual analogues for human rights and communal responsibility, ḥuqūq al-'ibād and farḍ al-kifāyah and other related constructs might be used to advance a moral argument for healthcare provision by the state. Moving from theory to application, I next illustrate how notions of human rights and social responsibility were used by Muslim stakeholders to buttress moral arguments to support American healthcare reform. In this way, the paper advance discourses on a universal bioethics and common morality by bringing into view the concordances and discordances between Islamic ethico-legal constructs and moral arguments advanced by transnational health policy advocates. It also provides insight into applied Islamic bioethics by demonstrating how Islamic ethico-legal values might inform the discursive outputs of Muslim organizations.


Graphene quantum dots against human IAPP aggregation and toxicity in vivo.
The development of biocompatible nanomaterials has become a new frontier in the detection, treatment and prevention of human amyloid diseases. Here we demonstrated the use of graphene quantum dots (GQDs) as a potent inhibitor against the in vivo aggregation and toxicity of human islet amyloid polypeptide (IAPP), a hallmark of type 2 diabetes. GQDs initiated contact with IAPP through electrostatic and hydrophobic interactions as well as hydrogen bonding, which subsequently drove the peptide fibrillization off-pathway to eliminate the toxic intermediates. Such interactions, probed in vitro by a thioflavin T kinetic assay, fluorescence quenching, circular dichroism spectroscopy, a cell viability assay and in silico by discrete molecular dynamics simulations, translated to a significant recovery of embryonic zebrafish from the damage elicited by IAPP in vivo, as indicated by improved hatching as well as alleviated reactive oxygen species production, abnormality and mortality of the organism. This study points to the potential of using zero-dimensional nanomaterials for in vivo mitigation of a range of amyloidosis.


Tofacitinib for the treatment of tumor necrosis factor-α inhibitor refractory esophageal Crohn's disease: a case report.
Esophageal Crohn's disease is reported as a rare manifestation, although its prevalence may be underestimated because upper endoscopies are not routinely performed in asymptomatic adults. Tofacitinib, an oral janus kinase inhibitor, is a new biologic that has shown promise in the treatment of ulcerative colitis and may be effective in the treatment of Crohn's disease according to phase 2 trials. We report the first case of esophageal Crohn's disease successfully treated with tofacitinib in a patient with worsening symptoms despite maintenance therapy with a tumor necrosis factor-α inhibitor. A 67-year-old Caucasian woman presented with new dysphagia and had findings of esophageal Crohn's disease on endoscopy. The dosage of her current biologic therapy-adalimumab-was increased in frequency, without improvement. Our patient was started on tofacitinib and demonstrated an improvement in symptoms, with a repeat endoscopy showing resolution of the previous lesions. Esophageal Crohn's disease is likely underdiagnosed but is an important consideration in a patient with new symptoms of dysphagia and known Crohn's disease. Tofacitinib, while a novel agent, could have a role in the treatment of esophageal Crohn's disease that does not improve with intensification of the current biologic therapy. It provides a different mechanism in patients who become refractory to maintenance therapy.


The ligand polyhedral model approach to the mechanism of complete carbonyl exchange in [Rh4(CO)12] and [Rh6(CO)16].
The Ligand Polyhedral Model (LPM) is applied to the carbonyl scrambling observed on the NMR timescale for the two cluster carbonyls [Rh4(CO)12] and [Rh6(CO)16]. For [Rh4(CO)12] the NMR data is completely consistent with the libration of the Rh4 central core about a C3 - rotational axis within the icosahedral shell of twelve CO ligands leading to a single-step concerted exchange process. Rotation of the Rh4 unit is also found to lead to the formation of a new all terminally bonded isomer which retains the icosahedral shell of CO ligands. Importantly, this new isomer does not have the [Ir4(CO)12] structure which is known to possess an cube-octahedral ligand shell. With [Rh6(CO)16] and its substituted derivative [Rh6(CO)15L] exchange is considered to take place via a polyhedral inter-conversion in which the external tetra-capped truncated tetrahedral shell of carbonyl ligands observed in the ground-state undergoes rearrangement first to the 2 : 6 : 6' : 2 complementary geometry and then returns to the ground-state structure. This leads to a single-step fully concerted CO exchange. The LPM approach also provides an understanding of the variation of activation energies observed in going from [Rh4(CO)12] to [Rh6(CO)16] and of the driving force to the fluxional process.


Intracellular transport and pathways of carbon flow in plants with crassulacean acid metabolism.
The massive daily reciprocal transfer of carbon between acids and carbohydrates that is unique to crassulacean acid metabolism (CAM) involves extensive and regulated transport of metabolites between chloroplasts, vacuoles, the cytosol and mitochondria. In this review of the CAM pathways of carbon flow and intracellular transport, we highlight what is known and what has been postulated. For three of the four CAM pathway variants currently known (malic enzyme- or PEP carboxykinase-type decarboxylase, and starch- or soluble sugar-type carbohydrate storage), the mechanisms of intracellular transport are still hypothetical and have yet to be demonstrated experimentally. Even in malic enzyme starch-storing species such as Kalanchoë daigremontiana Hamet et Perr. and Mesembryanthemum crystallinum L., the best-described variants of plants with the second-most common mode of photosynthetic carbon metabolism known, no tonoplast or mitochondrial transporter has been functionally described at a molecular level.


Systems approach to understanding electromechanical activity in the human heart: a national heart, lung, and blood institute workshop summary.
The National Heart, Lung, and Blood Institute (NHLBI) convened a workshop of cardiologists, cardiac electrophysiologists, cell biophysicists, and computational modelers on August 20 and 21, 2007, in Washington, DC, to advise the NHLBI on new research directions needed to develop integrative approaches to elucidate human cardiac function. The workshop strove to identify limitations in the use of data from nonhuman animal species for elucidation of human electromechanical function/activity and to identify what specific information on ion channel kinetics, calcium handling, and dynamic changes in the intracellular/extracellular milieu is needed from human cardiac tissues to develop more robust computational models of human cardiac electromechanical activity. This article summarizes the workshop discussions and recommendations on the following topics: (1) limitations of animal models and differences from human electrophysiology, (2) modeling ion channel structure/function in the context of whole-cell electrophysiology, (3) excitation-contraction coupling and regulatory pathways, (4) whole-heart simulations of human electromechanical activity, and (5) what human data are currently needed and how to obtain them. The recommendations can be found on the NHLBI Web site at http://www.nhlbi.nih.gov/meetings/workshops/electro.htm.


More than just a mouse click: research into work practices behind the assignment of medical trust marks on the World Wide Web.
Hyperlinked web trust marks have been a popular topic of discussion during the past 10 years. However, the discussion has focused mostly on what these trust marks are not doing in terms of helping patients (or other lay end users) find reliable medical information on the web. In this paper, we discuss how this focus on patients and their actions with respect to trust marks, has overshadowed, if not rendered invisible, what trust marks are doing to educate medical site/information providers. We draw on data from ethnographic research conducted at the Health on the Net Foundation in 2002 and 2003 in order to explore an alternate definition of what it means to be a 'user' of a trust mark and the importance of the review process in educating site providers. We argue that understanding the work involved in the process of assigning a seal is crucial to understanding the role that the seal plays as part of the medical internet.


Effects of Maternal Vitamin D3 Supplementation on Offspring Epigenetic Clock of Gestational Age at Birth: A Post-hoc Analysis of a Randomized Controlled Trial.
Vitamin D could be beneficial for healthy ageing in humans. We previously found that vitamin D supplementation may slow down epigenetic ageing in young African American adults. We tested new epigenetic clocks developed for neonates among a multiethnic population, and tested the hypothesis that maternal vitamin D supplementation would slow down the epigenetic gestational age acceleration (GAA) in newborn babies. Ninety-two pregnant women (aged 29.6 ± 4.8 y; 21% African Americans, 28% Hispanics) were randomized to receive 4000 IU/day vitamin D3 or placebo, plus prenatal vitamins containing 400 IU vitamin D3 during pregnancy in a randomized controlled trial (RCT). Cord blood genome-wide methylation analysis was performed on the Illumina Infinium MethylationEPIC Beadchip. DNA methylation gestational age was calculated based on two calculations developed by Knight and Bohlin. DNA methylation gestational ages calculated by Knight's clock and Bohlin' clock were highly correlated with the gestational age in the placebo group (correlation coefficients = 0.88, p s< 0.001, respectively). GAA was associated with higher birth weight (p = 0.039). In the entire cohort, vitamin D3 supplementation was not associated with GAA (p > 0.05). However, vitamin D3 supplementation decreased GAA by both Knight's clock (β = -0.89, p = 0.047) and Bohlin's clock (β = -0.71, p = 0.005) in the African American participants. Maternal vitamin D3 supplementation may slow down the epigenetic gestational ageing process in African American neonates. Long-term follow-up studies are warranted to determine the role of epigenetic age acceleration in the growth and development of offspring.


Changes in Characteristics and Practice Patterns of Ontario Psychiatrists.
The objective of this study was to evaluate the changes in demographic, geographic, and practice characteristics of all Ontario psychiatrists between 2003 and 2013 and their implication for access to psychiatrists. We included all psychiatrists who were clinically active in Ontario in any year from 2003 to 2013. For each psychiatrist, we reported age, sex, years since medical school graduation, geographic practice region, and practice characteristics such as total number of inpatients, outpatients, and outpatient visit frequencies. In 2013, there were 2070 psychiatrists, with nearly half (47%) more than 30 years since medical school graduation. Female psychiatrists comprised 41% of all psychiatrists in 2013 but 56% of all psychiatrists within 15 years of medical school graduation. Between 2003 and 2013, there was a 17% increase in the total number of psychiatrists, with the largest growth in psychiatrists occurring in the group more than 30 years from medical school graduation. Over these 11 years, the mean (SD) number of unique outpatients seen by a psychiatrist annually increased from 208 (228) to 249 (275) (19.5%; P = 0.001), with male psychiatrists, on average, seeing more outpatients annually than female psychiatrists. The number of outpatients seen by psychiatrists is slowly increasing. However, the large proportion of aging psychiatrists, the high concentration of psychiatrists in urban settings, and the increase in the number of female psychiatrists with smaller practices suggest that without radical changes to the way psychiatrists practice, access to psychiatrists will remain a challenge in Ontario.


Development of telmisartan in the therapy of spinal cord injury: pre-clinical study in rats.
Decrease of peroxisome proliferator-activated receptors-δ (PPARδ) expression has been observed after spinal cord injury (SCI). Increase of PPARδ may improve the damage in SCI. Telmisartan, the antihypertensive agent, has been mentioned to increase the expression of PPARδ. Thus, we are going to screen the effectiveness of telmisartan in SCI for the development of it in clinical application. In the present study, we used compressive SCI in rats. Telmisartan was then used to evaluate the influence in rats after SCI. Change in PPARδ expression was identified by Western blots. Also, behavioral tests were performed to check the recovery of damage. Recovery of damage from SCI was observed in telmisartan-treated rats. Additionally, this action of telmisartan was inhibited by GSK0660 at the dose sufficient to block PPARδ. However, metformin at the dose enough to activate adenosine monophosphate-activated protein kinase failed to produce similar action as telmisartan. Thus, mediation of adenosine monophosphate-activated protein kinase in this action of telmisartan can be rule out. Moreover, telmisartan reversed the expressions of PPARδ in rats with SCI. The obtained data suggest that telmisartan can improve the damage of SCI in rats through an increase in PPARδ expression. Thus, telmisartan is useful to be developed as an agent in the therapy of SCI.


Polyamines in foods: development of a food database.
Knowing the levels of polyamines (putrescine, spermidine, and spermine) in different foods is of interest due to the association of these bioactive nutrients to health and diseases. There is a lack of relevant information on their contents in foods. To develop a food polyamine database from published data by which polyamine intake and food contribution to this intake can be estimated, and to determine the levels of polyamines in Swedish dairy products. Extensive literature search and laboratory analysis of selected Swedish dairy products. Polyamine contents in foods were collected using an extensive literature search of databases. Polyamines in different types of Swedish dairy products (milk with different fat percentages, yogurt, cheeses, and sour milk) were determined using high performance liquid chromatography (HPLC) equipped with a UV detector. Fruits and cheese were the highest sources of putrescine, while vegetables and meat products were found to be rich in spermidine and spermine, respectively. The content of polyamines in cheese varied considerably between studies. In analyzed Swedish dairy products, matured cheese had the highest total polyamine contents with values of 52.3, 1.2, and 2.6 mg/kg for putrescine, spermidine, and spermine, respectively. Low fat milk had higher putrescine and spermidine, 1.2 and 1.0 mg/kg, respectively, than the other types of milk. The database aids other researchers in their quest for information regarding polyamine intake from foods. Connecting the polyamine contents in food with the Swedish Food Database allows for estimation of polyamine contents per portion.


Fishing diseased abalone to promote yield and conservation.
Past theoretical models suggest fishing disease-impacted stocks can reduce parasite transmission, but this is a good management strategy only when the exploitation required to reduce transmission does not overfish the stock. We applied this concept to a red abalone fishery so impacted by an infectious disease (withering syndrome) that stock densities plummeted and managers closed the fishery. In addition to the non-selective fishing strategy considered by past disease-fishing models, we modelled targeting (culling) infected individuals, which is plausible in red abalone because modern diagnostic tools can determine infection without harming landed abalone and the diagnostic cost is minor relative to the catch value. The non-selective abalone fishing required to eradicate parasites exceeded thresholds for abalone sustainability, but targeting infected abalone allowed the fishery to generate yield and reduce parasite prevalence while maintaining stock densities at or above the densities attainable if the population was closed to fishing. The effect was strong enough that stock and yield increased even when the catch was one-third uninfected abalone. These results could apply to other fisheries as the diagnostic costs decline relative to catch value.


Autism in Toddlers Born Very Preterm.
This study aimed to determine the prevalence of autism spectrum disorder (ASD) by using the Autism Diagnostic Observation Schedule-Generic (ADOS-G) classifications in children born very preterm during their toddler years. Two birth cohorts of toddlers (2 and 4 years old) each recruited over 12 months and born at <29 weeks' gestation were administered the Modified Checklist of Autism in Toddlers-Follow-up Interview (M-CHAT-FI) screen, the ADOS-G, and developmental assessments. The ADOS-G was conducted on toddlers with M-CHAT-FI-positive screens. Data were available on 88% (169/192) of children. In total, 22 (13%) toddlers screened positive and 3 (1.8%) were confirmed diagnostically with ASD. These 3 cases reached the highest ADOS-G threshold classification of autism. All but 1 child who scored below the ADOS-G thresholds (11/12) demonstrated some difficulty with social communication. Risk was significantly increased for co-occurring neurodevelopmental problems in 21 of the 22 positive-screen ASD cases. Adaptive behavior (P < .001) was the only co-occurring factor independently predictive of ASD in toddlers. Children born very preterm are at increased risk of ASD. By using the ADOS-G, we found a lower incidence of ASD in children born at <29 weeks' gestation compared with previous studies. Children who screened positive for ASD on the M-CHAT-FI had developmental delays consistent with subthreshold communication impairment.


Zinc oxide nanostructure-modified textile and its application to biosensing, photocatalysis, and as antibacterial material.
Recently, one-dimensional nanostructures with different morphologies (such as nanowires, nanorods (NRs), and nanotubes) have become the focus of intensive research, because of their unique properties with potential applications. Among them, zinc oxide (ZnO) nanomaterials has been found to be highly attractive, because of the remarkable potential for applications in many different areas such as solar cells, sensors, piezoelectric devices, photodiode devices, sun screens, antireflection coatings, and photocatalysis. Here, we present an innovative approach to create a new modified textile by direct in situ growth of vertically aligned one-dimensional (1D) ZnO NRs onto textile surfaces, which can serve with potential for biosensing, photocatalysis, and antibacterial applications. ZnO NRs were grown by using a simple aqueous chemical growth method. Results from analyses such as X-ray diffraction (XRD) and scanning electron microscopy (SEM) revealed that the ZnO NRs were dispersed over the entire surface of the textile. We have demonstrated the following applications of these multifunctional textiles: (1) as a flexible working electrode for the detection of aldicarb (ALD) pesticide, (2) as a photocatalyst for the degradation of organic molecules (i.e., Methylene Blue and Congo Red), and (3) as antibacterial agents against Escherichia coli. The ZnO-based textile exhibited excellent photocatalytic and antibacterial activities, and it showed a promising sensing response. The combination of sensing, photocatalysis, and antibacterial properties provided by the ZnO NRs brings us closer to the concept of smart textiles for wearable sensing without a deodorant and antibacterial control. Perhaps the best known of the products that is available in markets for such purposes are textiles with silver nanoparticles. Our modified textile is thus providing acceptable antibacterial properties, compared to available commercial modified textiles.


Electron microscopic study of reassociation of spectrin and actin with the human erythrocyte membrane.
Reassociation of spectrin and actin with human erythrocyte membranes was studied by stereoscopic electron microscopy of thin sections combined with tannic acid- glutaraldehyde fixation. Treatment of the erythrocyte membrane with 0.1 mM EDTA (pH 8.0) extracted more than 90 percent of the spectrin and actin and concomitantly removed filamentous meshworks underlying the membranes, followed by fragmentation into small inside-out vesicles. When such spectrin-depleted vesicles were incubated with the EDTA extract (crude spectrin), a filamentous meshwork, similar to those of the original membranes, was reformed on the cytoplasmic surface of the vesicles. The filamentous components, with a uniform thickness of 9 nm, took a tortuous course and joined one another often in an end-to-end fashion to form a irregular but continuous meshwork parallel to the membrane. Purified spectrin was also reassociated with the vesicles in a population density of filamentous components almost comparable to that of the crude spectrin-reassociated vesicles. However, the meshwork formation was much smaller in extent, showing many independent filamentous components closely applied to the vesicle surface. When muscle G-actin was added to the crude spectrin- or purified spectrin- reassociated vesicles under conditions which favor actin polymerization, actin filaments were seen to attach to the vesicles through the filamentous components. Two modes of association of actin filaments with the membrane were seen: end-to-membrane and side-to- membrane associations. In the end-to-membrane association, each actin filament was bound with several filamentous components exhibiting a spiderlike configuration, which was considered to be the unit of the filamentous meshwork of the original erythrocyte membrane.


Construction of plasmid cloning vectors for lactic streptococci which also replicate in Bacillus subtilis and Escherichia coli.
The cryptic Streptococcus cremoris Wg2 plasmid pWV01 (1.5 megadaltons) was genetically marked with the chloramphenicol resistance (Cmr) gene from pC194. The recombinant plasmid (pGK1, 2.4 megadaltons) replicated and expressed Cmr in Bacillus subtilis. From this plasmid an insertion-inactivation vector was constructed by inserting the erythromycin resistance (Emr) gene from pE194 cop-6. This plasmid (pGK12, 2.9 megadaltons) contained a unique BclI site in the Emr gene and unique ClaI and HpaII sites outside both resistance genes. It was stably maintained in B. subtilis at a copy number of approximately 5. pGK12 also transformed Escherichia coli competent cells to Cmr and Emr. The copy number in E. coli was about 60. Moreover, pGK12 transformed protoplasts of Streptococcus lactis. In this host both resistance genes are expressed. pGK12 is stably maintained in S. lactis at a copy number of 3.


Antiretroviral drugs induce oxidative stress and neuronal damage in the central nervous system.
HIV-associated neurocognitive disorder (HAND), characterized by a wide spectrum of behavioral, cognitive, and motor dysfunctions, continues to affect approximately 50 % of HIV(+) patients despite the success of combination antiretroviral drug therapy (cART) in the periphery. Of note, potential toxicity of antiretroviral drugs in the central nervous system (CNS) remains remarkably underexplored and may contribute to the persistence of HAND in the cART era. Previous studies have shown antiretrovirals (ARVs) to be neurotoxic in the peripheral nervous system in vivo and in peripheral neurons in vitro. Alterations in lipid and protein metabolism, mitochondrial damage, and oxidative stress all play a role in peripheral ARV neurotoxicity. We hypothesized that ARVs also induce cellular stresses in the CNS, ultimately leading to neuronal damage and contributing to the changing clinical and pathological picture seen in HIV-positive patients in the cART era. In this report, we show that ARVs are neurotoxic in the CNS in both pigtail macaques and rats in vivo. Furthermore, in vitro, ARVs lead to accumulation of reactive oxygen species (ROS), and ultimately induction of neuronal damage and death. Whereas ARVs alone caused some activation of the endogenous antioxidant response in vitro, augmentation of this response by a fumaric acid ester, monomethyl fumarate (MMF), blocked ARV-induced ROS generation, and neuronal damage/death. These findings implicate oxidative stress as a contributor to the underlying mechanisms of ARV-induced neurotoxicity and will provide an access point for adjunctive therapies to complement ARV therapy and reduce neurotoxicity in this patient population.


Diastereoselective Ireland-Claisen rearrangements of substituted allyl β-amino esters: applications in the asymmetric synthesis of C(5)-substituted transpentacins.
The diastereoselective Ireland-Claisen rearrangement of a range of substituted allyl β-amino esters gave the corresponding enantiopure α-substituted-β-amino esters with good diastereoselectivity. The application of this methodology in the asymmetric synthesis of a range of C(5)-substituted 1,2-anti-1,5-syn-transpentacins was demonstrated by the rearrangement of a range of β-amino esters derived from sorbic acid, followed by esterification, ring-closing metathesis, hydrogenolytic deprotection/reduction, and hydrolysis, which gave the C(5)-substituted transpentacins in only 9 steps from commercially available starting materials.


Self-standing nanoparticle membranes and capsules.
We perform coarse-grained molecular dynamics simulations of self-standing nanoparticle membranes observed in recent experiments (K. E. Mueggenburg et al., Nat. Mater., 2007, 6, 656). In order to make our simulations feasible, we model 2-3 times smaller gold nanoparticles (core radius of r(core) ≈ 0.8 nm) covered with alkanethiol ligands (length of l(ligand) ≈ 0.5-2.6 nm). We study the structure, stability, and mechanical properties of these membranes and show that these characteristics are controlled by the ratio of R(LC) = l(ligand)/r(core). For R(LC) ≈ 0.6, the ligated nanoparticles form well ordered monolayers with hexagonal packing, in agreement with the experiments (R(LC) ≈ 0.44). For R(LC) ≈ 1.6, the nanoparticles form less organized multilayers, which are more stable and flexible. We show that these membranes could potentially form stable capsules for molecular storage and delivery.


Mental healthcare in Kenya: exploring optimal conditions for capacity building.
The global burden of disease related to mental disorders is on the increase, with the World Health Organization (WHO) estimating that over 450 million people are affected worldwide. The Mental Health Global Action Program (mhGAP) was launched by the WHO in 2002 in order to address the widening gap in access to mental healthcare in low-income countries. Despite these efforts, access to mental healthcare in low-income countries remains poor and is often described as inadequate, inefficient and inequitable, with an 85% estimated treatment gap in low-income countries, as compared with 35% to 50% in high-income countries.In this article, the authors argue that integrating mental health services into primary healthcare settings through capacity building is vital with regard to achieving mhGAP goals. The article explores the challenges to and potential enablers for the improvement of the delivery of broad-based mental healthcare services in Kenya. The authors propose the integration of the conceptual dimensions of both the cosmopolitanism and capabilities approaches as a combined strategy for dealing with capacity building in heterogeneous settings such as Kenya.


Developmental neurotoxicity of cadmium on enzyme activities of crucial offspring rat brain regions.
Cadmium (Cd) is an environmental contaminant known to exert significant neurotoxic effects on both humans and experimental animals. The aim of this study was to shed more light on the effects of gestational (in utero) and lactational maternal exposure to Cd (50 ppm of Cd as Cd-chloride in the drinking water) on crucial brain enzyme activities in important rat offspring brain regions (frontal cortex, hippocampus, hypothalamus, pons and cerebellum). Our study provides a brain region-specific view of the changes in the activities of three crucial brain enzymes as a result of the developmental neurotoxicity of Cd. Maternal exposure to Cd during both gestation and lactation results into significant changes in the activities of acetylcholinesterase and Na(+),K(+)-ATPase in the frontal cortex and the cerebellum of the offspring rats, as well as in a significant increase in the hippocampal Mg(2+)-ATPase activity. These brain-region-specific findings underline the need for further research in the field of Cd-induced developmental neurotoxicity. Deeper understanding of the mechanisms underlying the neurodevelopmental deficits taking place due to in utero and early age exposure to Cd could shed more light on the causes of its well-established cognitive implications.


Association Between Olfactory Dysfunction and Cognitive Impairment in Dementia-Free Older Adults: A Prospective Cohort Study in Taiwan.
Previous studies assessing olfactory function and cognition have mostly been cross-sectional, and few have investigated the Asian geriatric population. To examine the relationships of olfaction with global or domain-specific cognitive function in Taiwanese community-dwelling older adults. This cohort study (2015-2019) is part of the Taiwan Initiative for Geriatric Epidemiological Research. The Taiwanese version of the Montreal Cognitive Assessment (MoCA-T) and a battery of neuropsychological tests were assessed at baseline and at a two-year follow-up. The cross-culture modified Sniffin' Sticks Identification Test (SSIT) was utilized to measure olfactory function. Generalized linear mixed models were used to examine the association of olfaction with cognitive performance over two years. Data were collected from 376 participants (55.1% women), with a mean age of 75.6 years. A one-point decrease in the SSIT score (worsening of olfaction) was associated with worse global cognition (MoCA-T: βˆ= -0.13), memory (βˆ= -0.08 to -0.06), and verbal fluency (βˆ= -0.07). Compared with an SSIT score ≥ 11 (normosmia), an SSIT score < 8 (anosmia) was associated with worse global cognition (MoCA-T: βˆ= -0.99), memory (βˆ= -0.48 to -0.42), executive function (Trail Making Test A: βˆ= -0.36), attention (digit span backward: βˆ= -0.34), and verbal fluency (βˆ= -0.45). After stratified analyses, the associations remained in older adults ≥ 75 years, males, and non-carriers of apolipoprotein E ɛ4 in terms of global cognition, memory, and verbal fluency. Odor identification deficits were associated with poor global or domain-specific cognitive function in a four-year cohort of community-dwelling older adults. Cognitive assessments should be conducted in dementia-free elderly individuals with impaired odor identification.


Genomic Biomarkers to Predict Resistance to Hypomethylating Agents in Patients With Myelodysplastic Syndromes Using Artificial Intelligence.
We developed an unbiased framework to study the association of several mutations in predicting resistance to hypomethylating agents (HMAs) in patients with myelodysplastic syndromes (MDS), analogous to consumer and commercial recommender systems in which customers who bought products A and B are likely to buy C: patients who have a mutation in gene A and gene B are likely to respond or not respond to HMAs. We screened a cohort of 433 patients with MDS who received HMAs for the presence of common myeloid mutations in 29 genes that were obtained before the patients started therapy. The association between mutations and response was evaluated by the Apriori market basket analysis algorithm. Rules with the highest confidence (confidence that the association exists) and the highest lift (strength of the association) were chosen. We validated our biomarkers in samples from patients enrolled in the S1117 trial. Among 433 patients, 193 (45%) received azacitidine, 176 (40%) received decitabine, and 64 (15%) received HMA alone or in combination. The median age was 70 years (range, 31 to 100 years), and 28% were female. The median number of mutations per sample was three (range, zero to nine), and 176 patients (41%) had three or more mutations per sample. Association rules identified several genomic combinations as being highly associated with no response. These molecular signatures were present in 30% of patients with three or more mutations/sample with an accuracy rate of 87% in the training cohort and 93% in the validation cohort. Genomic biomarkers can identify, with high accuracy, approximately one third of patients with MDS who will not respond to HMAs. This study highlights the importance of machine learning technologies such as the recommender system algorithm in translating genomic data into useful clinical tools.


Sexism in schools.
Sexism is gender-based prejudice or discrimination. As with other forms of prejudice and discrimination, it functions to maintain status and power differences between groups in society. One manifestation of sexism involves prejudice and discrimination against girls and women who seek to achieve in prestigious fields traditionally associated with males. Another manifestation of sexism, however, occurs when pressures are placed on boys and men to conform to traditional conceptions of masculinity. Over the last two decades, an increasing number of developmental and educational psychologists have become concerned about sexism directed toward children and adolescents in school contexts. Our chapter reviews the research on this topic. After providing an overview of different processes related to sexism, we examine how it is manifested in school contexts. Sexism is seen through gender-stereotyped biases against girls and boys in academic and athletic achievement. Also, it occurs through sexual harassment in social interactions. We also address factors related to children's awareness of sexism and coping responses to sexism. Finally, we consider possible ways to reduce sexism and foster effective coping in schools.


Time-window for sensitivity to cooling distinguishes the effects of hypothermia and protein synthesis inhibition on the consolidation of long-term memory.
The effects of hypothermia on memory formation have been examined extensively, and while it is clear that post-training cooling interferes with the process of consolidation, the nature of the temperature sensitive processes disrupted in this way remain poorly defined. Post-training manipulations that disrupt consolidation tend to be effective during specific time-windows of sensitivity, the timing and duration of which are directly related to the mechanism through which the treatment induces amnesia. As such, different treatments that target the same basic processes should be associated with similar time-windows of sensitivity. Using this rationale we have investigated the possibility that cooling induced blockade of long-term memory (LTM) stems from the disruption of protein synthesis. By varying the timing of post-training hypothermia we have determined the critical period during which cooling disrupts the consolidation of appetitive long-term memory in the pond snail Lymnaea. Post-training hypothermia was found to disrupt LTM only when applied immediately after conditioning, while delaying the treatment by 10 min left the 24 h memory trace intact. This brief (<10 min) window of sensitivity differs from the time-window we have previously described for the protein synthesis inhibitor anisomycin, which was effective during at least the first 30 min after conditioning [Fulton, D., Kemenes, I., Andrew, R. J., & Benjamin, P. R. (2005). A single time-window for protein synthesis-dependent long-term memory formation after one-trial appetitive conditioning. European Journal of Neuroscience, 21, 1347-1358]. We conclude that hypothermia and protein synthesis inhibition exhibit distinct time-windows of effectiveness in Lymnaea, a fact that is inconsistent with the hypothesis that cooling induced amnesia occurs through the direct disruption of macromolecular synthesis.


Amygdala activity in obsessive-compulsive disorder with contamination fear: a study with oxygen-15 water positron emission tomography.
Previous imaging studies of obsessive-compulsive symptom states have implicated frontal-striatal and limbic regions in the pathophysiology of obsessive-compulsive disorder (OCD). Functional imaging studies, however, have yielded inconsistent results, presumably due to methodological differences (patient inclusion criteria, stimulus paradigm, imaging technique, and absence of control groups). In the present study, randomized presentation of contamination-related and neutral visual stimuli was used to investigate the neurophysiological correlates of contamination fear in a group of medication-free OCD patients with washing behaviors and healthy controls. A total of 21 subjects (11 OCD patients and 10 healthy controls) were scanned using H(2)(15)O positron emission tomography (PET). Subjects were presented with pictures of clean and dirty surroundings and were requested to make indoor/outdoor decisions to control for attention differences. State anxiety and obsessionality were rated after each scan using visual analogue scales. Main effects of stimulus type (contamination vs. neutral) were found in bilateral occipital cortex in both groups. A significant group interaction effect was observed in the left amygdala reflecting enhanced activity in response to contamination stimuli in OCD patients. Sensitization effects were observed in the right amygdala in the OCD group; these paralleled an increase in levels of distress and obsessionality as well as a decrease in dorsolateral prefrontal activity. The findings of the present study are consistent with the hypothesis of decreased frontal-striatal control of limbic structures, specifically the amygdala, resulting in an inadequate fear response in OCD patients with contamination fear.


Effect of cold storage on immediate graft function in an experimental model of renal transplantation in cats.
OBJECTIVE To assess the effect of cold storage (CS) on immediate posttransplantation function of renal autografts in cats. ANIMALS 15 healthy 1-year-old cats. PROCEDURES Cats were assigned to 2 groups and underwent autotransplantation of the left kidney followed by nephrectomy of the right kidney. The left kidney was autotransplanted either immediately (IT group; n = 6) or after being flushed with a cold sucrose phosphate solution and stored on ice while the implant site was prepared (CS group; 9). Serum creatinine and BUN concentrations were monitored daily and autografts were ultrasonographically examined intermittently for 14 days after surgery. RESULTS Mean duration of CS was 24 minutes for the CS group. Posttransplantation serum creatinine and BUN concentrations for the CS group had lower peak values, returned to the respective reference ranges quicker, and were generally significantly lower than those for the IT group. Mean posttransplantation autograft size for the CS group was smaller than that for the IT group. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that immediate posttransplantation function of renal autografts following a short period of CS was better than that of renal autografts that did not undergo CS, which suggested CS protected grafts from ischemic injury and may decrease perioperative complications, speed recovery, and improve the long-term outcome for cats with renal transplants. IMPACT FOR HUMAN MEDICINE Cats metabolize immunosuppressive drugs in a manner similar to humans; therefore, renal transplantation in cats may serve as a desirable model for investigating the effects of renal transplantation in human patients.


Nasal cytology in children: scraping or swabbing?
Nasal cytology has become a valuable tool in the assessment of a multitude of nasal pathologies in children. Collection methods differ significantly and even though the use of the nasal curette is regarded as the most reliable in adults, most practitioners use the nasal swab in children. However, no studies have validated the reliability and supposed better tolerability of the latter. We have compared these two sampling methods regarding their tolerability and analysed the diagnostic accuracy of the cotton nasal swab (NSW) to identify nasal cytotypes and rhinitis phenotypes, using nasal scraping (NSC) for comparison. In a multicentric prospective study we recruited 208 children and performed nasal cytology by means of NSW and NSC. Microscopic evaluating of the nasal cytotypes was performed and tolerability of NSW and NSC was tested. Our data revealed a significantly inferior diagnostic accuracy of NSW compared to NSC regarding reliability and cell counts. Our study is the first to shed light on the role of the sampling tools for pediatric nasal cytology. We documented a poor diagnostic accuracy of NSW, thus suggesting using only the nasal curette in clinical practice. Furthermore, tolerability did not differ between the two, refuting the common thesis that swabs are to be preferred when doing nasal cytology in children.


Biomechanical Effect of an Exposed Dental Implant's First Thread: A Three-Dimensional Finite Element Analysis Study.
BACKGROUND The purpose of this study was to assess the effect of different exposure levels of a dental implant's first thread on adjacent bone stress and strain using the finite element analysis method. MATERIAL AND METHODS Three-dimensional models of 2 threaded implants and abutments with a mandibular bone segment were constructed to represent the covered (C) and exposed models. In the exposed models, the implant was first placed in the bone, and rotated around its axis a quarter-turn each time to simulate 4 different levels of first thread exposure at the mid-lingual side: Upper Flank (UF), Thread Crest (TC), Lower Flank (LF), and Thread Root (TR) models. Oblique forces were applied and analysis was performed. RESULTS Maximum compressive stress magnitude and distribution varied according to the exposed thread profile. In the exposed group, peak stress ranged from 136 MPa to 197 MPa in TC and LF models, respectively, compared to 141 MPa in C model. In LF, UF, and C models, peak stress was observed at the mid-lingual side of the crestal region, while in TC and TR models, peak stress shifted distally in accordance with thread profile. However, alveolar bone volumes which exhibited compressive microstrain levels within the physiological loading and maintenance windows were relatively close in all models. CONCLUSIONS Results suggest that the exposed thread profile influences stress and strain outcomes in the adjacent bone; however, this influence is only limited to a small region around the exposed thread.


Vibrotactile -Feedback Device for Postural Balance Among Malocclusion Patients.
Multiple studies have suggested that some associations exist between occlusal factors and postural alterations. This study aimed to evaluate the effectiveness of a vibrotactile posture trainer device, comprised a wearable device containing an accelerometer sensor to measure the angle of the neck flexion (input) and provided real-time vibrotactile biofeedback (output) for postural balance among patients with malocclusion. Twenty-four subjects were divided in 3 groups based on occlusion and using Angle's classification. Each group consisted of 8 patients for class I, II and III malocclusion. The Posture Trainer System was used for feedback concerning neck flexion angles when higher than 15 degrees. A 4-week training program to adjust posture balance in 2 axes (flexion-extension, lateral-flexion) was applied in activities for daily living. The assessments in this study were comprised of neck flexion angles from the Posture Trainer System and the center of pressure ([Formula: see text]) using a force plate. The effects of a vibrotactile posture trainer (baseline vs. post-training test) were evaluated using the paired t-test and were assumed to be significant at p < 0.05 (two-side). All analyses were conducted using the Statistical Package for Social Sciences, Version 21.0 (SPSS, Chicago, IL, USA). Neck flexion angles and center of pressure significantly decreased post-training by the Posture Trainer System among patients with class II malocclusion. No changes in the above parameters post-training were found in class I and class III. The results demonstrated that patients with class II malocclusion training by the Posture Trainer System lowered neck flexion angles and COP compared with pre-training. Clinical Impact: Feedback by the Posture Trainer System can help improve the postural balance in class II malocclusion.


Regulation of Protein Interactions by Mps One Binder (MOB1) Phosphorylation.
MOB1 is a multifunctional protein best characterized for its integrative role in regulating Hippo and NDR pathway signaling in metazoans and the Mitotic Exit Network in yeast. Human MOB1 binds both the upstream kinases MST1 and MST2 and the downstream AGC group kinases LATS1, LATS2, NDR1, and NDR2. Binding of MOB1 to MST1 and MST2 is mediated by its phosphopeptide-binding infrastructure, the specificity of which matches the phosphorylation consensus of MST1 and MST2. On the other hand, binding of MOB1 to the LATS and NDR kinases is mediated by a distinct interaction surface on MOB1. By assembling both upstream and downstream kinases into a single complex, MOB1 facilitates the activation of the latter by the former through a trans-phosphorylation event. Binding of MOB1 to its upstream partners also renders MOB1 a substrate, which serves to differentially regulate its two protein interaction activities (at least in vitro). Our previous interaction proteomics analysis revealed that beyond associating with MST1 (and MST2), MOB1A and MOB1B can associate in a phosphorylation-dependent manner with at least two other signaling complexes, one containing the Rho guanine exchange factors (DOCK6-8) and the other containing the serine/threonine phosphatase PP6. Whether these complexes are recruited through the same mode of interaction as MST1 and MST2 remains unknown. Here, through a comprehensive set of biochemical, biophysical, mutational and structural studies, we quantitatively assess how phosphorylation of MOB1A regulates its interaction with both MST kinases and LATS/NDR family kinases in vitro Using interaction proteomics, we validate the significance of our in vitro studies and also discover that the phosphorylation-dependent recruitment of PP6 phosphatase and Rho guanine exchange factor protein complexes differ in key respects from that elucidated for MST1 and MST2. Together our studies confirm and extend previous work to delineate the intricate regulatory steps in key signaling pathways.


Impact of metal ions in porphyrin-based applied materials for visible-light photocatalysis: key information from ultrafast electronic spectroscopy.
Protoporphyrin IX-zinc oxide (PP-ZnO) nanohybrids have been synthesized for applications in photocatalytic devices. High-resolution transmission electron microscopy (HRTEM), X-ray diffraction (XRD), and steady-state infrared, absorption, and emission spectroscopies have been used to analyze the structural details and optical properties of these nanohybrids. Time-resolved fluorescence and transient absorption techniques have been applied to study the ultrafast dynamic events that are key to photocatalytic activities. The photocatalytic efficiency under visible-light irradiation in the presence of naturally abundant iron(III) and copper(II) ions has been found to be significantly retarded in the former case, but enhanced in the latter case. More importantly, femtosecond (fs) transient absorption data have clearly demonstrated that the residence of photoexcited electrons from the sensitizer PP in the centrally located iron moiety hinders ground-state bleach recovery of the sensitizer, affecting the overall photocatalytic rate of the nanohybrid. The presence of copper(II) ions, on the other hand, offers additional stability against photobleaching and eventually enhances the efficiency of photocatalysis. In addition, we have also explored the role of UV light in the efficiency of photocatalysis and have rationalized our observations from femtosecond- to picosecond-resolved studies.


Chasing Aqueous Biphasic Systems from Simple Salts by Exploring the LiTFSI/LiCl/H2O Phase Diagram.
Aqueous biphasic systems (ABSs), in which two aqueous phases with different compositions coexist as separate liquids, were first reported more than a century ago with polymer solutions. Recent observations of ABS forming from concentrated mixtures of inorganic salts and ionic liquids raise the fundamental question of how "different" the components of such mixtures should be for a liquid-liquid phase separation to occur. Here we show that even two monovalent salts sharing a common cation (lithium) but with different anions, namely, LiCl and lithium bis(trifluoromethanesulfonyl)imide (LiTFSI), may result in the formation of ABSs over a wide range of compositions at room temperature. Using a combination of experimental techniques and molecular simulations, we analyze the coexistence diagram and the mechanism driving the phase separation, arising from the different anion sizes. The understanding and control of ABS may provide new avenues for aqueous-based battery systems.


Measurement of the Target-Normal Single-Spin Asymmetry in Quasielastic Scattering from the Reaction (3)He(↑)(e,e').
We report the first measurement of the target single-spin asymmetry, A(y), in quasielastic scattering from the inclusive reaction (3)He(↑)(e,e') on a (3)He gas target polarized normal to the lepton scattering plane. Assuming time-reversal invariance, this asymmetry is strictly zero for one-photon exchange. A nonzero A(y) can arise from the interference between the one- and two-photon exchange processes which is sensitive to the details of the substructure of the nucleon. An experiment recently completed at Jefferson Lab yielded asymmetries with high statistical precision at Q(2)=0.13, 0.46, and 0.97 GeV(2). These measurements demonstrate, for the first time, that the (3)He asymmetry is clearly nonzero and negative at the 4σ-9σ level. Using measured proton-to-(3)He cross-section ratios and the effective polarization approximation, neutron asymmetries of -(1-3)% were obtained. The neutron asymmetry at high Q(2) is related to moments of the generalized parton distributions (GPDs). Our measured neutron asymmetry at Q(2)=0.97 GeV(2) agrees well with a prediction based on two-photon exchange using a GPD model and thus provides a new, independent constraint on these distributions.


Withdrawal of alcohol promotes regression while continued alcohol intake promotes persistence of LPS-induced pancreatic injury in alcohol-fed rats.
Administration of repeated lipopolysaccharide (LPS) injections in alcohol-fed rats leads to significant pancreatic injury including fibrosis. However, it remains unknown whether alcoholic (chronic) pancreatitis has the potential to regress when alcohol is withdrawn. The aims of the study were (1) to compare the effect of alcohol withdrawal/continuation on pancreatic acute injury and fibrosis; and (2) to assess the effects of alcohol ± LPS on pancreatic stellate cell (PSC) apoptosis in vivo and in vitro. Rats fed isocaloric Liebere-De-Carli liquid diets ± alcohol for 10 weeks were challenged with LPS (3 mg/kg/week for 3 weeks) and then either switched to control diet or maintained on an alcohol diet for 3 days, 7 days or 3 weeks. Pancreatic sections were assessed for acute tissue injury, fibrosis, PSC apoptosis and activation. Cultured rat PSCs were exposed to 10 mM ethanol 6 1 mg/ml LPS for 48 or 72 h and apoptosis was assessed (Annexin V, caspase-3 and terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL)). Withdrawal of alcohol led to resolution of pancreatic lesions including fibrosis and to increased PSC apoptosis. Continued alcohol administration perpetuated pancreatic injury and prevented PSC apoptosis. Alcohol and LPS significantly inhibited PSC apoptosis in vitro, and the effect of LPS on PSC apoptosis could be blocked by Toll-like receptor 4 small interfering RNA. Induction of PSC apoptosis upon alcohol withdrawal is a key mechanism mediating the resolution of pancreatic fibrosis. Conversely, continued alcohol intake perpetuates pancreatic injury by inhibiting apoptosis and promoting activation of PSCs. Characterisation of the pathways mediating PSC apoptosis has the potential to yield novel therapeutic strategies for chronic pancreatitis.


Co-existing tuberculosis and malignant mesothelioma with multiple sites venous thrombosis: a case report.
Tuberculosis is endemic in India and almost 40 % of the Indian population is infected with tubercle bacilli. Tuberculosis being a great mimicker of infectious as well as non infectious diseases and recent rise of multi drug resistant and extended drug resistant cases have made diagnosis and management more difficult. To the best of our knowledge there have been no reported cases of tuberculosis coexisting with malignant peritoneal mesothelioma leading to multiple site venous thrombosis. Forty five year old male, belonging to Indian/Aryan ethnicity presented with cough, breathlessness and fever for 7 months with past history of pulmonary tuberculosis. On examination he was found to have pleural effusion for which he received anti-tuberculosis therapy empirically. Later his condition deteriorated and on further examination he was found to have ascites, multiple site venous thrombosis and pyothorax which was found positive for acid fast bacilli. Despite anti-tuberculosis therapy he did not improve and was suspected to be a multidrug resistant case. Later on computed tomography peritoneal nodule was detected and on biopsy revealed malignant mesothelioma. In a diagnosed case of tuberculosis with clinical findings compatible with it but not responding to anti tubercular therapy, underlying secondary co-existing pathology should be explored.


Identification of two cytotoxic T lymphocyte-recognized epitopes in the Ras protein.
We have investigated the possibility of inducing cytotoxic T lymphocytes (CTL) to Ras containing a mutation at position 61 or to normal Ras, using recombinant vaccinia viruses expressing these proteins. CTL from C57Bl/10 mice immunized with vaccinia expressing mutant Ras showed specificity for the mutant Ras protein and recognition of normal Ras was inefficient. The opposite specificity was observed after immunization with vaccinia expressing normal Ras, since CTL isolated from these mice recognized normal Ras well and mutant Ras inefficiently. Levels of endogenous Ras expression were insufficient for lysis by these CTL. One CTL epitope mapped to amino acids 60-67 and residue 61 was critical for T cell recognition. CTL generated against mutant Ras protein recognized peptide 60-67 containing mutant residue 61, while anti-normal Ras CTL recognized the wild-type 60-67 sequence. A second epitope mapped to residues 152-159 of Ras and was recognized equally well by CTL raised to normal or mutant Ras. The murine data raise the possibility of exploiting Ras-specific CTL for targeted immunotherapy of certain human cancers.


Perspectives of healthcare professionals in Qatar on causes of medication errors: A mixed methods study of safety culture.
There is a lack of robust, rigorous mixed methods studies of patient safety culture generally and notably those which incorporate behavioural theories of change. The study aimed to quantify and explain key aspects of patient safety culture which were of most concern to healthcare professionals in Qatar. A sequential explanatory mixed methods design of a cross-sectional survey followed by focus groups in Hamad Medical Corporation, Qatar. All doctors, nurses and pharmacists were invited to complete the Hospital Survey on Patient Safety Culture (HSOPS). Respondents expressing interest in focus group participation were sampled purposively, and discussions based on survey findings using the Theoretical Domains Framework (TDF) to explain behavioural determinants. One thousand, six hundred and four questionnaires were received (67.9% nurses, 13.3% doctors, 12.9% pharmacists). HSOPS composites with the lowest levels of positive responses were non-punitive response to errors (24.0% positive) and staffing (36.2%). Specific TDF determinants potentially associated with these composites were social/professional role and identity, emotions, and environmental context and resources. Thematic analysis identified issues of doctors relying on pharmacists to correct their errors and being reluctant to alter the prescribing of fellow doctors. There was a lack of recognition of nurses' roles and frequent policy non-adherence. Stress, workload and lack of staff at key times were perceived to be major contributors to errors. This study has quantified areas of concern relating to patient safety culture in Qatar and suggested important behavioural determinants. Rather than focusing on changing behaviour at the individual practitioner level, action may be required at the organisational strategic level to review policies, structures (including resource allocation and distribution) and processes which aim to promote patient safety culture.


Assessing accuracy of mammography in the presence of verification bias and intrareader correlation.
The performance of a medical diagnostic test is often evaluated by comparing the outcome of the test to the patient's true disease state. Receiver operating characteristic analysis may then be used to summarize test accuracy. However, such analysis may encounter several complications in actual practice. One complication is verification bias, i.e., gold standard assessment of disease status may only be partially available and the probability of ascertainment of disease may depend on both the test result and characteristics of the subject. A second issue is that tests interpreted by the same rater may not be independent. Using estimating equations, we generalize previous methods that address these problems. We contrast the performance of alternative estimators of accuracy using robust sandwich variance estimators to permit valid asymptotic inference. We suggest that in the context of an observational cohort study where rich covariate information is available, a weighted estimating equations approach may be preferable for its robustness against model misspecification. We apply the methodology to mammography as performed by community radiologists.


Comparing the effectiveness of selective laser trabeculoplasty with topical medication as initial treatment (the Glaucoma Initial Treatment Study): study protocol for a randomised controlled trial.
Glaucoma is the leading cause of irreversible blindness in the world. Estimated to affect 60 million people worldwide, this figure is expected to rise to 80 million by 2020. Untreated, glaucoma leads to visual decay and eventually to blindness, and can significantly reduce quality of life. First-line treatment in patients with primary open-angle glaucoma and exfoliative glaucoma is topical medical therapy with ocular hypotensives as eye drops. However, eye drops have several disadvantages including cost, possible local and systemic side effects, and adherence and perseverance issues. Randomised controlled trials have demonstrated that selective laser trabeculoplasty is equally as effective in lowering intraocular pressure as eye drops. However, the impact of these two treatment modalities from the patient and economic perspectives has not been adequately determined. Thus, it remains unclear whether topical medical therapy or selective laser trabeculoplasty should be recommended as first-line treatment for glaucoma. This protocol describes an international, multi-centre, randomised controlled trial to determine the optimum first-line therapy for people with primary open-angle glaucoma and exfoliative glaucoma. This study will compare the effect of selective laser trabeculoplasty and topical medication with respect to patients' generic and glaucoma-specific quality of life. The trial will also provide a detailed cost-effectiveness analysis and compare the clinical effectiveness with respect to the degree of intraocular pressure lowering and rates of treatment failure. Research coordinators in each centre will identify and recruit previously untreated patients with primary open-angle glaucoma and exfoliative glaucoma. Those who meet the eligibility criteria will be invited to enter a randomised controlled trial with either selective laser trabeculoplasty or topical ocular hypotensive therapy, according to a stepped regimen. Outcome assessment will be measured at 6 weeks and at 6, 12, and 24 months post-treatment. Regular clinic follow-ups will continue as clinically indicated between study outcome visits. The Glaucoma Initial Treatment Study is the first multi-centred RCT to determine the optimum first-line therapy for people with glaucoma. Our trial will have an unprecedented capacity to meaningfully transform the treatment and management of glaucoma in Australia and overseas. ACTRN12611000720910; Date registered: 11 July 2011.


Hepcidin is localised in gastric parietal cells, regulates acid secretion and is induced by Helicobacter pylori infection.
Hepcidin is an antimicrobial peptide and the central regulator of iron metabolism. Given that hepcidin was shown to be expressed in a variety of extrahepatic tissues and that stomach plays a role in iron absorption and in defence against infections, this study analysed the importance of hepcidin in the stomach. Expression and localisation of gastric hepcidin was studied by quantitative RT-PCR, western blot, immunofluorescence and in situ hybridisation. Regulation of gastric hepcidin expression was analysed both in vitro and in vivo. Hepcidin wild-type (WT) and knockout (KO) animals were used to determine the impact of hepcidin on gastric bacterial overgrowth as well as gastric acid secretion. Hepcidin was abundantly expressed in the gastric fundus and corpus of all tested species. Treatment of AGS cells with ferric nitrilotriacetate solution downregulated hepcidin expression levels, while desferroxamine, interleukin 6 and Helicobacter pylori infection upregulated it. In humans, gastric hepcidin expression was elevated during H pylori infection and normalised after successful eradication. Gastric hepcidin is localised in parietal cells that are indispensable for gastric acid secretion. Comparisons of WT and hepcidin KO mice revealed that acid secretion in hepcidin-deficient mice is markedly reduced and is associated with gastric bacterial overgrowth, expression changes in multiple factors involved in acid secretion (Atp4a, Cck2r,Gas, Sst and Sst2r) and with reduced circulating gastrin levels. In WT mice, pantoprazole activated and histamine downregulated hepcidin expression levels. Hepcidin is a product of parietal cells regulating gastric acid production and may contribute to development of gastric ulcers under stress conditions.


Chemical contaminants, health indicators, and reproductive biomarker responses in fish from the Colorado River and its tributaries.
Common carp (Cyprinus carpio), black bass (Micropterus spp.), and channel catfish (Ictalurus punctatus) were collected from 14 sites in the Colorado River Basin (CRB) to document spatial trends in accumulative contaminants, health indicators, and reproductive biomarkers. Organochlorine residues, 2,3,7,8-tetrachlorodibenzo-p-dioxin-like activity (TCDD-EQ), and elemental contaminants were measured in composite samples of whole fish, grouped by species and gender, from each site. Selenium (Se) and mercury (Hg) concentrations in fish were elevated throughout the CRB, and pesticide concentrations were greatest in fish from agricultural areas in the Lower Colorado River and Gila River. Selenium concentrations exceeded toxicity thresholds for fish (>1.0 microg/g ww) at all CRB sites except the Gila River at Hayden, Arizona. Mercury concentrations were elevated (>0.1 microg/g ww) in fish from the Yampa River at Lay, Colorado; the Green River at Ouray National Wildlife Refuge (NWR), Utah and San Rafael, Utah; the San Juan River at Hogback Diversion, New Mexico; and the Colorado River at Gold Bar Canyon, Utah, Needles, California, and Imperial Dam, Arizona. Concentrations of p,p'-DDE were relatively high in fish from the Gila River at Arlington, Arizona (>1.0 microg/g ww) and Phoenix, Arizona (>0.5 microg/g ww). Concentrations of other formerly used pesticides including toxaphene, total chlordanes, and dieldrin were also greatest at these two sites but did not exceed toxicity thresholds. Currently used pesticides such as Dacthal, endosulfan, gamma-HCH, and methoxychlor were also greatest in fish from the Gila River downstream of Phoenix. Total polychlorinated biphenyls (PCBs; >0.11 microg/g ww) and TCDD-EQs (>5 pg/g ww) exceeded wildlife guidelines in fish from the Gila River at Phoenix. Hepatic ethoxyresorufin O-deethylase (EROD) activity was also relatively high in carp from the Gila River at Phoenix and in bass from the Green River at Ouray NWR. Fish from some sites showed evidence of contaminant exposure as indicated by fish health indicators and reproductive biomarker results. Multiple health indicators including altered body and organ weights and high health assessment index scores may be associated with elevated Se concentrations in fish from the Colorado River at Loma, Colorado and Needles. Although grossly visible external or internal lesions were found on most fish from some sites, histopathological analysis determined many of these to be inflammatory responses associated with parasites. Edema, exophthalmos, and cataracts were noted in fish from sites with elevated Se concentrations. Intersex fish were found at seven of 14 sites and included smallmouth bass (M. dolomieu), largemouth bass (M. salmoides), catfish, and carp and may indicate exposure to endocrine disrupting compounds. A high proportion of smallmouth bass from the Yampa River at Lay (70%) was intersex but the cause of this condition is unknown. Male carp, bass, and catfish with low concentrations of vitellogenin were common in the CRB. Comparatively high vitellogenin concentrations (>0.2 mg/mL) were measured in male bass from the Green River at Ouray NWR and the Colorado River at Imperial Dam and indicate exposure to estrogenic or anti-androgenic chemicals. Anomalous reproductive biomarkers including low GSI and gonadal abnormalities (calcifications, edema, and parasites) observed in fish downstream of Phoenix are likely related to the poor water-quality of the Gila River in this area.


Primary correction of nasal deformity in unilateral incomplete cleft lip: a comparative study between three techniques.
Nasal deformities secondary to incomplete cleft lip are often underestimated in terms of their severity with resultant sub-optimal treatment. Constant refinements have led to the evolution of different surgical techniques in our institution for the treatment of these deformities. This study compared three different techniques in achieving nasal asymmetry for patients with unilateral incomplete cleft lip. Sixty-six patients who had primary correction of incomplete cleft lip nasal deformities at the age of 3 months were reviewed later at the age of 5 or 6. The patients were divided into three groups as according to the surgical treatment received: Group I (n=21) underwent a closed rhinoplasty with cartilage dissection and repositioning through lip incisions; Group II (n=25) underwent a semi-open rhinoplasty technique with cartilage dissection through bilateral rim incisions; and Group III (n=20) received a semi-open rhinoplasty technique through a Tajima incision on the cleft side and a rim incision on the contralateral side. Using photo-analysis, a total of seven measurements were obtained comparing the cleft side with the non-cleft sides, including bilateral nostril height, nostril width, height-to-width ratio, medial dome height, nasal sill height, nostril area, nasolabial angle and nostril axis. All the patients benefitted from primary correction of their incomplete cleft lip and nasal deformities. In addition, Group III patients achieved superior results over Groups I and II in terms of nostril height ratio and nostril axis (p<0.005). Primary correction of the nasal deformity is an important component of surgery at the time of lip correction. Our results indicated that a semi-open rhinoplasty technique accompanied by the Tajima incision provides the best overall nasal symmetry.


Cervical and endometrial metastases of appendiceal goblet cell carcinoid.
Appendiceal goblet cell carcinoid (GCC) is a rare tumor with histologic features of both adenocarcinoma and neuroendocrine tumor (carcinoid). Clinically, it behaves more aggressively than classic appendiceal carcinoid and commonly presents with peritoneal carcinomatosis. We report 2 cases of appendiceal GCC, one with uterine cervical involvement and the other with endometrial involvement as the initial presentations. The first patient's invasive cervical signet ring cell carcinoma was diagnosed on routine screening. The second patient presented with abnormal uterine bleeding, and endometrial curettage showed an adenocarcinoma with signet ring cell features. Primary appendiceal GCC was demonstrated in both cases after systematic clinical investigations. Metastatic appendiceal GCC to uterine cervix and endometrium can potentially be misinterpreted as primary cervical or endometrial signet ring cell carcinoma. Therefore, for any uterine cervical/endometrial signet ring cell carcinoma, a metastatic appendiceal GCC should be considered in the differential diagnosis, especially after excluding other primary sites.


Persistence of effort in apathy.
The syndrome of apathy has generated increasing interest in recent years as systematic evaluations have revealed its high prevalence and strong negative impact on quality of life across a wide range of neurological and psychiatric conditions. However, although several theoretical models have been proposed to account for various aspects of the condition, understanding of this syndrome is still incomplete. One influential model has proposed that apathy might be described as a quantitative reduction of goal-directed behaviour in comparison to an individual's prior level of functioning. Persistence of activity defined as the capacity to continue with a task - sometimes in the face of setbacks, high levels of difficulty or fatigue - is a crucial but understudied aspect of goal-directed behaviour. Surprisingly, it has not been investigated yet in the context of apathy. Here, we provide an overview of theoretical and experimental aspects of persistence in effort that might assist to develop methods for the investigation of persistence in human behaviour, particularly within the pathologic context of apathy.


Duration of labor and the risk of severe postpartum hemorrhage: A case-control study.
Our main objective was to investigate the association between duration of active labor and severe postpartum hemorrhage. We examined the effect of the total duration of active labor, the effect of each stage of active labor, and the gradient effect of duration of labor on severe postpartum hemorrhage. A case-control study was generated from a source population of all women admitted for delivery at Oslo University Hospital and Drammen Hospital in Buskerud municipality during the time period January 1, 2008 to December 31, 2011. The study population included all cases of severe postpartum hemorrhage (n = 859) and a random sample of controls (n = 1755). Severe postpartum hemorrhage was defined as postpartum blood loss ≥1500 mL or need for blood transfusion. Prolonged labor was defined as duration of active labor >12 hours according to the definition of the World Health Organization. We used logistic multivariable regression in the analysis. We observed a significantly longer mean duration of labor in women who experienced severe postpartum hemorrhage compared to controls (5.4 versus 3.8 hours, p<0.001). Women with severe postpartum hemorrhage also had a longer duration of all stages of active labor compared to controls. The association between the duration of active labor and severe postpartum changed from a linear dose-response association to a threshold association after adjusting for augmentation with oxytocin, induction of labor, primiparity, and fever during labor. Compared to controls, women with severe postpartum hemorrhage were more likely to have a prolonged labor >12 hours (adjusted odds ratio = 2.44, 95% confidence interval: 1.69-3.53, p< 0.001). Prolonged active labor (duration >12 hours) was associated with severe postpartum hemorrhage. Increased vigilance seems required when the labor is prolonged to reduce the risk of severe postpartum hemorrhage.


Nonketotic hyperglycinemia: treatment with diazepam--a competitor for glycine receptors.
Two female infants with nonketotic hyperglycinemia (NKH) were treated with diazepam for the control of seizures. The first infant had seizures, lethargy, and respiratory distress in the first 24 hours of life. The diagnosis of NKH was made at 3 weeks of age and she was then placed on a regimen of strychnine and a low-protein diet. Strychnine therapy was discontinued after three months of treatment because there was no improvement in the seizure control or in the patient's condition. At 5 months of age the patient was referred to our clinic for further work-up. The second infant had seizures, hypotonia, and respiratory distress shortly after birth. She was treated with phenobarbital and diphenylhydantoin, which had no effect on her seizures. The baby was referred to our clinic at 8 months of age and diagnostic studies revealed NKH. All previous medications were stopped and both infants were placed on diazepam, a competitor for glycine receptors in the CNS. Choline and folic acid were added for one-carbon unit transfer and sodium benzoate to bind excessive glycine. Both infants responded to this treatment with cessation of seizures; they became more responsive and alert, and their EEGs showed remarkable improvement despite the persistence of elevated glycine levels in plasma, CSF, and urine. Diazepam as a competitor for the receptors of glycine may prove helpful in controlling the intractable seizures associated with NKH.


Quantitative analysis of the expression of caspase 3 and caspase 9 in different types of atherosclerotic lesions in the human aorta.
The existing data on apoptotic processes in human atherosclerotic lesions is insufficient and is often contradictory. This study was undertaken to evaluate the levels of the expression of key apoptosis-related genes, namely, caspase 3 (CASP3) and caspase 9 (CASP9) in the normal (non-atherosclerotic) intima of the human aorta in comparison with those in different types of atherosclerotic lesions. Twenty-five autopsy samples of thoracic aorta were examined by polymerase chain reaction (PCR) analysis. The study revealed that the expressions of CASP3 and CASP9 genes were changed in different types of atherosclerotic lesions in course of the progression of the disease, but not in a unanimous way. The mRNA expression of CASP3 was found to be steadily decreasing with the progression of atherosclerosis while the expression of CASP9 showed a pattern which can be described as a "bell-shaped" relationship between gene mRNA expression and the type of atherosclerotic lesion, with the maximum being observed in fatty streaks. The fall in CASP3 expression may be associated with cellular senescence as well as with the domination of necrotic processes in atherosclerotic lesions, as shown by electron microscopic analysis. Our study provides novel quantitative data on the expression of CASP3 and CASP9 genes in different atherosclerotic lesions in the human aorta and thus, might assist in better understanding of the processes occurring during the development of lesions in human atherogenesis.