Lung cancer prognosis before and after recurrence in a population-based setting.
Population-based estimates of absolute risk of lung cancer recurrence, and of mortality rates after recurrence, can inform clinical management. We evaluated prognostic factors for recurrences and survival in 2098 lung cancer case patients from the general population of Lombardy, Italy, from 2002 to 2005. We conducted survival analyses and estimated absolute risks separately for stage IA to IIIA surgically treated and stage IIIB to IV non-surgically treated patients. Absolute risk of metastases exceeded that of local recurrence in every stage and cell type, highlighting the systemic threat of lung cancer. In stage I, the probability of dying within the first year after diagnosis was 2.7%, but it was 48.3% within first year after recurrence; in stage IV, the probabilities were 57.3% and 80.6%, respectively. Over half the patients died within one year of first metastasis. Although in stages IA to IB about one-third of patients had a recurrence, stage IIA patients had a recurrence risk (61.2%) similar to stage IIB (57.9%) and IIIA (62.8%) patients. Risk of brain metastases in stage IA to IIIA surgically treated non-small cell lung cancer patients increased with increasing tumor grade. Absolute risk of recurrence was virtually identical in adenocarcinoma and squamous cell carcinoma patients. This population-based study provides clinically useful estimates of risks of lung cancer recurrence and mortality that are applicable to the general population. These data highlight the need for more effective adjuvant treatments overall and within specific subgroups. The estimated risks of various endpoints are useful for designing clinical trials, whose power depends on absolute numbers of events.


The Causal Relationship between DNA Damage Induction in Bovine Lymphocytes and the Fukushima Nuclear Power Plant Accident.
The Fukushima Daiichi Nuclear Power Plant (FNPP) accident, the largest nuclear incident since the 1986 Chernobyl disaster, occurred when the plant was hit by a tsunami triggered by the Great East Japan Earthquake on March 11, 2011. The subsequent uncontrolled release of radioactive substances resulted in massive evacuations in a 20-km zone. To better understand the biological consequences of the FNPP accident, we have been measuring DNA damage levels in cattle in the evacuation zone. DNA damage was evaluated by assessing the levels of DNA double-strand breaks in peripheral blood lymphocytes by immunocytofluorescence-based quantification of γ-H2AX foci. A greater than two-fold increase in the fraction of damaged lymphocytes was observed in all animal cohorts within the evacuation zone, and the levels of DNA damage decreased slightly over the 700-day sample collection period. While the extent of damage appeared to be independent of the distance from the accident site and the estimated radiation dose from radiocesium, we observed age-dependent accumulation of DNA damage. Thus, this study, which was the first to evaluate the biological impact of the FNPP accident utilizing the γ-H2AX assays, indicated the causal relation between high levels of DNA damage in animals living in the evacuation zone and the FNPP accident.


The use of a task-based exposure assessment model (T-BEAM) for assessment of metal fume exposures during welding and thermal cutting.
Elevated disease rates have been documented among construction workers for cancer, pneumonoconiosis, asbestosis, and silicosis. However, methodologies for exposure assessment in construction are not well described in the U.S. literature. Working through a cooperative agreement with the National Institute for Occupational Safety and Health (NIOSH), the Center to Protect Workers' Rights--a research arm of the Building and Construction Trades Department, AFL-CIO--has developed and used a "Task-Based Exposure Assessment Model (T-BEAM)" for construction. The characteristic elements of T-BEAM are: (1) an emphasis on the identification, implementation, and evaluation of engineering and work practice controls; and (2) use of experienced, specially trained construction workers (construction safety and health specialists) in the exposure assessment process. A task-based approach was used because tasks, or specialized skills, form the single greatest thread of continuity in the dynamic environment of construction. Workers in the construction industry come from several crafts and are typically employed by a large number of contractors throughout their career. Project types (e.g., residential or industrial rehabilitation) are also highly variable and present unique health risks. Finally, because construction involves building, renovating, or dismantling physical surroundings, the work site is constantly changing. Between 1995 and 1996, T-BEAM was applied to the collection of approximately 200 personal exposure measurements associated with "hot work tasks"--welding and thermal cutting. Data were collected with the assistance of specially trained, journeyman ironworkers, pipe fitters, and boilermakers on nine construction sites located throughout the United States. Portable local exhaust ventilation was provided to participating contractors with the intent of measuring its impact on exposure. Results indicate that data collected in a standardized, systematic fashion from multiple work sites can be used to characterize exposures among sampled trades. Comparison of results to American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit values (TLVs) demonstrate a significant health hazard among sampled trades posed by welding and thermal cutting fume, manganese, nickel, and chromium VI. Direct estimates of the probability of exceeding the ACGIH TLV for respirable particulate suggests that boilermakers (100%) and ironworkers (71%) are at greatest risk. Other task variables evaluated with respect to exposure include task, whether work was performed indoors or outdoors, intermittency of work, and use of ventilation. Use of local or mechanical ventilation reduced mean exposures to fumes significantly.


Mechanisms of lysosomal enzyme release from leukocytes exposed to immune complexes and other particles.
Human PMN release lysosomal enzymes (beta-glucuronidase, acid phosphatase) when exposed to immune complexes, but do not release cytoplasmic LDH. The cells remain viable, and failure of LDH to appear in supernatants is not due to selective absorption or inactivation. Release of enzymes is not due to platelet contamination and is only partially enhanced by fresh serum. The selective release of lysosomal enzymes after uptake of complexes resembles that induced by inert particles of zymosan, and can be distinguished from the concurrent release of all enzymes after cell death induced by membrane-lytic crystals of MSU. Uptake of complexes, zymosan, or MSU particles is accompanied by concomitant increases in C-1 oxidation of glucose. Although MSU-induced damage can be retarded by the presence of Tris buffer, immune complexes and zymosan selectively release lysosomal hydrolases in the presence or absence of Tris buffer. Agents which elevate the level, within cells, of cAMP (PGE(1), theophylline, 2-CA) and cAMP itself inhibit the selective extrusion of acid hydrolases from leukocytes without affecting the viability of cells. Leukocytes may respond to immune particles by regurgitating a portion of their lysosomal hydrolases during phagocytosis.


Population pharmacokinetics of oral busulfan in young Japanese children before hematopoietic stem cell transplantation.
The objectives of this study were to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics of busulfan in Japanese pediatric patients who received high-dose oral busulfan as a conditioning regimen before hematopoietic stem cell transplantation. Population analysis was performed using retrospective therapeutic drug monitoring data (including test dose data) from 103 children. Their ages ranged from 2 months to 11 years old (mean age, 30 months; median age, 18 months). The plasma concentration of busulfan in all 1028 samples was measured with the same high-performance liquid chromatography method. Maximum likelihood estimates were sought for pharmacokinetic parameters with the NONMEM program. The best structural covariate-free model for busulfan was a one-compartment model with an exponential error model to account for intersubject variability and a proportional error model to account for intrasubject variability. The apparent oral clearance was found to be correlated with age, aspartate transaminase, and type of disease (malignant disease or other). The apparent volume of distribution was related to body weight. The busulfan formulation (1% powder form or crystal form) and dose (milligrams per kilogram) influenced the absorption rate constant. It was estimated that oral clearance expressed per kilogram of body weight is low at early infancy, then increases to a maximum at approximately 2 years of age and, thereafter, decreases. In conclusion, we have developed a population pharmacokinetic model of oral busulfan in children, particularly for those younger than 4 years old, that takes into consideration not only body size, but also several other covariates.


Effects of melatonin on the nitric oxide system and protein nitration in the hypobaric hypoxic rat hippocampus.
It is well documented that the nitric oxide (NO) might be directly involved in brain response to hypobaric hypoxia, and could contribute to memory deficiencies. Recent studies have shown that melatonin could attenuate hypoxia or ischemia-induced nerve injuries by decreasing the production of free radicals. The present study, using immunohistochemical and immunoblot methods, aimed to explore whether melatonin treatment may affect the expression of nitric oxide system and protein nitration, and provide neuroprotection in the rat hippocampus injured by hypobaric hypoxia. Prior to hypoxic treatment, adult rats were pretreated with melatonin (100 mg/kg, i.p.) before they were exposed to the altitude chamber with 48 Torr of the partial oxygen concentration (pO2) for 7 h to mimic the ambience of being at 9000 m in height. They were then sacrificed after 0 h, 1, and 3 days of reoxygenation. The results obtained from the immunohistochemical and immunoblotting analyses showed that the expressions of neuronal nitric oxide synthase (nNOS), endothelial nitric oxide synthase (eNOS), inducible nitric oxide synthase (iNOS), nitrotyrosine (Ntyr) and Caspase 3 in the hypoxic hippocampus were increased from 0 h to 3 days of reoxygenation. Interestingly, the hypoxia-induced increase of nNOS, eNOS, iNOS, Ntyr and Caspase 3 protein expression was significantly depressed in the hypoxic rats treated with melatonin. Activation of the nitric oxide system and protein nitration constitutes a hippocampal response to hypobaric hypoxia and administration of melatonin could provide new therapeutic avenues to prevent and/or treat the symptoms produced by hypobaric hypoxia.


New thinking: theory vs practice. A case study illustrating evidence-based therapeutic decision making.
Evidence-based medicine (EBM) plays a key role for decision making in clinical practice. Clinicians are encouraged to adhere to treatment guidelines based on high quality clinical trials, systematic reviews and meta-analyses, that are the focus of the Cochrane Collaboration. EBM is not, however, a panacea for medical decision making. The results of randomized clinical trials apply to populations of patients, and the challenge is to translate the results to individuals. Individual patients require different thought processes because presentation and response vary, and external factors (e.g. patient preference) influence the choice of treatment. The application of EBM demands clinical judgement. The case of a 28 year old scientist who presented with typical features of moderate ulcerative colitis, illustrates the dilemma. At each stage of his illness the treatment options based on EBM were discussed, including high dose 5-aminosalicyclic acid with or without topical therapy, corticosteroids, infliximab, immunomodulation, complementary therapy and surgery. Ultimately, therapeutic decisions depended on the patient's circumstances, preferences and response. Decisions should avoid circular motion caused by the illusion of progress and always consider the direction of travel.


Correlative light electron ion microscopy reveals in vivo localisation of bedaquiline in Mycobacterium tuberculosis-infected lungs.
Correlative light, electron, and ion microscopy (CLEIM) offers huge potential to track the intracellular fate of antibiotics, with organelle-level resolution. However, a correlative approach that enables subcellular antibiotic visualisation in pathogen-infected tissue is lacking. Here, we developed correlative light, electron, and ion microscopy in tissue (CLEIMiT) and used it to identify the cell type-specific accumulation of an antibiotic in lung lesions of mice infected with Mycobacterium tuberculosis. Using CLEIMiT, we found that the anti-tuberculosis (TB) drug bedaquiline (BDQ) is localised not only in foamy macrophages in the lungs during infection but also accumulate in polymorphonuclear (PMN) cells.


Pydpiper: a flexible toolkit for constructing novel registration pipelines.
Using neuroimaging technologies to elucidate the relationship between genotype and phenotype and brain and behavior will be a key contribution to biomedical research in the twenty-first century. Among the many methods for analyzing neuroimaging data, image registration deserves particular attention due to its wide range of applications. Finding strategies to register together many images and analyze the differences between them can be a challenge, particularly given that different experimental designs require different registration strategies. Moreover, writing software that can handle different types of image registration pipelines in a flexible, reusable and extensible way can be challenging. In response to this challenge, we have created Pydpiper, a neuroimaging registration toolkit written in Python. Pydpiper is an open-source, freely available software package that provides multiple modules for various image registration applications. Pydpiper offers five key innovations. Specifically: (1) a robust file handling class that allows access to outputs from all stages of registration at any point in the pipeline; (2) the ability of the framework to eliminate duplicate stages; (3) reusable, easy to subclass modules; (4) a development toolkit written for non-developers; (5) four complete applications that run complex image registration pipelines "out-of-the-box." In this paper, we will discuss both the general Pydpiper framework and the various ways in which component modules can be pieced together to easily create new registration pipelines. This will include a discussion of the core principles motivating code development and a comparison of Pydpiper with other available toolkits. We also provide a comprehensive, line-by-line example to orient users with limited programming knowledge and highlight some of the most useful features of Pydpiper. In addition, we will present the four current applications of the code.


Genetic variation in IL28B and spontaneous clearance of hepatitis C virus.
Hepatitis C virus (HCV) infection is the most common blood-borne infection in the United States, with estimates of 4 million HCV-infected individuals in the United States and 170 million worldwide. Most (70-80%) HCV infections persist and about 30% of individuals with persistent infection develop chronic liver disease, including cirrhosis and hepatocellular carcinoma. Epidemiological, viral and host factors have been associated with the differences in HCV clearance or persistence, and studies have demonstrated that a strong host immune response against HCV favours viral clearance. Thus, variation in genes involved in the immune response may contribute to the ability to clear the virus. In a recent genome-wide association study, a single nucleotide polymorphism (rs12979860) 3 kilobases upstream of the IL28B gene, which encodes the type III interferon IFN-3, was shown to associate strongly with more than a twofold difference in response to HCV drug treatment. To determine the potential effect of rs12979860 variation on outcome to HCV infection in a natural history setting, we genotyped this variant in HCV cohorts comprised of individuals who spontaneously cleared the virus (n = 388) or had persistent infection (n = 620). We show that the C/C genotype strongly enhances resolution of HCV infection among individuals of both European and African ancestry. To our knowledge, this is the strongest and most significant genetic effect associated with natural clearance of HCV, and these results implicate a primary role for IL28B in resolution of HCV infection.


Decompressive craniectomy for intractable cerebral edema: experience of a single center.
Several case reports and small clinical series have reported benefits of decompressive hemicraniectomy in patients with intractable cerebral edema and early clinical herniation. Specific indications and timing for this intervention remain unclear. We present our experience with this procedure in a subset of 18 patients with massive cerebral edema refractory to medical management, treated with decompressive craniectomy over a 3-year period (1997 to 2000). Computerized tomography (CT) scans were independently analyzed by a neuroradiologist blinded to clinical outcome. Eleven male and seven female patients, ages 20 to 69 years (mean +/- SEM, 46 +/- 14 years), underwent hemicraniectomy for the following diagnoses: 12 hemispheric infarcts, 3 traumatic intracerebral hemorrhages/contusions, 2 nontraumatic intraparenchymal hemorrhages (ICH), and 1 subdural empyema. This population included four patients with aneurysmal subarachnoid hemorrhage (SAH). Patients were followed for a mean of 10 months. Clinical factors including age, side of lesion, preoperative herniation signs, and early surgery (<12 or <24 hours) were not significantly associated with mortality or Glasgow outcome score (GOS). Preoperative CT evidence of transtentorial herniation (present in 5/17 patients) was associated with mortality ( = 0.04), while preoperative uncal herniation (8/17 patients) was associated with poor outcome (GOS > 1) ( = 0.01). Favorable outcome (GOS > 3) occurred in six patients, three with spontaneous or traumatic focal hematomas. Of four patients with SAH, one died while the others were severely disabled (GOS 3). Seven of nine patients with malignant MCA infarctions unrelated to SAH had poor outcomes. The overall mortality was 4/18 (22%). Patients with refractory cerebral swelling secondary to focal hematomas may have better outcomes following decompressive craniectomy. Patients with preexisting SAH seem to have poor outcomes, possibly related to other neurologic comorbidities. Hemicraniectomy requires definition of proper timing. Preoperative CT findings, especially transtentorial and uncal herniation may be useful in defining when decompressive surgery should not be performed.


A systematic review of community-based interventions for the treatment of adolescents with overweight and obesity.
Adolescent obesity is a risk factor for obesity and other chronic disease in adulthood. Evidence for the effectiveness of community-based obesity treatment programs for adolescents is required to inform policy and clinical decisions. This systematic review aims to evaluate recent effective and scalable community-based weight management programs for adolescents (13-17 years) who are overweight or obese. Eight databases (Medline, Embase, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Informit, and Scopus) were searched for studies published between January 2011-2 March 2017 which are scalable in a community setting and reported primary outcome measures relating to weight. Following deduplication, 10,074 records were screened by title/abstract with 31 publications describing 21 programs included in this review. Programs were heterogeneous in nature (including length, number and frequency of sessions, parent-involvement and technology involvement). Reduction in adolescent BMIz ranged from 2 to 9% post-program and from 2 to 11% after varied lengths of follow-up. Study quality varied (n = 5 weak; n = 8 moderate; n = 8 high), and findings are limited by the risk of selection and retention bias in the included studies. Factors including the effectiveness and acceptability to the target population must be considered when selecting such community programs.


Effect of fermentation and sterilization on anthocyanins in blueberry.
Blueberry products have various health benefits due to their high content of dietary anthocyanins. The aim of this study was to investigate the impact of fermentation and sterilization on total anthocyanin content, composition and some quality attributes of blueberry puree. The blueberry puree used here was fermented for 40 h at 37 °C by Lactobacillus after sterilization. The method of ultra-performance liquid chromatography-mass spectrometry was optimized for the rapid analysis of anthocyanins. Quality attributes including pH, color, total soluble solids and viscosity were measured. A total of 21 anthocyanins and five anthocyanidins were quantified by ultra-performance liquid chromatography. Fermented blueberry had reduced total anthocyanin content (29%) and levels of individual anthocyanins compared with fresh blueberry. Total anthocyanin content was decreased 46% by sterilization, and different degradation behavior of individual anthocyanin was appeared between fermented and sterilized-fermented blueberry puree. Fermentation and sterilization decreased the total soluble solids and pH and changed color parameters, while minimally influencing viscosity. The loss of total anthocyanin content by fermentation was related to the unstable structure of blueberry anthocyanins. Anthocyanins are sensitive to temperature (>80 °C), and degradation of anthocyanins by sterilization in blueberry should be considered in the fermentation procedure. © 2016 Society of Chemical Industry.


Responses of carotid body chemosensory activity and blood flow to stimulation of sympathetic nerves in the cat.
1. The effects of electrical stimulation of sympathetic nerves on sinus nerve chemosensory activity and carotid body blood flow were investigated in anaesthetized cats. 2. Two categories, designated as types I and II, of excitatory responses of chemosensory discharges to sympathetic stimulation were distinguished. Type I responses displayed elevations in impulse frequencies which were usually maximal in the initial 10-20 sec of stimulation, resisted alpha-adrenoceptor antagonism induced by phentolamine or phenoxybenzamine and were enhanced after administration of the dopamine antagonist, haloperidol. Type II responses showed increases in impulse frequencies which became more pronounced as stimulation progressed. These responses were susceptible to alpha-adrenoceptor blockade, were unaffected by haloperidol administration and were usually recorded during systemic hypotension. 3. Inhibitory changes due to activation of sympathetic fibres were recorded in 10% of chemosensory preparations. These effects were usually either abolished or replaced by type I excitatory responses after haloperidol administration. 4. Sympathetic stimulation caused reductions of carotid body blood flow during both natural and artificial perfusion of the organ. This effect was abolished or considerably attenuated by alpha-adrenoceptor antagonism and was unaffected by haloperidol administration. 5. Possible mechanisms which could account for the influences of sympathetic stimulation on chemoreceptor activity and carotid body blood flow are discussed. It is concluded that inhibitory and type I excitatory responses probably arise from activation of sympathetic fibres with non-vascular terminations within the carotid body. Type II excitatory responses are most likely due to blood flow changes.


Membrane Interaction of botulinum neurotoxin A translocation (T) domain. The belt region is a regulatory loop for membrane interaction.
The translocation of the catalytic domain through the membrane of the endosome to the cell cytoplasm is a key step of intoxication by botulinum neurotoxin (BoNT). This step is mediated by the translocation (T) domain upon endosome acidification, although the mechanism of interaction of the T domain with the membrane is still poorly understood. Using physicochemical approaches and spectroscopic methods, we studied the interaction of the BoNT/A T domain with the membrane as a function of pH. We found that the interaction with membranes does not involve major secondary or tertiary structural changes, as reported for other toxins like diphtheria toxin. The T domain becomes insoluble around its pI value and then penetrates into the membrane. At that stage, the T domain becomes able to permeabilize lipid vesicles. This occurs for pH values lower than 5.5, in agreement with the pH encountered by the toxin within endosomes. Electrostatic interactions are also important for the process. The role of the so-called belt region was investigated with four variant proteins presenting different lengths of the N-extremity of the T domain. We observed that this part of the T domain, which contains numerous negatively charged residues, limits the protein-membrane interaction. Indeed, interaction with the membrane of the protein deleted of this extremity takes place for higher pH values than for the entire T domain. Overall, the data suggest that acidification eliminates repulsive electrostatic interactions between the T domain and the membrane, allowing its penetration into the membrane without triggering detectable structural changes.


Androgen deprivation and thromboembolic events in men with prostate cancer.
Androgen deprivation therapy (ADT) improves prostate cancer outcomes in specific clinical settings, but is associated with adverse effects, including cardiac complications and possibly thromboembolic complications. The objective of this study was to estimate the impact of ADT on thromboembolic events (TEs) in a population-based cohort. In the linked Surveillance, Epidemiology and End Results-Medicare database, we identified men older than 65 who were diagnosed with nonmetastatic prostate cancer between 1999 and 2005. Medical or surgical ADT was identified by Medicare claims for gonadotropin-releasing hormone agonists or bilateral orchiectomy at any time following diagnosis. TEs included deep venous thrombosis, pulmonary embolism, and arterial embolism. The impact of ADT on the risk of any TE and on total number of events was estimated, controlling for patient and tumor characteristics. Of 154,611 patients with prostate cancer, 58,466 (38%) received ADT. During a median follow-up of 52 months, 15,950 men had at least 1 TE, including 8829 (55%) who had ADT and 7121 (45%) with no ADT. ADT was associated with increased risk of a TE (adjusted hazard ratio = 1.56; 95% confidence interval, 1.50-1.61; P < .0001), and duration of ADT was associated with the total number of events (P < .0001). In this population-based cohort, ADT was associated with increased risk of a TE, and longer durations of ADT were associated with more TEs. Men with intermediate- and low-risk prostate cancer should be assessed for TE risk factors before starting ADT and counseled regarding the risks and benefits of this therapy.


Depletion of activated macrophages with a folate receptor-beta-specific antibody improves symptoms in mouse models of rheumatoid arthritis.
Most therapies for autoimmune and inflammatory diseases either neutralize or suppress production of inflammatory cytokines produced by activated macrophages (e.g., TNFα, IL-1, IL-6, IL-17, GM-CSF). However, no approved therapies directly target this activated subset of macrophages. First, we undertook to examine whether the folate receptor beta (FR-β) positive subpopulation of macrophages, which marks the inflammatory subset in animal models of rheumatoid arthritis, might constitute the prominent population of macrophages in inflamed lesions in humans. Next, we utilized anti-FR-β monoclonal antibodies capable of mediating antibody-dependent cell cytotoxicity (ADCC) to treat animal models of rheumatoid arthritis and peritonitis. Human tissue samples of rheumatoid arthritis, Crohn's disease, ulcerative colitis, idiopathic pulmonary fibrosis, nonspecific interstitial pneumonia, chronic obstructive pulmonary disease, systemic lupus erythematosus, psoriasis, and scleroderma are all characterized by dramatic accumulation of macrophages that express FR-β, a protein not expressed on resting macrophages or any other healthy tissues. A monoclonal antibody to FR-β accumulates specifically in inflamed lesions of murine inflammatory disease models and successfully treats such models of rheumatoid arthritis and peritonitis. More importantly, elimination of FR-β-positive macrophages upon treatment with an anti-FR-β monoclonal antibody promotes the departure of other immune cells, including T cells, B cells, neutrophils, and dendritic cells from the inflamed lesions. These data suggest that specific elimination of FR-β-expressing macrophages may constitute a highly specific therapy for multiple autoimmune and inflammatory diseases and that a recently developed human anti-human FR-β monoclonal antibody (m909) might contribute to suppression of this subpopulation of macrophages.


Velocity matching by pulse front tilting for large area THz-pulse generation.
We propose a generally applicable velocity matching method for THz-pulse generation by optical rectification in the range below the phonon frequency of the nonlinear material. Velocity matching is based on pulse front tilting of the ultrashort excitation pulse and is able to produce a large area THz beam. Tuning of the THz radiation by changing the tilt angle is experimentally demonstrated for a narrow line in the range between 0.8- 0.97 times the phonon frequency. According to model calculations broadband THz radiation can be generated at lower frequencies. Advantages of the new velocity matching technique in comparison to the electro-optic Cherenkov effect and non-collinear beam mixing are discussed.


The impact of body mass index on the associations of lipids with the risk of coronary heart disease in the Asia Pacific region.
To assess whether body mass index (BMI) modifies the associations of lipids with coronary heart disease (CHD). In the Asia Pacific Cohort Studies Collaboration, total cholesterol (TC), high density lipoprotein cholesterol (HDLC) and triglycerides (TG) were measured for 333,297, 71,777 and 84,015 participants, respectively. All participants had measured BMI, categorized into underweight, normal, high-normal, overweight and obese, using standard definitions. For each BMI subgroup the effects of lipids on CHD were estimated per 1 standard deviation (SD) increase using Cox proportional hazard models, stratified by study and sex, adjusted for age and smoking. They were compared across the BMI groups, testing for interactions. In the analyses for TC, HDLC and TG, there were 3121, 714 and 808 CHD events during a mean follow-up of 6.7 years. The risk of CHD increased monotonically with increasing TC and decreasing HDLC in all BMI subgroups without evidence of heterogeneity (p for interaction > 0.4). In contrast, the hazard ratio for CHD for a one SD increase in log-transformed TG increased from 1.07 (95%CI 0.72-1.59) in underweight, 1.26 (1.10-1.44) in normal weight, 1.27 (1.08-1.49) in high-normal weight, 1.37 (1.22-1.55) in overweight, to 1.61(1.30-1.99) in obesity (p = 0.01 for interaction trend). These associations were attenuated (p = 0.07 for interaction) but remained significant in the overweight and obese after further adjustment for TC and HDLC. Greater excess body weight exacerbated the effects of TG, but not TC or HDLC, on CHD, suggesting that additional effort is required to reduce TG in the overweight and obese.


Complement abnormalities with lower extremities discomfort in Vietnamese immigrants.
The objective was to measure complement C'l esterase inhibitor (CIINH) in a group of Vietnamese outpatients with lower extremities discomfort of undetermined etiology. All 25 female patients were followed between 1992 and 1995. Their age ranged from 24 to 82 years old (mean age, 46.68 +/- 13.77). They presented with unexplained lower extremities discomfort. They were found to have low levels of CIINH (mean, 11.36 +/- 1.44 mg/dL versus control subjects, 15.64 +/- 2.22 mg/dL). Twenty-one patients were treated with oral Danazol 200 mg daily for 1-2 months. The improvement of the symptoms in our patients coincided with increased CIINH level in all of our patients (pretreatment, 11.33 +/- 1.46 mg/dL versus posttreatment, 16.82 +/- 2.98 mg/dL with p < 0.001) and the return to normal functional activity of CIINH associated with and without Danazol treatment. These patients may represent a form of androgen-responsive limited to the lower extremity's discomfort associated with low levels of CIINH, normal levels of Clq and normal ratio of C4d/C4 that differentiated them from angioedema (hereditary or acquired form), having no known precipitating factors or a family history of hereditary angioedema.


Molecular basis for N-terminal acetylation by human NatE and its modulation by HYPK.
The human N-terminal acetyltransferase E (NatE) contains NAA10 and NAA50 catalytic, and NAA15 auxiliary subunits and associates with HYPK, a protein with intrinsic NAA10 inhibitory activity. NatE co-translationally acetylates the N-terminus of half the proteome to mediate diverse biological processes, including protein half-life, localization, and interaction. The molecular basis for how NatE and HYPK cooperate is unknown. Here, we report the cryo-EM structures of human NatE and NatE/HYPK complexes and associated biochemistry. We reveal that NAA50 and HYPK exhibit negative cooperative binding to NAA15 in vitro and in human cells by inducing NAA15 shifts in opposing directions. NAA50 and HYPK each contribute to NAA10 activity inhibition through structural alteration of the NAA10 substrate-binding site. NAA50 activity is increased through NAA15 tethering, but is inhibited by HYPK through structural alteration of the NatE substrate-binding site. These studies reveal the molecular basis for coordinated N-terminal acetylation by NatE and HYPK.


Intravenous immunoglobulin and rituximab versus placebo treatment of antibody-associated psychosis: study protocol of a randomised phase IIa double-blinded placebo-controlled trial (SINAPPS2).
Evidence is conflicting about a causal role of inflammation in psychosis and, specifically, regarding antibodies binding to neuronal membrane targets, especially N-methyl-D-aspartate receptors. NMDAR, LGI1 and GABA-A antibodies were found more prevalent in people with psychosis than in healthy controls. We aim to test whether these antibodies are pathogenic and may cause isolated psychosis. The SINAPPS2 phase IIa double-blinded randomised controlled trial will test the efficacy and safety of immunoglobulin and rituximab treatment versus placebo for patients with acute psychosis symptoms as added to psychiatric standard of care. We will screen approximately 2500 adult patients with acute psychosis to identify 160 with antibody-positive psychosis without co-existing neurological disease and recruit about 80 eligible participants to the trial in the period from September 2017 to September 2021 across the UK. Eligible patients will be randomised 1:1 either to intravenous immunoglobulin (IVIG) followed by rituximab or to placebo infusions of 1% albumin followed by 0.9% sodium chloride, respectively. To detect a time-to-symptomatic-recovery hazard ratio of 0.322 with a power of 80%, 56 participants are needed to complete the trial, allowing for up to 12 participants to drop out of each group. Eligible patients will be randomised and assessed at baseline within 4 weeks of their eligibility confirmation. The treatment will start with IVIG or 1% albumin placebo infusions over 2-4 consecutive days no later than 7 days from baseline. It will continue 4-5 weeks later with a rituximab or sodium chloride placebo infusion and will end 2-3 weeks after this with another rituximab or placebo infusion. The primary outcome is the time to symptomatic recovery defined as symptomatic remission sustained for at least 6 months on the following Positive and Negative Syndrome Scale items: P1, P2, P3, N1, N4, N6, G5 and G9. Participants will be followed for 12 months from the first day of treatment or, where sustained remission begins after the first 6 months, for an additional minimum of 6 months to assess later response. The SINAPPS2 trial aims to test whether immunotherapy is efficacious and safe in psychosis associated with anti-neuronal membrane antibodies. ISRCTN, 11177045. Registered on 2 May 2017. EudraCT, 2016-000118-31. Registered on 22 November 2016. ClinicalTrials.gov, NCT03194815. Registered on 21 June 2017.


Airway gene therapy.
Given both the accessibility and the genetic basis of several pulmonary diseases, the lungs and airways initially seemed ideal candidates for gene therapy. Several routes of access are available, many of which have been refined and optimized for nongene drug delivery. Two respiratory diseases, cystic fibrosis (CF) and alpha1-antitrypsin (alpha1-AT) deficiency, are relatively common; the single gene responsible has been identified and current treatment strategies are not curative. This type of inherited disease was the obvious initial target for gene therapy, but it has become clear that nongenetic and acquired diseases, including cancer, may also be amenable to this approach. The majority of preclinical and clinical studies in the airway have involved viral vectors, although for diseases such as CF, likely to require repeated application, non-viral delivery systems have clear advantages. However, with both approaches a range of barriers to gene expression have been identified that are limiting success in the airway and alveolar region. This chapter reviews these issues, strategies aimed at overcoming them, and progress into clinical trials with non-viral vectors in a variety of pulmonary diseases.


[Implications of Alzheimer's disease for the caregiver's quality of life: a comparative study].
This study aimed to compare overall and dimension-specific perceptions of quality of life between a group of caregivers of elderly patients with Alzheimer's disease and a group of non-caregivers, matched for sociodemographic variables. Quality of life was measured with the Quality of Life Evaluation Scale in Alzheimer's Disease (Caregiver Version). Statistical analyses were performed (descriptive and ordinal logistic regression). Caregivers showed significantly higher odds of negatively evaluating the dimensions of physical health, disposition, mood, memory, you in general, and the capacity to perform leisure activities as compared to non-caregivers. Mean total quality of life score was 38.83 for caregivers and 41.81 for non-caregivers. The data suggest that contact with Alzheimer's disease negatively influences the total score and some dimensions of quality of life for family caregivers.


Quantitative polymerase chain reaction.
Quantitative PCR (qPCR) has entered widespread use with the increasing availability of real-time PCR. By the incorporation of fluorescent dyes in the reaction mixture, increases in amplification products can be monitored throughout the reaction, enabling measurements to be taken in the exponential phase of the reaction, before the reaction plateau. Whatever the platform or chemistry involved, the starting point of a real-time assay is a tissue-specific RNA and the end point of a real-time reaction is an amplification plot. As such, rather than focusing on specific platforms or chemistries, herein we address the basic principles that underlie sample preparation, experimental design, use of internal controls, assay considerations, and approaches to data analysis. The advent of real-time PCR has enabled high-throughput analysis of multiple transcripts from small tissue samples, with an unparalleled dynamic range and sensitivity. However, to new users, this technique may seem to require extensive optimization and troubleshooting to obtain reliable data; this is further compounded by the mass of technical variations present throughout the literature. The aim of this article is to provide the necessary basics to get a quantitative real-time PCR assay up and running, and to address some of the problems that may arise and how these may be resolved.


A longitudinal analysis of HIV treatment adherence among men who have sex with men: a cognitive escape perspective.
HIV is best managed by adhering to both medication and HIV care appointment schedules. Nonetheless, many HIV-positive men who have sex with men (MSM) report low levels of adherence to both. To explain this, we tested a cognitive escape model whereby drug and alcohol use mediate the effects of depression on HIV medication and appointment adherence. We used longitudinal data (n=856) from a behavioral intervention promoting increased treatment adherence among HIV-positive MSM. All model variables predicted appointment adherence, and our mediation hypotheses were supported. Conversely, although depression related to medication adherence, substance use did not mediate this relationship, as predicted. Self-reported appointment, but not medication, adherence related to changes in viral load over time. Therefore, cognitive escape characterizes appointment, but not medication, adherence within this sample. Future behavioral interventions for this population should target HIV appointment adherence, given its relationship to important clinical, psychological, and behavioral outcomes.


Isolation and characterization of catalytic and calmodulin-binding domains of Bordetella pertussis adenylate cyclase.
A truncated Bordetella pertussis cya gene product was expressed in Escherichia coli and purified by affinity chromatography on calmodulin-agarose. Trypsin cleavage of the 432-residue recombinant protein (Mr = 46,659) generated two fragments of 28 kDa and 19 kDa. These fragments, each containing a single Trp residue, were purified and analyzed for their catalytic and calmodulin-binding properties. The 28-kDa peptide, corresponding to the N-terminal domain of the recombinant adenylate cyclase, exhibited very low catalytic activity, and was still able to bind calmodulin weakly, as evidenced by using a fluorescent derivative of the activator protein. The 19-kDa peptide, corresponding to the C-terminal domain of the recombinant adenylate cyclase, interacted only with calmodulin as indicated by a shift in its intrinsic fluorescence emission spectrum or by the enhancement of fluorescence of dansyl-calmodulin. T28 and T19 fragments exhibited an increased sensitivity to denaturation by urea as compared to uncleaved adenylate cyclase, suggesting that interactive contacts between ordered portions of T28 and T19 in the intact protein participate both in their own stabilization and in stabilization of the whole tertiary structure. The two fragments reassociated into a highly active calmodulin-dependent species. Reassociation was enhanced by calmodulin itself, which 'trapped' the two complementary peptides into a stable, native-like, ternary complex, which shows similar catalytic properties to intact adenylate cyclase.


Alterations in Muscle Networks in the Upper Extremity of Chronic Stroke Survivors.
Muscle networks describe the functional connectivity between muscles quantified through the decomposition of intermuscular coherence (IMC) to identify shared frequencies at which certain muscles are co-modulated by common neural input. Efforts have been devoted to characterizing muscle networks in healthy subjects but stroke-linked alterations to muscle networks remain unexplored. Muscle networks were assessed for eight key upper extremity muscles during isometric force generation in stroke survivors with mild, moderate, and severe impairment and compared against healthy controls to identify stroke-specificalterations in muscle connectivity. Coherence matrices were decomposed using non-negative matrix factorization. The variance accounted for thresholding was then assessed to identify the number of muscle networks. Results showed that the number of muscle networks decreased in stroke survivors compared to age-matched healthy controls (four networks in the healthy control group) as the severity of post-stroke motor impairment increased (three in the mild- and two in the moderate- and severe-strokegroups). Statistically significant reductions of IMC in the synergistic deltoid muscles in the alpha-band in stroke patients versus healthy controls ( p < 0.05) were identified. This study represents the first effort, to the best of our knowledge, to assess stroke-linked alterations in functional intermuscular connectivity using muscle network analysis. The findings revealed a pattern of alterations to muscle networks in stroke survivors compared to healthy controls, as a result of the loss of brain function associated with the stroke. These alterations in muscle networks reflected underlying pathophysiology. These findings can help better understand the motor impairment and motor control in stroke and may advance rehabilitation efforts for stroke by identifying the impaired neuromuscular coordination among multiple muscles in the frequency domain.


The Implementation of an Integrated Management System at Qatar Biobank.
Qatar Biobank (QBB) is a platform that will make vital health research possible through its collection of samples and information on health and lifestyle from the local population of Qatar. The goal of QBB is to collect, process, store, and finally share high-quality biological samples and associated data for research purposes with the research community. To do this, a series of standardized procedures following evidence-based practices are required, and QBB is achieving this by implementing an integrated management system (IMS) that incorporates ISO 9001: 2015 and ISO 27001: 2013 standards. ISO 9001 is one of the most commonly implemented quality management systems as it is applicable to any size of organization. ISO 27001: 2013 is increasingly popular as organizations look to manage their data and information security, especially in the light of the recent General Data Protection Regulation legislation and an ever-changing digital landscape. QBB has achieved certification in both ISO 9001: 2015 (originally 2008 standard) and ISO 27001: 2013 since 2014. In 2016, during preparations for recertification of both standards in 2017, QBB chose to integrate both of the management systems in preference to running them in parallel, without compromising the goals and objectives of QBB. The IMS has ensured that rigorous processes and controls are implemented to not only manage the quality of internal and external processes and services provided, but the privacy and confidentiality of data collected during a participant visit are consistently protected as well as a proactive approach to identifying and managing risk within the organization. This article will explore the impact of implementing an IMS on the continuous improvement of services within QBB.


Delta 4-3-oxosteroid 5 beta-reductase deficiency: failure of ursodeoxycholic acid treatment and response to chenodeoxycholic acid plus cholic acid.
In some infants with liver disease, 3-oxo-delta 4 bile acids are the major bile acids in urine, a phenomenon attributed to reduced activity of the delta 4-3-oxosteroid 5 beta-reductase required for synthesis of chenodeoxycholic acid and cholic acid. These patients form a heterogeneous group. Many have a known cause of hepatic dysfunction and plasma concentrations of chenodeoxycholic acid and cholic acid that are actually greater than those of the 3-oxo-delta 4 bile acids. It is unlikely that these patients have a primary genetic deficiency of the 5 beta-reductase enzyme. To document the bile acid profile, clinical phenotype, and response to treatment of an infant with cholestasis, increased plasma concentrations of 3-oxo-delta 4 bile acids, low plasma concentrations of chenodeoxycholic acid and cholic acid, and no other identifiable cause of liver disease. This infant was compared with normal infants and infants with cholestasis of known cause. Analysis of bile acids by liquid secondary ionisation mass spectrometry and gas chromatography-mass spectrometry. The plasma bile acid profile of the patient was unique. She had chronic cholestatic liver disease associated with malabsorption of vitamins D and E and a normal gamma-glutamyltranspeptidase when the transaminases were increased. The liver disease failed to improve with ursodeoxycholic acid but responded to a combination of chenodeoxycholic acid and cholic acid. Treatment of primary 5 beta-reductase deficiency requires the use of bile acids that inhibit cholesterol 7 alpha-hydroxylase.


Present and future potential of plant-derived products to control arthropods of veterinary and medical significance.
The use of synthetic pesticides and repellents to target pests of veterinary and medical significance is becoming increasingly problematic. One alternative approach employs the bioactive attributes of plant-derived products (PDPs). These are particularly attractive on the grounds of low mammalian toxicity, short environmental persistence and complex chemistries that should limit development of pest resistance against them.Several pesticides and repellents based on PDPs are already available, and in some cases widely utilised, in modern pest management. Many more have a long history of traditional use in poorer areas of the globe where access to synthetic pesticides is often limited. Preliminary studies support that PDPs could be more widely used to target numerous medical and veterinary pests, with modes of action often specific to invertebrates.Though their current and future potential appears significant, development and deployment of PDPs to target veterinary and medical pests is not without issue. Variable efficacy is widely recognised as a restraint to PDPs for pest control. Identifying and developing natural bioactive PDP components in place of chemically less-stable raw or 'whole' products seems to be the most popular solution to this problem. A limited residual activity, often due to photosensitivity or high volatility, is a further drawback in some cases (though potentially advantageous in others). Nevertheless, encapsulation technologies and other slow-release mechanisms offer strong potential to improve residual activity where needed.The current review provides a summary of existing use and future potential of PDPs against ectoparasites of veterinary and medical significance. Four main types of PDP are considered (pyrethrum, neem, essential oils and plant extracts) for their pesticidal, growth regulating and repellent or deterrent properties. An overview of existing use and research for each is provided, with direction to more extensive reviews given in many sections. Sections to highlight potential issues, modes of action and emerging and future potential are also included.


Adenotonsillectomy for obstructive sleep apnea in children: outcome evaluated by pre- and postoperative polysomnography.
To evaluate the outcome of adenotonsillectomy for obstructive sleep apnea (OSA) in children using objective data from polysomnography supplemented by subjective proxy reports from the OSA-18 quality of life instrument. Prospective cohort study. Children 3 to 14 years of age with OSA diagnosed principally on the basis of polysomnography as having an obstructive apnea/hypopnea index (AHI) of 5 or greater underwent adenotonsillectomy. OSA was classified as mild (AHI > or = 5 < 10), moderate (AHI > or = 10 < 20), or severe (AHI > or =20). Children enrolled in the study also had postoperative polysomnography 3 to 6 months after surgery. Caregivers completed the OSA-18 survey before surgery and within 6 months after surgery. Pearson correlation was used to compare the pre- and postoperative AHI values with the pre- and postoperative OSA-18 total scores. SAS procedures (SAS Corp., Cary, NC) were used for statistical analyses. A P value less than or equal to .05 was considered significant. The study population included 79 healthy children, 40 of who were male. The mean age was 6.3 (range, 3.0-14.0) years. Only tonsillar size was correlated significantly with a high preoperative AHI. For all children, the preoperative AHI value was higher than the postoperative value. The mean preoperative AHI for the study population was 27.5, whereas the mean postoperative AHI was 3.5. This change was highly significant (P < .001). The percentage of children with normal polysomnography parameters after adenotonsillectomy ranged from 71% to 90% as a function of the criteria used to define OSA. It was highest when an obstructive apnea index less than 1 was used and lowest when an AHI less than 1 was used to define resolution of OSA. Overnight respiratory parameters after adenotonsillectomy were normal for all children with mild OSA. Three (12%) children with moderate preoperative OSA, and 13 (36%) children with severe preoperative OSA had persistent OSA after adenotonsillectomy. Resolution of OSA occurred in all children with a preoperative AHI less than or equal to 10 and in 73% of children with a preoperative AHI greater than 10. The mean total OSA-18 score and the mean scores for all domains showed significant improvement after surgery (P < .001). The preoperative AHI values had a fair correlation with the preoperative total OSA-18 scores (r = 0.28), but postoperative AHI values had a poor correlation with the postoperative total OSA-18 scores (r = 0.16). Caregivers reported snoring some, most, or all of the time in 22 (28%) children; this group included all children with persistent OSA. Adenotonsillectomy for OSA results in a dramatic improvement in respiratory parameters as measured by polysomnography in the majority of healthy children. Quality of life also improves significantly after adenotonsillectomy for OSA in children. However, the correlation between improvements in respiratory parameters and improvements in quality of life is poor. Severe preoperative OSA is associated with persistence of OSA after adenotonsillectomy. Postoperative reports of symptoms such as snoring and witnessed apneas correlate well with persistence of OSA after adenotonsillectomy.


FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours.
Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis. To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes. Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1-216 mo) or until death. FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the chi(2), Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model. FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract. FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.


Aggravation of atherosclerosis by hypertension in a subhuman primate model with coarctation of the aorta.
The interrelationships between hypertension and atherosclerosis were investigated in a subhuman primate model (cynomolgus monkey) with hypertension produced by surgically coarcting the miathoracic aorta. The hypertensive coarcted monkey fed a low cholesterol diet for 6 months did not develop complicating atherosclerosis but did develop focal intimal lesions as well as marked thickening of the musculoelastic media of both the large and small arteries. Fibrocellular thickening of the intima and media occurred in the vessels proximal to the coarctation but not distal to the coarctation suggesting that a high level of blood pressure with resulting increase in arterial wall tension is responsible for these changes. The hypertensive coarcted monkey fed a hypercholesterolemic diet (2% cholesterol and 10% butter) for 6 months developed severe coronary atherosclerotic disease with fibrous plaque formation. The disease produced over 65% luminal narrowing of the major coronary arteries and their extramural and intramural branches. In contrast the noncoarcted normotensive animal fed the same diet developed mild atherosclerosis of only the major coronary arteries which caused an average luminal narrowing of 12%. Aggravation of atherosclerosis by hypertension also appeared to occur in the other arteries above the coarctation particularly the cerebral arteries. When the hypertensive coarcted monkey with preestablished coronary atherosclerosis was treated with a low cholesterol diet and a combination of antihypertensive drugs (hydrochlorothiazide, hydralazine, and reserpine), the progression of the disease was arrested. There also was evidence that treatment caused some regression of the coronary lesions which appeared to "heal" by fibrosis. The treatment of both hyperlipidemia and hypertension appeared to be more effective than the treatment of hyperlipidemia, alone.


Inhibition by dexamethasone of histamine production in allergic inflammation in rats.
In an allergic inflammation model of air pouch type in rats, histamine level in the pouch fluid and histidine decarboxylase activity of pouch wall tissues in the postanaphylaxis phase were increased. Although treatment with dexamethasone failed to inhibit histamine release from mast cells in the anaphylaxis phase, histamine production in the postanaphylaxis phase was inhibited dose dependently. Histamine production-increasing activity in the pouch fluid collected 8 h after the Ag challenge, which was estimated by an activity to stimulate histamine production by bone marrow cells, was decreased by the administration of dexamethasone at the time of the Ag challenge. The addition of steroidal antiinflammatory drugs, dexamethasone, prednisolone, or hydrocortisone, into the incubation medium inhibited the pouch fluid-induced histamine production by bone marrow cells. Hydrocortisone mesylate antagonized the inhibitory effect of dexamethasone on histamine production by bone marrow cells. However, hydrocortisone mesylate failed to recover the decrease in histamine production-increasing activity of the pouch fluid collected from dexamethasone-treated rats. In addition, the dialyzed sample of pouch fluid obtained from dexamethasone-treated nonsensitized rats did not reduce the stimulated histamine production by the pouch fluid sample obtained from the sensitized rats. However, increase in histamine production of bone marrow cells stimulated by the pouch fluid was not inhibited by cyclosporin A that inhibited histamine production induced by Con A. This observation indicates that the pouch fluid has no effect to induce production of the histamine production-increasing factor by bone marrow cells. Consequently, it is suggested that dexamethasone inhibits not only the production of histamine production-increasing factor but also the response of histamine-producing cells to this factor.


Virtue, Vice, and "Voracious" Science: How should we approach the ethics of primate research?.
Philosophical approaches to animal research have typically asked whether nonhuman animals have rights that would prohibit such research or whether the benefit of such research on the whole balances out the harms to animals. The professional ethics approach instead promotes compliance with regulatory norms that aim to support science progress. In Voracious Science and Vulnerable Animals: A Primate Scientist's Ethical Journey (2016), John Gluck struggles with issues that relate to each of these ethical frameworks, but the notion of an ethical "journey" also raises questions of character that are underdeveloped in animal research ethics. This essay considers how virtue ethics may allow us to revisit the ethical significance of the research of one of Gluck's mentors, Harry F. Harlow. Harlow's torturous, but highly influential, experiments with infant macaques made him one of the most controversial figures in animal research in the second half of the 20th century. A virtue ethical approach to his case poses a unique set of questions, including: Was Harlow compassionate or cruel? Why are human-animal bonds important in ethical primate research? And what is a good life for a research monkey?


Fear, lockdown, and diversion: Comparing drivers of pandemic economic decline 2020.
The collapse of economic activity in 2020 from COVID-19 has been immense. An important question is how much of that collapse resulted from government-imposed restrictions versus people voluntarily choosing to stay home to avoid infection. This paper examines the drivers of the economic slowdown using cellular phone records data on customer visits to more than 2.25 million individual businesses across 110 different industries. Comparing consumer behavior over the crisis within the same commuting zones but across state and county boundaries with different policy regimes suggests that legal shutdown orders account for only a modest share of the massive changes to consumer behavior (and that tracking county-level policy conditions is significantly more accurate than using state-level policies alone). While overall consumer traffic fell by 60 percentage points, legal restrictions explain only 7 percentage points of this. Individual choices were far more important and seem tied to fears of infection. Traffic started dropping before the legal orders were in place; was highly influenced by the number of COVID deaths reported in the county; and showed a clear shift by consumers away from busier, more crowded stores toward smaller, less busy stores in the same industry. States that repealed their shutdown orders saw symmetric, modest recoveries in consumer visits, further supporting the small estimated effect of policy. Although the shutdown orders had little aggregate impact, they did have a significant effect in reallocating consumer visits away from "nonessential" to "essential" businesses and from restaurants and bars toward groceries and other food sellers.


Parathyroid hormone linked to a collagen binding domain promotes hair growth in a mouse model of chemotherapy-induced alopecia in a dose-dependent manner.
Chemotherapy-induced alopecia is a major source of psychological stress in patients undergoing cancer chemotherapy, and it can influence treatment decisions. Although there is currently no therapy for alopecia, a fusion protein of parathyroid hormone and collagen binding domain (PTH-CBD) has shown promise in animal models. The aim of this study was to determine whether there are dose-dependent effects of PTH-CBD on chemotherapy-induced alopecia in a mouse model. C57BL/6J mice were waxed to synchronize hair follicles; treated on day 7 with vehicle or PTH-CBD (100, 320, and 1000 mcg/kg subcutaneous injection); and treated on day 9 with vehicle or cyclophosphamide (150 mg/kg intraperitoneally). Mice were photographed every 3-4 days and killed on day 63 for histological analysis. Photographs were quantified by gray scale analysis to assess hair content. Mice not receiving chemotherapy showed regrowth of hair 2 weeks after waxing and normal histology after 2 months. Mice receiving chemotherapy alone showed marked hair loss after chemotherapy, which was sustained for 10 days and was followed by rapid regrowth of a normal coat. Histological analysis revealed rapid cycling dystrophic anagen/catagen follicles. Animals receiving chemotherapy and PTH-CBD showed decreased hair loss and more rapid regrowth of hair than that seen with chemotherapy alone (increased hair growth by gray scale analysis, P<0.05), and the effects were dose dependent. Histologically, hair follicles in animals receiving the highest dose of PTH-CBD were in a quiescent phase, similar to that in mice that did not receive chemotherapy. Single-dose subcutaneous administration of PTH-CBD showed dose-dependent effects in minimizing hair loss and speeding up recovery from chemotherapy-induced alopecia.


Feeding frequency has diet-dependent effects on plasma hormone concentrations but does not affect oocyte quality in dairy heifers fed fibre- or starch-based diets.
The post-fertilisation developmental capacity of bovine oocytes recovered by ultrasound guided transvaginal follicular aspiration (ovum pick-up, OPU) is influenced by diet-induced changes in hormone and metabolite concentrations. The objectives of this experiment were first to determine whether post-prandial changes in hormone concentrations, induced by changing the frequency of feeding, influenced oocyte quality and second whether changes in plasma glucagon concentration were associated with oocyte quality. Using a 2 × 2 factorial design, Holstein heifers (six per treatment) were fed either fibre- or starch-based diets containing either 189 or 478 g starch/kg dry matter. The diets were offered in either two or four equal meals per day and supplied twice the maintenance energy requirement. Blood samples were obtained both at weekly intervals (three samples per heifer, collected before feeding) during the experiment and throughout an entire 24-h period (15 or 17 samples per heifer for twice or four times daily-fed heifers, respectively). Each heifer underwent six sessions of OPU (twice weekly) beginning 25 days after introduction of the diets. Oocyte quality was assessed by development to the blastocyst stage in synthetic oviductal fluid following in vitro fertilisation. Mean weekly plasma insulin concentrations did not differ between diets, but plasma glucagon concentrations were greatest when heifers were fed the starch-based diet twice daily compared with the other diets. When heifers were offered four meals per day, there were no meal-related changes in hormone concentrations. However, when heifers were offered two meals per day, plasma insulin concentration increased after feeding the starch-based, but not the fibre-based diet. Plasma glucagon concentration increased after meals when heifers were fed twice daily and the increase was substantially greater when the starch-based diet was fed. Treatments did not influence (overall mean with mean ± s.e.) ovarian follicle size distribution or oocyte recovery by OPU (6.2 ± 0.4 per heifer), the proportion of oocytes that cleaved following insemination (0.57 ± 0.030) or blastocyst yield (0.27 ± 0.027 of oocytes cleaved). In conclusion, by feeding diets differing in carbohydrate source at different frequencies of feeding, meal-related changes in plasma hormone profiles were altered significantly, but oocyte quality was not affected. Therefore effects of diet on oocyte quality appear not to be mediated by meal-related fluctuations in hormone concentrations.


Are immunizations an incentive for well-child visits?
To assess the beliefs of parents and the visit patterns of their children to determine whether immunizations act as an incentive to use well-child care. Medical record audits provided data on immunizations and well-child visits. Two questions from a parent interview were used to identify 4 groups of parents: (1) motivated and (2) unmotivated to keep a well-child care appointment regardless of whether immunizations are scheduled, (3) vaccine-motivated and (4) checkup-motivated (parents who were influenced negatively by the prospect of receiving vaccinations). The percentage of children with a visit at each age window for well-child visits and the percentage up-to-date for their immunizations at given ages were compared across the 4 groups. The 4 groups were also compared for other parental attitudes about immunizations and well-child visits, and on sociodemographic and access characteristics. Most (73.3%) of the 502 parents surveyed were classified as motivated and 5% as unmotivated to keep a well-child care appointment regardless of whether an immunization was scheduled. Only 18.3% were categorized as vaccine-motivated and 3.4% as checkup-motivated. For all 4 groups, there was no discernible difference in attendance between immunization and nonimmunization visits. Attendance in the windows for well-child visits and percentage of children up-to-date on immunizations declined with increasing age. In this inner-city population, attendance patterns at visits did not support the incentive hypothesis. This finding should reassure clinicians that providing immunizations outside of regular well-child care visits will not necessarily decrease attendance at visits for well-child care.


Demanding and effective: participants' experiences of internet-delivered prolonged exposure provided within two months after exposure to trauma.
Background: The use of remotely delivered early intervention after trauma may prevent and/or reduce symptoms of post-traumatic stress. Our research group evaluated a novel three-week therapist-guided internet-delivered intervention based on prolonged exposure (Condensed Internet-Delivered Prolonged Exposure; CIPE) in a pilot trial. The results indicated that the intervention was feasible, acceptable and reduced symptoms of post-traumatic stress at post-intervention compared to a waiting-list condition. Exposure to traumatic memories can be emotionally demanding and there is a need for detailed investigation of participants' experiences in receiving this type of intervention remotely. Objective: Investigate participants' experiences of receiving CIPE early after trauma. Method: In this study, qualitative thematic analysis was used and semi-structured interviews with 11 participants six months after intervention completion were conducted. All interviews were audio-recorded and transcribed verbatim. Results: One overarching theme labelled as 'demanding and effective' was identified. Participants expressed that treatment effects could only be achieved by putting in a lot of effort and by being emotionally close to the trauma memory during exposure exercises. Participants reported CIPE to be a highly credible- and educative intervention that motivated them to fully engage in exposure exercises. The most distressing parts of the intervention was perceived as tolerable and important to do to heal psychologically after trauma. For many participants, the possibility to engage in the intervention whenever and where it suited them was helpful, although some participants described it as challenging to find a balance between their own responsibility and when to expect therapist support. The internet-based format was perceived as a safe forum for self-disclosure that helped some participants overcome avoidance due to shame during imaginal exposure. Conclusion: CIPE was considered demanding, yet effective by the interviewed participants. The most distressing parts of the intervention was perceived to be the most important and were tolerable and feasible to provide online.


Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography Is Associated With Severely Impaired Coronary Flow Reserve, Not Obstructive Disease.
Cardiovascular disease (CVD) fatality rates are higher for women than for men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR), an integrated measure of large- and small-vessel CAD and myocardial ischemia, identifies patients at risk for CVD death, but is not routinely measured in clinical practice. We sought to investigate the impact of sex, CFR, and angiographic CAD severity on adverse cardiovascular events. Consecutive patients (n=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography and with left ventricular ejection fraction >40% were followed (median, 3.0 years) for a composite end point of major adverse cardiovascular events, including cardiovascular death and hospitalization for nonfatal myocardial infarction or heart failure. The extent and severity of angiographic CAD were estimated by using the CAD prognostic index, and CFR was quantified by using positron emission tomography. Although women in comparison with men had lower pretest clinical scores, rates of prior myocardial infarction, and burden of angiographic CAD (P<0.001), they demonstrated greater risk of CVD events, even after adjustment for traditional risk factors, imaging findings, and early revascularization (adjusted hazard ratio, 2.05; 95% confidence interval, 1.05-4.02; P=0.03). Impaired CFR was similarly present among women and men, but in patients with low CFR (<1.6, n=163), women showed a higher frequency of nonobstructive CAD, whereas men showed a higher frequency of severely obstructive CAD (P=0.002). After also adjusting for CFR, the effect of sex on outcomes was no longer significant. When stratified by sex and CFR, only women with severely impaired CFR demonstrated significantly increased adjusted risk of CVD events (P<0.0001, P for interaction=0.04). Women referred for coronary angiography had a significantly lower burden of obstructive CAD in comparison with men but were not protected from CVD events. Excess cardiovascular risk in women was independently associated with impaired CFR, representing a hidden biological risk, and a phenotype less amenable to revascularization. Impaired CFR, particularly absent severely obstructive CAD, may represent a novel target for CVD risk reduction.


Fluoride levels and fluoride contamination of fruit juices.
Increasing consumption of beverages as a replacement for water have made fluoride content in beverages an important issue. In this study, forty-three ready-to-drink fruit juices were examined for fluoride ion concentration. It was found that 42% of the samples had more than 1 ppm of fluoride. It was also determined that "pure" fruit juices, often grape juices, contained high levels of fluoride. Juice made from grapes separated from the skin did not contain any fluoride. Since it is common practice to use fluoride-containing insecticide in growing grapes, it is believed that contamination of these juices is occurring. Washing of grape skins produced appreciable quantities of fluoride. Given that increasing numbers of people are consuming beverages instead of water, fluoride supplementation should not be based solely upon the concentration of the drinking water, but should also consider the amount of different beverages consumed and their fluoride content.


Genome wide association study of response to interval and continuous exercise training: the Predict-HIIT study.
Low cardiorespiratory fitness (V̇O2peak) is highly associated with chronic disease and mortality from all causes. Whilst exercise training is recommended in health guidelines to improve V̇O2peak, there is considerable inter-individual variability in the V̇O2peak response to the same dose of exercise. Understanding how genetic factors contribute to V̇O2peak training response may improve personalisation of exercise programs. The aim of this study was to identify genetic variants that are associated with the magnitude of V̇O2peak response following exercise training. Participant change in objectively measured V̇O2peak from 18 different interventions was obtained from a multi-centre study (Predict-HIIT). A genome-wide association study was completed (n = 507), and a polygenic predictor score (PPS) was developed using alleles from single nucleotide polymorphisms (SNPs) significantly associated (P < 1 × 10-5) with the magnitude of V̇O2peak response. Findings were tested in an independent validation study (n = 39) and compared to previous research. No variants at the genome-wide significance level were found after adjusting for key covariates (baseline V̇O2peak, individual study, principal components which were significantly associated with the trait). A Quantile-Quantile plot indicates there was minor inflation in the study. Twelve novel loci showed a trend of association with V̇O2peak response that reached suggestive significance (P < 1 × 10-5). The strongest association was found near the membrane associated guanylate kinase, WW and PDZ domain containing 2 (MAGI2) gene (rs6959961, P = 2.61 × 10-7). A PPS created from the 12 lead SNPs was unable to predict V̇O2peak response in a tenfold cross validation, or in an independent (n = 39) validation study (P > 0.1). Significant correlations were found for beta coefficients of variants in the Predict-HIIT (P < 1 × 10-4) and the validation study (P < × 10-6), indicating that general effects of the loci exist, and that with a higher statistical power, more significant genetic associations may become apparent. Ongoing research and validation of current and previous findings is needed to determine if genetics does play a large role in V̇O2peak response variance, and whether genomic predictors for V̇O2peak response trainability can inform evidence-based clinical practice. Trial registration Australian New Zealand Clinical Trials Registry (ANZCTR), Trial Id: ACTRN12618000501246, Date Registered: 06/04/2018, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=374601&isReview=true .


The global avian invasions atlas, a database of alien bird distributions worldwide.
The introduction of species to locations where they do not naturally occur (termed aliens) can have far-reaching and unpredictable environmental and economic consequences. Therefore there is a strong incentive to stem the tide of alien species introduction and spread. In order to identify broad patterns and processes of alien invasions, a spatially referenced, global dataset on the historical introductions and alien distributions of a complete taxonomic group is required. Here we present the Global Avian Invasions Atlas (GAVIA)-a new spatial and temporal dataset comprising 27,723 distribution records for 971 alien bird species introduced to 230 countries and administrative areas spanning the period 6000BCE-AD2014. GAVIA was initiated to provide a unified database of records on alien bird introductions, incorporating records from all stages of invasion, including introductions that have failed as well as those that have succeeded. GAVIA represents the most comprehensive resource on the global distribution of alien species in any major taxon, allowing the spatial and temporal dynamics of alien bird distributions to be examined.


Inhibition of TPA-induced protein kinase C and transcription activator protein-1 binding activities by theaflavin-3,3'-digallate from black tea in NIH3T3 cells.
Tea is one of the most popular beverages in the world. Several reports have shown that both green tea and black tea were able to inhibit tumor cell proliferation in animal models. In this study, we investigated the inhibitory effects of black tea polyphenols including theaflavin (TF-1), the mixture (TF-2) of theaflavin-3-gallate (TF-2a), and theaflavin-3'-gallate (TF-2b), theaflavin-3,3'-digallate (TF-3), thearubigin (TR), and a major green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) on 12-O-tetradecanoylphorbol 13-acetate (TPA)-induced protein kinase C (PKC) and transcription activator protein-1 (AP-1) binding activities in NIH3T3 cells. On analysis of PKC activity with partial purified preparation, TPA (100 ng/mL) treatment was able to elevate membrane-associated PKC activity approximately 3-fold, and treatment with TF-3 (20 microM) and EGCG (20 microM) showed 94.5% and 9.4% suppression on TPA-induced PKC activity, respectively. Translocation of PKCalpha protein from cytosol to membrane was detected in TPA-treated NIH3T3 cells, and TF-3 was able to block its translocation. By in vitro kinase assay using myelin basic protein (MBP) as a PKC-specific substrate, we found that TPA treatment was able to increase PKC kinase activity by detection of phosphorylated MBP protein and TF-3 showed strongest inhibitory effect on its phosphorylation while EGCG was shown to be less effective. We also analyzed the AP-1 binding activity by electrophoretic mobility shift assay and c-Jun gene expression by northern blot and western blot, the results showed that TF-3 is the most potent inhibitor on TPA-induced AP-1 binding activity and c-Jun gene expression among these five tea polyphenols. Our results might provide new molecular basis for understanding the inhibitory effects of tea polyphenols on TPA-mediated tumor promotion.


Genetic disruption of both tryptophan hydroxylase genes dramatically reduces serotonin and affects behavior in models sensitive to antidepressants.
The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesis of serotonin is regulated by two rate-limiting enzymes, tryptophan hydroxylase-1 and -2 (TPH1 and TPH2). We used a gene-targeting approach to generate mice with selective and complete elimination of the two known TPH isoforms. This resulted in dramatically reduced central 5-HT levels in Tph2 knockout (TPH2KO) and Tph1/Tph2 double knockout (DKO) mice; and substantially reduced peripheral 5-HT levels in DKO, but not TPH2KO mice. Therefore, differential expression of the two isoforms of TPH was reflected in corresponding depletion of 5-HT content in the brain and periphery. Surprisingly, despite the prominent and evolutionarily ancient role that 5-HT plays in both vertebrate and invertebrate physiology, none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered. These behavioral changes were subtle in the TPH2KO mice; they were enhanced in the DKO mice. Herein, we confirm findings from prior descriptions of TPH1 knockout mice and present the first reported phenotypic evaluations of Tph2 and Tph1/Tph2 knockout mice. The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders.


Altering Knee Abduction Angular Impulse Using Wedged Insoles for Treatment of Patellofemoral Pain in Runners: A Six-Week Randomized Controlled Trial.
Determine if a change in internal knee abduction angular impulse (KAAI) is related to pain reduction for runners with patellofemoral pain (PFP) by comparing lateral and medial wedge insole interventions, and increased KAAI and decreased KAAI groups. Randomized controlled clinical trial (ClinicalTrials.gov ID# NCT01332110). Biomechanics laboratory and community. Thirty-six runners with physician-diagnosed PFP enrolled in the trial, and 27 were analyzed. Runners with PFP were randomly assigned to either an experimental 3 mm lateral wedge or control 6 mm medial wedge group. Participants completed a biomechanical gait analysis to quantify KAAIs with their assigned insole, and then used their assigned insole for six-weeks during their regular runs. Usual pain during running was measured at baseline and at six-week follow-up using a visual analog scale. Statistical tests were performed to identify differences between wedge types, differences between biomechanical response types (i.e. increase or decrease KAAI), as well as predictors of pain reduction. Percent change in KAAI relative to neutral, and % change in pain over six weeks. Clinically meaningful reductions in pain (>33%) were measured for both footwear groups; however, no significant differences between footwear groups were found (p = 0.697). When participants were regrouped based on KAAI change (i.e., increase or decrease), again, no significant differences in pain reduction were noted (p = 0.146). Interestingly, when evaluating absolute change in KAAI, a significant relationship between absolute % change in KAAI and % pain reduction was observed (R2 = 0.21; p = 0.030), after adjusting for baseline pain levels. The greater the absolute % change in KAAI during running, the greater the % reduction in pain over six weeks, regardless of wedge type, and whether KAAIs increased or decreased. Lateral and medial wedge insoles were similar in effectiveness for treatment of PFP. Altering KAAI should be a focus of future PFP research. Lateral wedges should be studied further as an alternative therapy to medial wedges for management of PFP. ClinicalTrials.gov NCT01332110.


Tracer arrival timing-insensitive technique for estimating flow in MR perfusion-weighted imaging using singular value decomposition with a block-circulant deconvolution matrix.
Relative cerebral blood flow (CBF) and tissue mean transit time (MTT) estimates from bolus-tracking MR perfusion-weighted imaging (PWI) have been shown to be sensitive to delay and dispersion when using singular value decomposition (SVD) with a single measured arterial input function. This study proposes a technique that is made time-shift insensitive by the use of a block-circulant matrix for deconvolution with (oSVD) and without (cSVD) minimization of oscillation of the derived residue function. The performances of these methods are compared with standard SVD (sSVD) in both numerical simulations and in clinically acquired data. An additional index of disturbed hemodynamics (oDelay) is proposed that represents the tracer arrival time difference between the AIF and tissue signal. Results show that PWI estimates from sSVD are weighted by tracer arrival time differences, while those from oSVD and cSVD are not. oSVD also provides estimates that are less sensitive to blood volume compared to cSVD. Using PWI data that can be routinely collected clinically, oSVD shows promise in providing tracer arrival timing-insensitive flow estimates and hence a more specific indicator of ischemic injury. Shift maps can continue to provide a sensitive reflection of disturbed hemodynamics.


High-efficiency subwavelength diffractive element patterned in a high-refractive-index material for 633 nm.
We propose the use of high-index materials for the fabrication of subwavelength diffractive components operating in the visible domain. This approach yields a reduction of fabrication constraints and an improvement of theoretical performance. A blazed grating with subwavelength binary features and with a period of 5.75 wavelengths is designed and fabricated in a TiO(2) layer coated upon a glass substrate. The first-order diffraction efficiency measured with a He-Ne laser beam is 83%, which is slightly larger than that achieved theoretically by the best standard (continuous profile) blazed grating fabricated in glass with the same period.


The engrailed-expressing secondary head spots in the embryonic crayfish brain: examples for a group of homologous neurons in Crustacea and Hexapoda?
Hexapoda have been traditionally seen as the closest relatives of the Myriapoda (Tracheata hypothesis) but molecular studies have challenged this hypothesis and rather have suggested a close relationship of hexapods and crustaceans (Tetraconata hypothesis). In this new debate, data on the structure and development of the arthropod nervous system contribute important new data ("neurophylogeny"). Neurophylogenetic studies have already provided several examples for individually identifiably neurons in the ventral nerve cord that are homologous between insects and crustaceans. In the present report, we have analysed the emergence of Engrailed-expressing cells in the embryonic brain of a parthenogenetic crayfish, the marbled crayfish (Marmorkrebs), and have compared our findings to the pattern previously reported from insects. Our data suggest that a group of six Engrailed-expressing neurons in the optic anlagen, the so-called secondary head spot cells can be homologised between crayfish and the grasshopper. In the grasshopper, these cells are supposed to be involved in establishing the primary axon scaffold of the brain. Our data provide the first example for a cluster of brain neurons that can be homologised between insects and crustaceans and show that even at the level of certain cell groups, brain structures are evolutionary conserved in these two groups.


Correlation between viral resistance to zidovudine and resistance at the reverse transcriptase level for a panel of human immunodeficiency virus type 1 mutants.
Using a large panel of human immunodeficiency virus type 1 site-directed mutants, we have observed a higher correlation than has previously been demonstrated between zidovudine (AZT)-triphosphate resistance data at the reverse transcriptase (RT) level and corresponding viral AZT resistance. This enhanced-resistance effect at the RT level was seen with ATP and to a lesser extent with PP(i) when ATP was added at physiological concentrations. The ATP-dependent mechanism (analogous to pyrophosphorolysis) appears to be dominant in the mutants bearing the D67N and K70R or 69 insertion mutations, whereas the Q151M mutation seems independent of ATP for decreased binding to AZT-triphosphate.


Advances for studying clonal evolution in cancer.
The "clonal evolution" model of cancer emerged and "evolved" amid ongoing advances in technology, especially in recent years during which next generation sequencing instruments have provided ever higher resolution pictures of the genetic changes in cancer cells and heterogeneity in tumors. It has become increasingly clear that clonal evolution is not a single sequential process, but instead frequently involves simultaneous evolution of multiple subclones that co-exist because they are of similar fitness or are spatially separated. Co-evolution of subclones also occurs when they complement each other's survival advantages. Recent studies have also shown that clonal evolution is highly heterogeneous: different individual tumors of the same type may undergo very different paths of clonal evolution. New methodological advancements, including deep digital sequencing of a mixed tumor population, single cell sequencing, and the development of more sophisticated computational tools, will continue to shape and reshape the models of clonal evolution. In turn, these will provide both an improved framework for the understanding of cancer progression and a guide for treatment strategies aimed at the elimination of all, rather than just some, of the cancer cells within a patient.


Regional resources buffer the impact of functional limitations on perceived autonomy in older adults with multiple illnesses.
Retaining perceptions of autonomy is a key component of successful aging. Perceived autonomy refers to the capacity to make and enact self-directed decisions. These perceptions are often threatened in older adults with multiple illnesses, when functional limitations resulting from these illnesses impede the enactment of self-directed decisions. Regional resources (in Germany specifically at the level of administrative districts) might counteract these impediments of autonomy. Economically stronger districts can provide more-concrete support resources for older adults, buffering the negative effect of functional limitations on self-perceived autonomy. This study assessed participants aged over 65 with 2 or more chronic conditions. In total, N = 287 provided data (Mage = 73.3, SD = 5.07), and n = 97 were women. Gross domestic product (GDP) per capita was used as a proxy measure of administrative district wealth in Germany. Hierarchical multilevel regression analyses with cross-level interactions were conducted. Results suggest that the detrimental effect of functional limitations on perceived autonomy is less pronounced for participants residing in higher GDP districts. Conversely, for participants in lower GDP districts, the effect is exacerbated. This finding suggests that districts with greater financial resources might be better able to invest in supports that promote and facilitate autonomy and, thus, provide a buffer against threats to individual perceived autonomy.


Refuge cover decreases the incidence of bite wounds in laboratory South African clawed frogs (Xenopus laevis).
The Guide for the Care and Use of Laboratory Animals recommends environmental enrichment for all laboratory animals, including amphibians. In this study, we evaluated the effect of adding environmental enrichment in the form of acrylonitrile- butadiene-styrene (ABS) pipes as covered refuge for laboratory Xenopus laevis housed in 2 pond-style tanks (capacity, 300 l; stocking density, approximately 150 frogs/tank; dimensions, 1.3 x 1.8 x 1.3 m). Medical records from animals housed in these 2 ponds between 1 January 2001 to 31 December 2003 revealed the incidence of bite wounds to be 5.0%, 4.0%, and 5.0% annually, respectively, and indicated 2 episodes of cannibalism (in 2003). In January 2004, we added ABS pipes as refuge housing to these tanks and continued to monitor the number of bite wounds and cannibalism. Over the following 24 mo (1 January 2004 to 1 January 2006), the incidence of bite wounds declined to 0.3% and 0.7% annually, respectively; no episodes of cannibalism were reported. The results of this investigation indicate that environmental enrichment in the form of ABS pipes for refuge cover has a quantifiable beneficial effect on the physical and social wellbeing of laboratory Xenopus laevis.


Disaster curricula in medical education: pilot survey.
An understanding of disaster medicine and the health care system during mass-casualty events is vital to a successful disaster response, and has been recommended as an integral part of the medical curriculum by the Association of American Medical Colleges (AAMC). It has been documented that medical students do not believe that they have received adequate training for responding to disasters. The purpose of this pilot study was to determine the inclusion of disaster medicine in the required course work of medical students at AAMC schools in the United States, and to identify the content areas addressed. An electronic on-line survey was developed based upon published core competencies for health care workers, and distributed via e-mail to the education liaison for each medical school in the United States that was accredited by the AAMC. The survey included questions regarding the inclusion of disaster medicine in the medical school curricula, the type of instruction, and the content of instruction. Of the 29 (25.2%) medical schools that completed the survey, 31% incorporated disaster medicine into their medical school curricula. Of those schools that included disaster medicine in their curricula, 20.7% offered disaster material as required course work, and 17.2% offered it as elective course work. Disaster medicine topics provided at the highest frequency included pandemic influenza/severe acute respiratory syndrome (SARS, 27.5%), and principles of triage (10.3%). The disaster health competency included most frequently was the ability to recognize a potential critical event and implement actions at eight (27.5%) of the responding schools. Only a small percentage of US medical schools currently include disaster medicine in their core curriculum, and even fewer medical schools have incorporated or adopted competency-based training within their disaster medicine lecture topics and curricula.


Management of child abuse in Hong Kong: results of a territory-wide inter-hospital prospective surveillance study.
To study suspected child abuse among children in hospital in terms of clinical characteristics and the outcome of multidisciplinary case conferences. Prospective observational study. All public hospitals in Hong Kong with a paediatric department. Anonymous data were prospectively collected from July 1997 to June 1999 using a standard report form for each case of suspected child abuse. The characteristics of the incidents and factors influencing the conclusion at the multidisciplinary case conference were studied. Data for 592 cases of suspected child abuse were evaluated. Two hundred and eighty-seven of the children were boys and 305 were girls. The mean age was 7.3 years (range, 0-16.7 years). Physical abuse, alone or in combination with other forms of maltreatment, accounted for 277 (86.6%) of the 320 substantiated cases. Either, or both, biological parents comprised 71.3% of the perpetrators. Seven (1.2%) children died. Of the 540 children about whom a multidisciplinary case conference was held, abuse was established for 281 (52.0%) children. Abuse was more likely to be established if the victim had been known to a childcare agency (odds ratio=2.2; 95% confidence interval, 1.4-3.5), the abuse was not sexual (odds ratio=2.7; 95% confidence interval, 1.4-5.0), or if the child was seen at a hospital that handled more than 100 cases of suspected abuse during the study period (odds ratio=3.6; 95% confidence interval, 2.4-5.4). Child abuse identified in the hospital setting is predominantly physical in nature and death is not uncommon. Appraisal of suspected child abuse by multidisciplinary case conference appears to be influenced by the region of Hong Kong in which the case was handled.