The crystal structures of the α-subunit of the α(2)β (2) tetrameric Glycyl-tRNA synthetase.
Aminoacyl-tRNA synthetases (AARSs) are ligases (EC.6.1.1.-) that catalyze the acylation of amino acids to their cognate tRNAs in the process of translating genetic information from mRNA to protein. Their amino acid and tRNA specificity are crucial for correctly translating the genetic code. Glycine is the smallest amino acid and the glycyl-tRNA synthetase (GlyRS) belongs to Class II AARSs. The enzyme is unusual because it can assume different quaternary structures. In eukaryotes, archaebacteria and some bacteria, it forms an α(2) homodimer. In some bacteria, GlyRS is an α(2)β(2) heterotetramer and shows a distant similarity to α(2) GlyRSs. The human pathogen eubacterium Campylobacter jejuni GlyRS (CjGlyRS) is an α(2)β(2) heterotetramer and is similar to Escherichia coli GlyRS; both are members of Class IIc AARSs. The two-step aminoacylation reaction of tetrameric GlyRSs requires the involvement of both α- and β-subunits. At present, the structure of the GlyRS α(2)β(2) class and the details of the enzymatic mechanism of this enzyme remain unknown. Here we report the crystal structures of the catalytic α-subunit of CjGlyRS and its complexes with ATP, and ATP and glycine. These structures provide detailed information on substrate binding and show evidence for a proposed mechanism for amino acid activation and the formation of the glycyl-adenylate intermediate for Class II AARSs.


A rare cause of hypocalcemia.
Many factors influence serum calcium concentration, but the major determinants of calcium homeostatsis are parathyroid hormone (PTH), vitamin D, the ionized calcium, and phosphate [1]. Therefore, deranged calcium metabolism is often seen in the presence of disordered parathyroid hormone (PTH) and/or vitamin D actions. Among these causes is end-organ resistance to the biological effect of parathyroid hormone. In this paper, we report a case of a patient who presented with flu like symptoms and incidental finding of hypocalcemia that is consistent with parathyroid hormone resistance. Familial causes of hypocalcemia, although rare, should be thought about after ruling out the other common causes of hypocalcemia.


The experience of lived space in persons with dementia: a systematic meta-synthesis.
Identifying how persons with dementia experience lived space is important for enabling supportive living environments and creating communities that compensate for the fading capabilities of these persons. Several single studies have explored this topic; however, few studies have attempted to explicitly review and synthesize this research literature. The aim of this systematic meta-synthesis was therefore to interpret and synthesize knowledge regarding persons with dementia's experience of space. A systematic, computerized search of AgeLine, CINAHL Complete, Embase, Medline and PsycINFO was conducted using a search strategy that combined MeSH terms and text words for different types of dementia with different descriptions of experience. Studies with 1) a sample of persons with dementia, 2) qualitative interviews as a research method and 3) a description of experiences of lived space were included. The search resulted in 1386 articles, of which 136 were identified as eligible and were read and assessed using the CASP criteria. The analysis was inspired by qualitative content analyses. This interpretative qualitative meta-synthesis included 45 articles encompassing interviews with 672 persons with dementia. The analysis showed that living in one's own home and living in long-term care established different settings and posed diverse challenges for the experience of lived space in persons with dementia. The material revealed four main categories that described the experience of lived space: (1) belonging; (2) meaningfulness; (3) safety and security; and (4) autonomy. It showed how persons with dementia experienced a reduction in their lived space due to the progression of dementia. A comprehensive understanding of the categories led to the latent theme: "Living with dementia is like living in a space where the walls keep closing in". This meta-synthesis reveals a process whereby lived space gradually becomes smaller for persons with dementia. This underscores the importance of being aware of the experiences of persons with dementia and the spatial dimensions of their life-world. To sustain person-centred care and support the preservation of continuity and identity, one must acknowledge not only the physical and social environment but also space as an existential experience for persons with dementia.


Construct validity of the Moral Development Scale for Professionals (MDSP).
The aim of this study was to investigate the construct validity of the Moral Development Scale for Professionals (MDSP) using structural equation modeling. The instrument is a 12-item self-report instrument, developed in the Scandinavian cultural context and based on Kohlberg's theory. A hypothesized simplex structure model underlying the MDSP was tested through structural equation modeling. Validity was also tested as the proportion of respondents older than 20 years that reached the highest moral level, which according to the theory should be small. A convenience sample of 339 nursing students with a mean age of 25.3 years participated. Results confirmed the simplex model structure, indicating that MDSP reflects a moral construct empirically organized from low to high. A minority of respondents >20 years of age (13.5%) scored more than 80% on the highest moral level. The findings support the construct validity of the MDSP and the stages and levels in Kohlberg's theory.


A SPE-HPLC-MS/MS method for the simultaneous determination of prioritised pharmaceuticals and EDCs with high environmental risk potential in freshwater.
This work describes the development, optimisation and validation of an analytical method for the rapid determination of 17 priority pharmaceutical compounds and endocrine disrupting chemicals (EDCs). Rather than studying compounds from the same therapeutic class, the analyses aimed to determine target compounds with the highest risk potential (with particular regard to Scotland), providing a tool for further monitoring in different water matrices. Prioritisation was based on a systematic environmental risk assessment approach, using consumption data; wastewater treatment removal efficiency; environmental occurrence; toxicological effects; and pre-existing regulatory indicators. This process highlighted 17 compounds across various therapeutic classes, which were then quantified, at environmentally relevant concentrations, by a single analytical methodology. Analytical determination was achieved using a single-step solid phase extraction (SPE) procedure followed by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The fully optimised method performed well for the majority of target compounds, with recoveries >71% for 15 of 17 analytes. The limits of quantification for most target analytes (14 of 17) ranged from 0.07 ng/L to 1.88 ng/L in river waters. The utility of this method was then demonstrated using real water samples associated with a rural hospital/setting. Eight compounds were targeted and detected, with the highest levels found for the analgesic, paracetamol (at up to 105,910 ng/L in the hospital discharge). This method offers a robust tool to monitor high priority pharmaceutical and EDC levels in various aqueous sample matrices.


Activation of Antioxidative Functions by Radon Inhalation Enhances the Mitigation Effects of Pregabalin on Chronic Constriction Injury-Induced Neuropathic Pain in Mice.
Radon inhalation brings pain relief for chronic constriction injury- (CCI-) induced neuropathic pain in mice due to the activation of antioxidative functions, which is different from the mechanism of the pregabalin effect. In this study, we assessed whether a combination of radon inhalation and pregabalin administration is more effective against neuropathic pain than radon or pregabalin only. Mice were treated with inhaled radon at a concentration of 1,000 Bq/m(3) for 24 hours and pregabalin administration after CCI surgery. In mice treated with pregabalin at a dose of 3 mg/kg weight, the 50% paw withdrawal threshold of mice treated with pregabalin or radon and pregabalin was significantly increased, suggesting pain relief. The therapeutic effects of radon inhalation or the combined effects of radon and pregabalin (3 mg/kg weight) were almost equivalent to treatment with pregabalin at a dose of 1.4 mg/kg weight or 4.1 mg/kg weight, respectively. Radon inhalation and the combination of radon and pregabalin increased antioxidant associated substances in the paw. The antioxidant substances increased much more in radon inhalation than in pregabalin administration. These findings suggested that the activation of antioxidative functions by radon inhalation enhances the pain relief of pregabalin and that this combined effect is probably an additive effect.


A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham Elderly Thyroid study.
Subclinical hypothyroidism (SCH) and cognitive dysfunction are both common in the elderly and have been linked. It is important to determine whether T4 replacement therapy in SCH confers cognitive benefit. Our objective was to determine whether administration of T4 replacement to achieve biochemical euthyroidism in subjects with SCH improves cognitive function. We conducted a double-blind placebo-controlled randomized controlled trial in the context of United Kingdom primary care. Ninety-four subjects aged 65 yr and over (57 females, 37 males) with SCH were recruited from a population of 147 identified by screening. T4 or placebo was given at an initial dosage of one tablet of either placebo or 25 microg T4 per day for 12 months. Thyroid function tests were performed at 8-weekly intervals with dosage adjusted in one-tablet increments to achieve TSH within the reference range for subjects in treatment arm. Fifty-two subjects received T4 (31 females, 21 males; mean age 73.5 yr, range 65-94 yr); 42 subjects received placebo (26 females, 16 males; mean age 74.2 yr, 66-84 yr). Mini-Mental State Examination, Middlesex Elderly Assessment of Mental State (covering orientation, learning, memory, numeracy, perception, attention, and language skills), and Trail-Making A and B were administered. Eighty-two percent and 84% in the T4 group achieved euthyroidism at 6- and 12-month intervals, respectively. Cognitive function scores at baseline and 6 and 12 months were as follows: Mini-Mental State Examination T4 group, 28.26, 28.9, and 28.28, and placebo group, 28.17, 27.82, and 28.25 [not significant (NS)]; Middlesex Elderly Assessment of Mental State T4 group, 11.72, 11.67, and 11.78, and placebo group, 11.21, 11.47, and 11.44 (NS); Trail-Making A T4 group, 45.72, 47.65, and 44.52, and placebo group, 50.29, 49.00, and 46.97 (NS); and Trail-Making B T4 group, 110.57, 106.61, and 96.67, and placebo group, 131.46, 119.13, and 108.38 (NS). Linear mixed-model analysis demonstrated no significant changes in any of the measures of cognitive function over time and no between-group difference in cognitive scores at 6 and 12 months. This RCT provides no evidence for treating elderly subjects with SCH with T4 replacement therapy to improve cognitive function.


Differentiating what is humorous from what is not.
After 2.5 millennia of philosophical deliberation and psychological experimentation, most scholars have concluded that humor arises from incongruity. We highlight 2 limitations of incongruity theories of humor. First, incongruity is not consistently defined. The literature describes incongruity in at least 4 ways: surprise, juxtaposition, atypicality, and a violation. Second, regardless of definition, incongruity alone does not adequately differentiate humorous from nonhumorous experiences. We suggest revising incongruity theory by proposing that humor arises from a benign violation: something that threatens a person's well-being, identity, or normative belief structure but that simultaneously seems okay. Six studies, which use entertainment, consumer products, and social interaction as stimuli, reveal that the benign violation hypothesis better differentiates humorous from nonhumorous experiences than common conceptualizations of incongruity. A benign violation conceptualization of humor improves accuracy by reducing the likelihood that joyous, amazing, and tragic situations are inaccurately predicted to be humorous. (PsycINFO Database Record


Associations of alcohol consumption with diabetes mellitus and impaired fasting glycemia among middle-aged and elderly Chinese.
The U-shaped relationship between alcohol consumption and diabetes mellitus was observed among western populations. However, few studies have systematically evaluated the association in Chinese. We aimed to investigate the associations of alcohol consumption with diabetes mellitus and impaired fasting glycemia (IFG) among middle-aged and elderly Chinese. We examined 1,458 men and 1,831 women aged 50 to 70 from Beijing and Shanghai China in a cross-sectional survey. Fasting glucose, adipokines and markers of inflammation were measured. Macronutrients and alcohol consumption were assessed with standardized questionnaires. Compared with abstainers, alcohol consumption was associated with a decreased risk of having diabetes mellitus in women (OR: 0.41, 95%CI: 0.22-0.78) after controlling for socio-demographic factors, physical activity, smoking, family income, family history of cardiovascular disease or diabetes, macronutrients intake, body mass index, and markers of inflammation and adipokines. In men, both low and high alcohol consumptions were associated with increased risks of having combined diabetes and IFG (ORs 1.36 [95%CI: 1.02-1.82] and 1.50 [95%CI: 1.04-2.15], respectively]. In the multivariable stratified analyses among men, moderate drinkers who had drinking days of ≥ 5 days/week had a deceased likelihood (OR: 0.61, 95%CI: 0.37-0.98) and liquor drinkers had an increased likelihood (OR: 1.47, 95%CI: 1.09-1.98) of having combined diabetes and IFG respectively, compared with the abstainers. An approximately J-shaped association was observed between alcohol consumption and combined diabetes and IFG among men compared with abstainers in Chinese. Whether moderate alcohol intake could help decrease diabetic risk among Chinese people warrants further investigation.


Turmeric curcumin inhibits entry of all hepatitis C virus genotypes into human liver cells.
Hepatitis C virus (HCV) infection causes severe liver disease and affects more than 160 million individuals worldwide. People undergoing liver organ transplantation face universal re-infection of the graft. Therefore, affordable antiviral strategies targeting the early stages of infection are urgently needed to prevent the recurrence of HCV infection. The aim of the study was to determine the potency of turmeric curcumin as an HCV entry inhibitor. The antiviral activity of curcumin and its derivatives was evaluated using HCV pseudo-particles (HCVpp) and cell-culture-derived HCV (HCVcc) in hepatoma cell lines and primary human hepatocytes. The mechanism of action was dissected using R18-labelled virions and a membrane fluidity assay. Curcumin treatment had no effect on HCV RNA replication or viral assembly/release. However, co-incubation of HCV with curcumin potently inhibited entry of all major HCV genotypes. Similar antiviral activities were also exerted by other curcumin derivatives but not by tetrahydrocurcumin, suggesting the importance of α,β-unsaturated ketone groups for the antiviral activity. Expression levels of known HCV receptors were unaltered, while pretreating the virus with the compound reduced viral infectivity without viral lysis. Membrane fluidity experiments indicated that curcumin affected the fluidity of the HCV envelope resulting in impairment of viral binding and fusion. Curcumin has also been found to inhibit cell-to-cell transmission and to be effective in combination with other antiviral agents. Turmeric curcumin inhibits HCV entry independently of the genotype and in primary human hepatocytes by affecting membrane fluidity thereby impairing virus binding and fusion.


Proton relaxation rates of water in brain and brain tumors.
The distribution of relaxation rates of water in "normal" (autopsy) samples of canine and human brain shows considerable overlap with that for brain tumor samples. The following ranges of values for the spin-spin relaxation rates were observed: for normal brain gray matter, 8.6 to 11.3 sec(-1) (mean, 9.5 sec(-1)); for normal brain white matter, 13.3 to 15.7 sec(-1) (mean, 15.5 sec(-1)); for six types of malignant tumor, 4.8 to 13.4 sec(-1) (mean, 9.3 sec(-1)); for five types of benign tumor, 7.1 to 16.4 sec(-1) (mean, 11.5 sec(-1)). Spin-lattice relaxation rates showed a similar pattern. At least two nonexchanging water components with different relaxation rates were indicated by the analysis of the spin-spin relaxation measurements for the white matter samples.


Influence of treatment with beclomethasone, cromoglycate and theophylline on perception of bronchoconstriction in patients with bronchial asthma.
1. Perception of asthma by patients can be assessed from the relationship between symptom scores and peak expiratory flows. This study was designed to investigate the possibility that medication can affect perception of the sensation of asthma independently of changes in lung function. 2. Twelve subjects whose asthma was inadequately controlled by inhaled bronchodilator alone were studied during four different drug treatments over 3 months. Subjective self-assessment of asthma was scored on a 10 cm visual analogue scale and followed by three consecutive measurements of peak expiratory flow, using a coded electronic peak flow meter. This was recorded not less than three times daily on diary cards. Observations were recorded during the second week of each of four treatments: (i) a run-in period using only inhaled salbutamol as required, (ii) inhaled beclomethasone, (iii) inhaled cromoglycate and (iv) oral theophylline at a dose adjusted to achieve blood levels of 10-20 mg/l. Inhaled salbutamol was permitted during the other treatments as required. Changes in the slope and position of the regression lines of asthma scores on PEF were used to measure changes in perception of asthma on each treatment. Dynamic lung volumes were measured in the clinic before the study and after each treatment period. 3. In the group as a whole, theophylline improved lung function (mean peak flow and dynamic lung volumes) without affecting mean visual analogue scores, beclomethasone improved mean visual analogue scores with much less effect on lung function, while cromoglycate had a small though consistent effect on both. 4. Perception of asthma, measured by the relationship between peak flow rate and visual analogue scores, was unaffected by cromoglycate. On theophylline, perception of asthma was heightened in five subjects despite a definite improvement in their peak flow. On beclomethasone, perception of asthma was reduced in most subjects, often with no discernible improvement in mean peak flow or dynamic spirometry. 5. Perception of bronchoconstriction in asthma can be affected by drugs independently of control of the condition. Theophylline may produce a paradoxical increase in awareness of asthma in some individuals. With beclomethasone therapy a reduction in symptoms of asthma may occur without any improvement in tests of air flow.


Green tea consumption and cognitive function: a cross-sectional study from the Tsurugaya Project 1.
Although considerable experimental and animal evidence shows that green tea may possess potent activities of neuroprotection, neurorescue, and amyloid precursor protein processing that may lead to cognitive enhancement, no human data are available. The objective was to examine the association between green tea consumption and cognitive function in humans. We analyzed cross-sectional data from a community-based Comprehensive Geriatric Assessment (CGA) conducted in 2002. The subjects were 1003 Japanese subjects aged > or =70 y. They completed a self-administered questionnaire that included questions about the frequency of green tea consumption. We evaluated cognitive function by using the Mini-Mental State Examination with cutoffs of <28, <26, and <24 and calculated multivariate-adjusted odds ratios (ORs) of cognitive impairment. Higher consumption of green tea was associated with a lower prevalence of cognitive impairment. At the <26 cutoff, after adjustment for potential confounders, the ORs for the cognitive impairment associated with different frequencies of green tea consumption were 1.00 (reference) for < or =3 cups/wk, 0.62 (95% CI: 0.33, 1.19) for 4-6 cups/wk or 1 cup/d, and 0.46 (95% CI: 0.30, 0.72) for > or =2 cups/d (P for trend = 0.0006). Corresponding ORs were 1.00 (reference), 0.60 (95% CI: 0.35, 1.02), and 0.87 (95% CI: 0.55, 1.38) (P for trend = 0.33) for black or oolong tea and 1.00 (reference), 1.16 (95% CI: 0.78, 1.73), and 1.03 (95% CI: 0.59, 1.80) (P for trend = 0.70) for coffee. The results were essentially the same at cutoffs of <28 and <24. A higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans.


Effect of Propolis on Diet-Induced Hyperlipidemia and Atherogenic Indices in Mice.
Obesity, a major health problem worldwide, is associated with increased cardiovascular risk factors, such as dyslipidemia, glucose intolerance, and hypertension. We investigated the antioxidative capacity of the ethanol extract of propolis (EEP) and its effect on the lipid profile, the hepatorenal function, and the atherogenic indices in mice fed with a high-fat diet (HFD). EEP (50 mg/kg) was given orally to mice for 30 days. After the treatments, levels of the serum total triglyceride and cholesterol, the high density lipoprotein (HDL-c) and low density lipoprotein (LDL-c) cholesterols, the serum enzymes, and the metabolites were measured, and atherogenic indices [atherogenic index of plasma (AIP); cardiac risk ratio (CRR); cardioprotective index (CPI); atherogenic coefficient (AC)] were calculated and compared with the antioxidant, the reducing power, the radical-scavenging, and the chelating activity of EEP. The HFD diet with EEP significantly reduced the negative lipid profile and lowered AIP, CRR, and AC and increased CPI in animals on a HFD. In addition, EEP reduced the weight of mice and lipid accumulation in the liver, and it had significant in vitro antioxidative activities. The EEP possesses anti-hyperlipidemic and antioxidant activity and exhibits protective action on the cardiovascular system and hepatorenal functions. Our results contribute towards the validation of the traditional use of propolis as a food supplement in aiding hyperlipidemic disorders.


Stimulation of tyrosine hydroxylase gene transcription rate by nicotine in rat adrenal medulla.
The administration of nicotine stimulates the transcription rate of the tyrosine hydroxylase gene in rat adrenal medulla. This stimulation occurs very rapidly (within 10 min) after the subcutaneous injection of nicotine and persists for at least 1 hr after a single injection of the drug. Repeated injections of the drug (seven injections once every 30 min) are associated with a more persistent activation of the gene (for at least 3 hr) and elicit the induction of tyrosine hydroxylase mRNA and tyrosine hydroxylase protein. Quantitatively, the increases in tyrosine hydroxylase gene transcription rate, mRNA, and protein are approximately equivalent. The effect of nicotine is dose dependent; a significant increase in tyrosine hydroxylase gene transcription rate is observed using 1.0 mg/kg nicotine, whereas 0.33 mg/kg nicotine produces no effect. The nicotinic receptor antagonists hexamethonium and mecamylamine partially inhibit the nicotine-mediated stimulation of the tyrosine hydroxylase gene. The lack of total blockade of the nicotine-mediated effect suggests that nicotine acting centrally may elicit the release of substances from the splanchnic nerve, that interact with receptors (other than the nicotinic receptor) that play a role in regulating the tyrosine hydroxylase gene. The administration of carbachol also stimulates rat adrenomedullary tyrosine hydroxylase gene transcription rate. The effect of carbachol is not inhibited by hexamethonium but is completely blocked by the muscarinic antagonist atropine. The muscarinic agonist bethanechol also stimulates this gene in rat adrenal medulla. Our results suggest that multiple receptors and signal transduction pathways are involved in the regulation of the tyrosine hydroxylase gene in the rat adrenal medulla.


Safety and effectiveness of physostigmine: a 10-year retrospective review<sup/>.
Physostigmine has long been recognized as an antidote to reverse anticholinergic delirium. However, its effectiveness, safety profile, and dosing have been disputed. To describe effectiveness, adverse events, and dosing associated with the use of physostigmine to reverse anticholinergic delirium. A retrospective cohort study of hospitalized patients reported to a regional poison center system between 2003 and 2012 who received physostigmine to reverse an anticholinergic toxidrome. Data extraction of a priori defined variables were recorded with concurrence of investigators. The cases were stratified by the primary ingestant as the presumed causative agent and associations for response were performed using odds ratios (ORs), 95% confidence intervals (CI's), and p values. Of the 1422 cases identified, 191 met the inclusion criteria. Patients exposed to non-diphenhydramine antihistamines (n = 14), antipsychotics (n = 4), and tricyclic antidepressants (n = 3) had 100% response to physostigmine, whereas anticholinergic plants (n = 46/67; 68.7%, OR: 0.70; CI: 0.36-1.35), diphenhydramine (n = 43/56; 64.2%, OR: 1.30; CI: 0.63-2.68), and combination products (n = 8/10; 80%, OR: 1.48; CI: 0.30-7.24) had partial response rates. Of the included patients, 142 (74.3%) were treated with physostigmine alone, and 16 (8.4%) of these patients were discharged directly from the emergency department (ED). Most patients, 182 (95.3%), had no documented adverse effects. Four patients (2.1%) experienced emesis, two experienced QTc prolongation (1.0%), and two experienced seizures (1.0%). There was a single fatality 6 h after physostigmine administration. Average initial total doses of physostigmine ranged from 1.0 to 1.75 mg. Most patients were admitted to the ICU (n = 110; 57.6%), however, 36 (18.8%) patients were discharged directly from the ED. In this retrospective cohort study, physostigmine administration to reverse anticholinergic delirium had a good safety profile, and often improved or resolved anticholinergic delirium when administered in doses less than 2 mg.


Phenotypic changes associated with deletion and overexpression of a stage-regulated gene family in Leishmania.
The LmcDNA16 locus of Leishmania major contains three highly related genes HASPA1, HASPA2 and HASPB, encoding hydrophilic, acylated surface proteins and a tandem pair of unrelated sequences, SHERP1 and SHERP2, coding for a small, hydrophilic protein that localizes to the endoplasmic reticulum and outer mitochondrial membrane. Differential regulation of these genes results in expression of a subset of the HASP proteins and SHERP only in infective stage parasites. To assess the contribution of these molecules to parasite virulence, the diploid LmcDNA16 gene locus has been removed by targeted gene deletion. Homozygous null mutants have precise deletions of both alleles and exhibit no HASP or SHERP expression. They are at least as virulent as wild-type parasites in macrophage invasion and intracellular survival assays, both in vitro and in vivo. Conversely, null mutants engineered to overexpress the entire LmcDNA16 gene locus are unable to survive within the intramacrophage environment despite their differentiation into infective metacyclic parasites. Both null and overexpressing null parasites show increased sensitivity to complement-mediated lysis, suggesting perturbation of their surface architecture. Avirulence in overexpressing parasites correlates with selective depletion of a specific lipid species, decreased expression of the major surface glycoprotein GP63, but no significant downregulation of the glycoconjugate lipophosphoglycan.


Cumulative dietary risk characterisation of pesticides that have chronic effects on the thyroid.
A retrospective chronic cumulative risk assessment of dietary exposure to pesticide residues, supported by an uncertainty analysis based on expert knowledge elicitation, was conducted for two effects on the thyroid, hypothyroidism and parafollicular cell (C-cell) hypertrophy, hyperplasia and neoplasia. The pesticides considered in this assessment were identified and characterised in the scientific report on the establishment of cumulative assessment groups of pesticides for their effects on the thyroid. Cumulative exposure assessments were conducted through probabilistic modelling by EFSA and the Dutch National Institute for Public Health and the Environment (RIVM) using two different software tools and reported separately. These exposure assessments used monitoring data collected by Member States under their official pesticide monitoring programmes in 2014, 2015 and 2016 and individual consumption data from 10 populations of consumers from different countries and different age groups. This report completes the characterisation of cumulative risk, taking account of the available data and the uncertainties involved. For each of the 10 populations, it is concluded with varying degrees of certainty that cumulative exposure to pesticides that have the chronic effects on the thyroid mentioned above does not exceed the threshold for regulatory consideration established by risk managers.


Scoliosis and vertebral anomalies: additional abnormal phenotypes associated with chromosome 16p11.2 rearrangement.
The typical chromosome 16p11.2 rearrangements are estimated to occur at a frequency of approximately 0.6% of all samples tested clinically and have been identified as a major cause of autism spectrum disorders, developmental delay, behavioral abnormalities, and seizures. Careful examination of patients with these rearrangements revealed association with abnormal head size, obesity, dysmorphism, and congenital abnormalities. In this report, we extend this list of phenotypic abnormalities to include scoliosis and vertebral anomalies. We present detailed characterization of phenotypic and radiological data of 10 new patients, nine with the 16p11.2 deletion and one with the duplication within the coordinates chr16:29,366,195 and 30,306,956 (hg19) with a minimal size of 555 kb. We discuss the phenotypical and radiological findings in our patients and review 5 previously reported patients with 16p11.2 rearrangement and similar skeletal abnormalities. Our data suggest that patients with the recurrent 16p11.2 rearrangement have increased incidence of scoliosis and vertebral anomalies. However, additional studies are required to confirm this observation and to establish the incidence of these anomalies. We discuss the potential implications of our findings on the diagnosis, surveillance and genetic counseling of patients with 16p11.2 rearrangement.


Recording and surveillance systems for periodontal diseases.
This paper describes tools used to measure periodontal diseases and the integration of these tools into surveillance systems. Tools to measure periodontal diseases at the surveillance level have focussed on current manifestations of disease (e.g. gingival inflammation) or disease sequelae (e.g. periodontal pocket depth or loss of attachment). All tools reviewed in this paper were developed based on the state of the science of the pathophysiology of periodontal disease at the time of their design and the need to provide valid and reliable measurements of the presence and severity of periodontal diseases. Therefore, some of these tools are no longer valid. Others, such as loss of periodontal attachment, are the current de-facto tools but demand many resources to undertake periodical assessment of the periodontal health of populations. Less complex tools such as the Community Periodontal Index, have been used extensively to report periodontal status. Laboratory tests for detecting putative microorganisms or inflammatory agents present in periodontal diseases have been used at the clinical level, and at least one has been tested at the population level. Other approaches, such as self-report measures, are currently under validation. In this paper, we do not review indices designed to measure plaque or residual accumulation around the tooth, indices focussed only on gingival inflammation or radiographic approaches with limited applicability in surveillance systems. Finally, we review current case-definitions proposed for surveillance of periodontal disease severity.


Appearance Normalization of Histology Slides.
This paper presents a method for automatic color and intensity normalization of digitized histology slides stained with two different agents. In comparison to previous approaches, prior information on the stain vectors is used in the estimation process, resulting in improved stability of the estimates. Due to the prevalence of hematoxylin and eosin staining for histology slides, the proposed method has significant practical utility. In particular, it can be used as a first step to standardize appearances across slides, that is very effective at countering effects due to differing stain amounts and protocols, and to slide fading. The approach is validated using synthetic experiments and 13 real datasets.


Functional outcomes of posttraumatic lower limb salvage: a pilot study of anterolateral thigh perforator flaps versus muscle flaps.
Functional outcomes of lower extremity reconstruction compared with amputation have been evaluated. However, there are little comparative data among the different reconstructive options. With the recent increase in perforator flaps, we compared the functional outcomes of muscle and perforator flaps. We conducted a retrospective review of 136 lower extremity trauma patients who underwent reconstruction with either a free muscle or perforator flap during a 7-year period. Forty-two of these patients completed the study. Patients answered the short musculoskeletal functional assessment form and supplemental questions. A physical therapist evaluated performance of physical tasks. Donor site sensation was measured with the pressure specified sensing device. Radiographic fracture union was evaluated by an orthopedic surgeon. Of the 42 patients enrolled, 20 had coverage with perforator flaps and 22 with muscle flaps. Quality of life and functional outcomes demonstrate no difference (p > 0.05). Ninety-three percent of patients would go through the limb salvage process to avoid amputation. Sensation at the donor site was diminished in all patients; however, the perforator flap donor site had more significant sensory loss (p = 0.005). Time to bony union (p = 0.51), union in the presence of infection (p = 0.85), and infection after flap (p = 0.87) was not related to flap type. Both muscle and perforator flaps provide vascularized coverage, which nourishes the fracture but muscle flaps pilfer a functional unit which may not be inconsequential in a patient trauma. This pilot study suggests that functional outcomes of perforator skin flaps are equal to muscle flaps and a larger prospective study is warranted.


Rhizobium sp. BR816 produces a complex mixture of known and novel lipochitooligosaccharide molecules.
Rhizobial lipochitooligosaccharide (LCO) signal molecules induce various plant responses, leading to nodule development. We report here the LCO structures of the broadhost range strain Rhizobium sp. BR816. The LCOs produced are all pentamers, carrying common C18:1 or C18:0 fatty acyl chains, N-methylated and C-6 carbamoylated on the nonreducing terminal N-acetylglucosamine and sulfated on the reducing/terminal residue. A second acetyl group can be present on the penultimate N-acetylglucosamine from the nonreducing terminus. Two novel characteristics were observed: the reducing/terminal residue can be a glucosaminitol (open structure) and the degree of acetylation of this glucosaminitol or of the reducing residue can vary.


Expression of E-cadherin during craniofacial development.
The cell adhesion molecule E-cadherin is assumed to play an important role in organogenesis and histogenesis. We have analyzed the presence of E-cadherin during normal and disturbed craniofacial development with respect to palate and tooth formation by immunohistochemistry using a rat monoclonal antibody (DECMA-1) and by in situ hybridization using an oligonucleotide probe. Cleft palate was induced by retinoic acid (RA) treatment of pregnant dams. Normal and RA-treated fetuses of gestational days 14-18 were examined. E-cadherin was present in epithelia of both ectodermal and endodermal origin, including developing teeth and epithelia of the palate as well as respiratory and oral epithelia. The expression level of E-cadherin increased with age and differentiation. In normal fetuses, at day 18, the expression was higher in the epithelia of the oral cavity than in the forming nasal cavity. The expression pattern of E-cadherin implies that this molecule has a role during normal development of the epithelia of the craniofacial complex.


The shifting balance of diversity among major marine animal groups.
The fossil record demonstrates that each major taxonomic group has a consistent net rate of diversification and a limit to its species richness. It has been thought that long-term changes in the dominance of major taxonomic groups can be predicted from these characteristics. However, new analyses show that diversity limits may rise or fall in response to adaptive radiations or extinctions. These changes are idiosyncratic and occur at different times in each taxa. For example, the end-Permian mass extinction permanently reduced the diversity of important, previously dominant groups such as brachiopods and crinoids. The current global crisis may therefore permanently alter the biosphere's taxonomic composition by changing the rules of evolution.


Positive impacts on rural and regional workforce from the first seven cohorts of James Cook University medical graduates.
The regionally-based James Cook University (JCU) School of Medicine aims to meet its mission to address the health needs of the region by combining selection and curriculum strategies shown to increase rural career recruitment outcomes. The School has graduated 536 students in its first seven cohorts from 2005 to 2011. This paper presents the early career practice locations and the specialty training undertaken by these cohorts, and describes the association between later practice location with both hometown at application and internship location. Hometown at application' data for JCU Bachelor of Medicine, Bachelor of Surgery (MBBS) graduates was retrieved from administrative databases held by the university, while postgraduate location and career data were obtained either from personal contact via email, telephone, Facebook or electronically from the Australian Health Practitioner Regulation Authority website. Practice location was described across Australian Standard Geographical Classification Remoteness Area (RA) categories. Data for the primary practice location of 536 JCU MBBS graduates across postgraduate years (PGY) 1 to 7 is 99% complete. A total of 65% of JCU graduates undertook their internship in non-metropolitan locations including 20% in RA 2 and 44% in RA 3-5, a pattern of practice different to that of other Australian clinicians. For the internship year, 'non-metropolitan-origin' JCU MBBS graduates predominantly worked in RA 2-5 locations, while 'metropolitan origin' graduates were more likely to work in major cities. However, by PGY 7, the distribution of 'rural' and 'metropolitan' origin JCU graduates across RA categories was similar. The RA category of internship location - either 'metropolitan (RA 1) or 'non-metropolitan' (RA 2-5) - was associated with the location of subsequent practice across PGY 2-7. This comprehensive data set provides the first real evidence from one of Australia's new medical schools on actual postgraduate practice location, as compared to 'intent to practice'. The geographic profile by RA of JCU graduates' hometown and patterns of postgraduate practice is different to that of other Australian medical students and doctors. This early evidence supports the JCU model of distributed non-metropolitan medical education, and suggests more regionally-located internship and specialty training places would further increase the medical workforce in northern and/or rural Australia. The workforce impact of the seven cohorts of graduates in this study is starting to be felt in rural and regional Australia, and, if these trends continue, will result in significant workforce improvements over the next decade. These results support further investment in regional and rural medical education.


Testosterone and growth hormone normalization: a retrospective study of health outcomes.
Age-related declines in testosterone and growth hormone (GH) are associated with increased adiposity and decreases in lean mass and bone mineral density (BMD). A long-term retrospective study examined the effects of testosterone and/or GH supplementation on body composition and quality of life (QoL). A database survey assessed the records of 91 men and 97 women (ages 25-82) in treatment groups based on their hormonal status: dehydroepiandrosterone but no hormonal supplementation (control); testosterone only (Tes); GH only (GH); and testosterone plus GH (Tes+GH). Pre-and post-treatment assessments recorded changes in fat and lean mass, BMD, and QoL. After an average of 3 years of treatment, weight decreased in women in the control and Tes+GH groups but remained stable in men in all groups. Tes and Tes+GH produced statistically significant increases in lean mass, reductions in fat mass, and improvements in BMD in both sexes; GH produced similar changes in women. QoL and mood improved in all groups. Treatments were generally safe and well tolerated. In this retrospective survey, treatment with testosterone and/or GH was associated with favorable effects in men and women across a wide age range.


Human breast adenocarcinoma cell lines promote angiogenesis by providing cells with uPA-PAI-1 and by enhancing their expression.
During angiogenesis, endothelial cells use uPA and PAI-1 to migrate and degrade the basement membrane surrounding capillary blood vessels. Invasive tumor cells produce a large amount of uPA that could bind uPAR present at the endothelial cell surface to facilitate their invasion. To verify this hypothesis, endothelial cells were incubated with conditioned medium (CM) from two breast cancer cell lines (MCF7 and MDA MB 231 cells). Within a short incubation period (30 min) with both CM, an increase of uPA, PAI-1 and uPA-PAI-1 complex was detected in endothelial cell layer as assessed by casein zymography, ELISA and uPA immunostaining. The extent of this enhancement was related to the levels of uPA secreted by tumor cells (high in MDA MB 231 cells and low in MCF7 cells). After 2 hr of incubation, the CM from both tumor cells upregulated uPA and PAI-1 mRNA levels in endothelial cells in a time-dependent manner. The uPA increase in the cell layer could not be attributable to an increase of uPAR level. Only the CM from highly invasive MDA MB 231 cells increased the angiogenic morphotype of endothelial cells assessed in a collagen gel. A single addition of amino-terminal fragment of uPA (ATF) was able to abolish the angiogenic effect induced by MDA MB 231 cell CM. Our data demonstrate that the interactions occurring between breast tumor cells and endothelial cells can modulate tumor angiogenesis at least by two mechanisms: an increase of uPA and PAI-1 cell surface-binding and of their expression by endothelial cells.


St. John's Wort (Hypericum perforatum): clinical effects on depression and other conditions.
St. John's Wort (Hypericum perforatum), a perennial flowering plant, has been used medicinally for thousands of years, and has most recently been identified as an effective treatment for mild to moderate depression. Clinical studies on the use of this plant for depression have utilized liquid tinctures and standardized solid extracts (0.3% hypericin--300 mg three times a day). Severe depression may also respond to this botanical, although it appears a larger dose is needed (600 mg solid extract three times a day). Hypericum has been favorably compared to numerous antidepressant drugs, the studies having revealed equivalent results and a much more favorable incidence of side effects. Studies have also demonstrated its efficacy in treating seasonal affective disorder. In vitro investigations of Hypericum show antiviral activity, although there is evidence these promising results might not occur in vivo. Traditional actions and uses include enhancement of wound healing, as well as anti-inflammatory and analgesic activity.


Regulation of Ca(2+) transient by PP2A in normal and failing heart.
Calcium transient in cardiomyocytes is regulated by multiple protein kinases and phosphatases. PP2A is a major protein phosphatase in the heart modulating Ca(2+) handling through an array of ion channels, antiporters and pumps, etc. The assembly, localization/translocation, and substrate specificity of PP2A are controlled by different post-translational mechanisms, which in turn are linked to the activities of upstream signaling molecules. Abnormal PP2A expression and activities are associated with defective response to β-adrenergic stimulation and are indication and causal factors in arrhythmia and heart failure.


Cerebral activation during thermal stimulation of patients who have burning mouth disorder: an fMRI study.
The pathophysiology of burning mouth disorder (BMD) is not clearly understood, but central neuropathic mechanisms are thought to be involved. The aim of this study was to gain insight into the pathophysiology associated with BMD by using functional magnetic resonance imaging (fMRI). Areas of brain activation following thermal stimulation of the trigeminal nerve of eight female patients with BMD (mean age 49.1+/-10.1) were mapped using fMRI and compared with those of eight matched pain-free volunteers (mean age 50.3+/-12.3). Qualitative and quantitative differences in brain activation patterns between the two study groups were demonstrated. BMD patients displayed greater fractional signal changes in the right anterior cingulate cortex (BA 32/24) and bilateral precuneus than did controls (p<0.005). The control group showed larger fractional signal changes in the bilateral thalamus, right middle frontal gyrus, right pre-central gyrus, left lingual gyrus, and cerebellum than did the BMD patients (p<0.005). In addition, BMD patients had less volumetric activation throughout the entire brain compared to the control group. Overall, BMD patients displayed brain activation patterns similar to those of patients with other neuropathic pain conditions and appear to process thermal painful stimulation to the trigeminal nerve qualitatively and quantitatively different than pain-free individuals. These findings suggest that brain hypoactivity may be an important feature in the pathophysiology of BMD.


Structural basis for spumavirus GAG tethering to chromatin.
The interactions between a retrovirus and host cell chromatin that underlie integration and provirus expression are poorly understood. The prototype foamy virus (PFV) structural protein GAG associates with chromosomes via a chromatin-binding sequence (CBS) located within its C-terminal region. Here, we show that the PFV CBS is essential and sufficient for a direct interaction with nucleosomes and present a crystal structure of the CBS bound to a mononucleosome. The CBS interacts with the histone octamer, engaging the H2A-H2B acidic patch in a manner similar to other acidic patch-binding proteins such as herpesvirus latency-associated nuclear antigen (LANA). Substitutions of the invariant arginine anchor residue in GAG result in global redistribution of PFV and macaque simian foamy virus (SFVmac) integration sites toward centromeres, dampening the resulting proviral expression without affecting the overall efficiency of integration. Our findings underscore the importance of retroviral structural proteins for integration site selection and the avoidance of genomic junkyards.


A comparison of surface and intramuscular myoelectric signal classification.
The surface myoelectric signal (MES) has been used as an input to controllers for powered prostheses for many years. As a result of recent technological advances it is reasonable to assume that there will soon be implantable myoelectric sensors which will enable the internal MES to be used as input to these controllers. An internal MES measurement should have less muscular crosstalk allowing for more independent control sites. However, it remains unclear if this benefit outweighs the loss of the more global information contained in the surface MES. This paper compares the classification accuracy of six pattern recognition-based myoelectric controllers which use multi-channel surface MES as inputs to the same controllers which use multi-channel intramuscular MES as inputs. An experiment was designed during which surface and intramuscular MES were collected simultaneously for 10 different classes of isometric contraction. There was no significant difference in classification accuracy as a result of using the intramuscular MES measurement technique when compared to the surface MES measurement technique. Impressive classification accuracy (97%) could be achieved by optimally selecting only three channels of surface MES.


Exposure to nerve growth factor worsens nephrotoxic effect induced by Cyclosporine A in HK-2 cells.
Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkA(NTR) and p75(NTR). Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a down-regulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an up-regulation of p75 (NTR) and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75(NTR) down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A.


Chromosomal basis of dosage compensation in Drosophila. IX. Cellular autonomy of the faster replication of the X chromosome in haplo-X cells of Drosophila melanogaster and synchronous initiation.
[(3)H]Thymidine labeling patterns have been examined in gynandric mosaic salivary glands of drosophila melanogaster. The Ring-X stock, R(1) w(ve)/In(1)dl 49, l (1) J1 y w lz(s), was used for this purpose. 365 labeled XX2A and 40 labeled XO2A nuclei were obtained from a total of 624 nuclei in nine pairs of mosaic salivary glands. It was observed that in all but those nuclei which had DD, 1C, and 2C patterns, the X chromosome of the XO2A nuclei always had fewer sites labeled than the X chromosomes of the XX2A nuclei, for a given pattern of the autosomes in either sex. Such asynchronous labeling of the X chromosome in the XO2A (male) nuclei was observed regardless of the proportion of the XO2A cells (2.0-73.7 percent), in the mosaic glands. Moreover, while the frequency of [(3)H]thymidine labeling for all of the 39 replicating units except the two late replicating sites (3C and 11A) in the X chromosome of the XO2A nuclei, was consistently lower than in the X chromosome of the XX2A nuclei, the mean number of grains on the X chromosome was relatively (to autosomes) similar in both XX2A and XO2A cells. The results, therefore, suggest that, as in XY2A larval glands, the X chromosome in the XO2A cells also completes the replication earlier than autosomes and that the XO2A nuclei show cellular autonomy with respect to the early replication of the X chromosome, like its counterpart, RNA transcription. Absence of the asynchrony during the initial phase (DD-2C) further completes the replication earlier but that the rate of replication of its DNA is possibly faster, and (b) that there might be a common regulation with respect to the initiation of replication of different chromosomes in a genome.


Young children fail to fully generalize a novel argument structure construction when exposed to the same input as older learners.
The present study exposed five-year-olds (M=5 ; 2), seven-year-olds (M=7 ; 6) and adults (M=22 ; 4) to instances of a novel phrasal construction, then used a forced choice comprehension task to evaluate their learning of the construction. The abstractness of participants' acquired representations of the novel construction was evaluated by varying the degree of lexical overlap that test items had with exposure items. We found that both child groups were less proficient than adults, but seven-year-olds showed evidence of across-the-board generalization whereas five-year-olds were sensitive to lexical overlap at test. This outcome is consistent with more conservative, item-based learning of syntactic patterns in younger children. Additionally, unlike adults and seven-year-olds, five-year-olds showed no evidence of having mastered the novel construction's linking rules. Thus, younger learners are less likely to generalize abstract argument structure constructions when exposed to the same systematic input as older learners.


Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants.
Heterosexual intercourse remains the major route of HIV-1 transmission worldwide, with almost 5 million new infections occurring each year. Women increasingly bear a disproportionate burden of the pandemic, thus there is an urgent need to develop new strategies to reduce HIV-1 transmission that could be controlled by women themselves. The potential of topical microbicides to reduce HIV transmission across mucosal surfaces has been clearly identified, and some agents are currently under evaluation in clinical trials. Many of these "first generation" microbicides consist of polyanionic compounds designed to interfere with viral attachment. Here we have evaluated two candidate polyanion compounds in clinical trials, PRO 2000 and dextrin sulphate (DxS) to determine their safety and efficacy against in vitro HIV-1 and HSV-2 infection using cellular and tissue explant models. PRO 2000 and DxS potently inhibited infection by HIV-1 X4 and R5 isolates when present during viral exposure. However PRO 2000 required 10-fold and DxS 2000-fold more compound to block infection with R5 virus than X4. While both compounds were virucidal for X4 HIV-1, neither was virucidal for R5 virus. PRO 2000 efficiently inhibited infection of cervical explants and dissemination of virus by migratory DC. DxS was less active, able to completely inhibit cervical explant infection, but providing only partial reduction of virus dissemination by DC. PRO 2000, but not DxS, also inhibited HIV-1 binding to DC-SIGN+ cells and trans infection of co-cultured target cells. The inflammatory potential of both compounds was screened by measurement of cytokine production from cervical explants, and statistically significant increases were only observed for IL-1beta and RANTES following treatment with PRO 2000. Both compounds also demonstrated potent activity against HSV-2 infection of cervical epithelial cells. Our results demonstrate that PRO 2000 is a potent inhibitor of R5 HIV-1 infection and dissemination pathways in human cervical explants. DxS, while demonstrating significant inhibition of R5 infection, was less active against DC mediated dissemination pathways. PRO 2000 has now entered human phase III efficacy trials.


Beneficial effects of Cirsium japonicum var. maackii on menopausal symptoms in ovariectomized rats.
In women, menopause refers to a series of physiological and mental symptoms of distress that result from a decrease in 17β-estradiol. In addition to the loss of fertility, the symptoms include facial flushing, depression, osteoporosis, sexual dysfunction, and genitourinary atrophy. Cirsium japonicum var. maackii is a perennial herbaceous species found in the mountains and fields of Korea, China, and Japan. The medicinal uses of C. japonicum include antioxidant, antidiabetic, antitumor, antifungal, and anti-inflammatory activities. We investigated the effect of C. japonicum extract in a rat model of menopause that exhibited rapid estrogen decline induced by ovariectomy (OVX rats). The rats were treated with C. japonicum extract for 10 weeks and the following parameters were measured: food intake, feed efficiency, body weight, total cholesterol, triglyceride, LDL-cholesterol, HDL-cholesterol, liver weight, 17β-estradiol, uterus weight, AST, ALT, bone mineral density (BMD), bone alkaline phosphatase, calcitonin, and osteocalcin. In OVX rats, the administration of 50 and 100 mg kg-1C. japonicum extract significantly decreased body weight, total cholesterol, triglyceride, HDL-cholesterol, and LDL-cholesterol and significantly increased 17β-estradiol and BMD. During the light/dark box test, the C. japonicum treatment group (100 mg kg-1) spent more time in the light chamber than in the dark area, which was reflective of their diurnal nature. Using a molecular docking simulation, we predicted the plausible binding mode of the active compounds of C. japonicum with the ligand binding domain of estrogen receptor (ER)-α and ER-β. These results showed that C. japonicum extract can treat the symptoms before and after the menopause.


The impact of occupational load carriage on carrier mobility: a critical review of the literature.
Military personnel and firefighters are required to carry occupational loads and complete tasks in hostile and unpredictable environments where a lack of mobility may risk lives. This review critically examines the literature investigating the impacts of load carriage on the mobility of these specialist personnel. Several literature databases, reference lists, and subject matter experts were employed to identify relevant studies. Studies meeting the inclusion criteria were critiqued using the Downs and Black protocol. Inter-rater agreement was determined by Cohen's κ. Twelve original research studies, which included male and female participants from military and firefighting occupations, were critiqued (κ = .81). A review of these papers found that as the carried load weight increased, carrier mobility during aerobic tasks (like road marching) and anaerobic tasks (like obstacle course negotiation) decreased. As such, it can be concluded that the load carried by some specialist personnel may increase their occupational risk by reducing their mobility.


Case study of an adaptation and implementation of a Diabetes Prevention Program for individuals with serious mental illness.
The Diabetes Prevention Program (DPP) is an evidence-based lifestyle intervention developed to decrease the risk for type 2 diabetes and promote weight loss in individuals at risk for diabetes. Individuals with serious mental illness have a greater risk for developing diabetes compared with the general population. In this article, the authors provide a detailed description of the adaptation process of the DPP for individuals with serious mental illness (DPP-SMI). The adaptation process was based on a cultural adaptation framework for modifying evidence-based interventions. To assess the effectiveness of the DPP-SMI, 11 individuals from a community mental health residential agency completed a 22-session pilot study of the adapted program and provided physiological measures before and after the intervention. As primary outcomes, participants were expected to report decreased body weight and increased physical activity per week. Completers had an average weight loss of 19 lbs (8%) and their physical activity increased from 161 to 405 min per week. These preliminary results together with participants' feedback informed further refinement of the DPP-SMI. This case study supports that individuals with serious mental illness can benefit from the DPP-SMI, which is tailored to meet the unique needs of this population group.


The Slx5-Slx8 complex affects sumoylation of DNA repair proteins and negatively regulates recombination.
Recombination is important for repairing DNA lesions, yet it can also lead to genomic rearrangements. This process must be regulated, and recently, sumoylation-mediated mechanisms were found to inhibit Rad51-dependent recombination. Here, we report that the absence of the Slx5-Slx8 complex, a newly identified player in the SUMO (small ubiquitin-like modifier) pathway, led to increased Rad51-dependent and Rad51-independent recombination. The increases were most striking during S phase, suggesting an accumulation of DNA lesions during replication. Consistent with this view, Slx8 protein localized to replication centers. In addition, like SUMO E2 mutants, slx8Delta mutants exhibited clonal lethality, which was due to the overamplification of 2 microm, an extrachromosomal plasmid. Interestingly, in both SUMO E2 and slx8Delta mutants, clonal lethality was rescued by deleting genes required for Rad51-independent recombination but not those involved in Rad51-dependent events. These results suggest that sumoylation negatively regulates Rad51-independent recombination, and indeed, the Slx5-Slx8 complex affected the sumoylation of several enzymes involved in early steps of Rad51-independent recombination. We propose that, during replication, the Slx5-Slx8 complex helps prevent DNA lesions that are acted upon by recombination. In addition, the complex inhibits Rad51-independent recombination via modulating the sumoylation of DNA repair proteins.


Center-level Variation in HLA-incompatible Living Donor Kidney Transplantation Outcomes.
Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.


Mental health training in emergency homeless shelters.
The prevalence of mental illness among homeless persons points to the importance of providing mental health training to emergency shelter staff. The authors report on their own work and argue that such training offers the potential to significantly improve shelter staffs ability to respond to the needs of shelter residents with mental illness, and to the behavioral problems some of these individuals may pose for shelter operation. Mental health care providers should take into consideration organizational dynamics when planning and implementing such training.


Understanding acute ankle ligamentous sprain injury in sports.
This paper summarizes the current understanding on acute ankle sprain injury, which is the most common acute sport trauma, accounting for about 14% of all sport-related injuries. Among, 80% are ligamentous sprains caused by explosive inversion or supination. The injury motion often happens at the subtalar joint and tears the anterior talofibular ligament (ATFL) which possesses the lowest ultimate load among the lateral ligaments at the ankle. For extrinsic risk factors to ankle sprain injury, prescribing orthosis decreases the risk while increased exercise intensity in soccer raises the risk. For intrinsic factors, a foot size with increased width, an increased ankle eversion to inversion strength, plantarflexion strength and ratio between dorsiflexion and plantarflexion strength, and limb dominance could increase the ankle sprain injury risk. Players with a previous sprain history, players wearing shoes with air cells, players who do not stretch before exercising, players with inferior single leg balance, and overweight players are 4.9, 4.3, 2.6, 2.4 and 3.9 times more likely to sustain an ankle sprain injury. The aetiology of most ankle sprain injuries is incorrect foot positioning at landing - a medially-deviated vertical ground reaction force causes an explosive supination or inversion moment at the subtalar joint in a short time (about 50 ms). Another aetiology is the delayed reaction time of the peroneal muscles at the lateral aspect of the ankle (60-90 ms). The failure supination or inversion torque is about 41-45 Nm to cause ligamentous rupture in simulated spraining tests on cadaver. A previous case report revealed that the ankle joint reached 48 degrees inversion and 10 degrees internal rotation during an accidental grade I ankle ligamentous sprain injury during a dynamic cutting trial in laboratory. Diagnosis techniques and grading systems vary, but the management of ankle ligamentous sprain injury is mainly conservative. Immobilization should not be used as it results in joint stiffness, muscle atrophy and loss of proprioception. Traditional Chinese medicine such as herbs, massage and acupuncture were well applied in China in managing sports injuries, and was reported to be effective in relieving pain, reducing swelling and edema, and restoring normal ankle function. Finally, the best practice of sports medicine would be to prevent the injury. Different previous approaches, including designing prophylactice devices, introducing functional interventions, as well as change of games rules were highlighted. This paper allows the readers to catch up with the previous researches on ankle sprain injury, and facilitate the future research idea on sport-related ankle sprain injury.


DeltaProt: a software toolbox for comparative genomics.
Statistical bioinformatics is the study of biological data sets obtained by new micro-technologies by means of proper statistical methods. For a better understanding of environmental adaptations of proteins, orthologous sequences from different habitats may be explored and compared. The main goal of the DeltaProt Toolbox is to provide users with important functionality that is needed for comparative screening and studies of extremophile proteins and protein classes. Visualization of the data sets is also the focus of this article, since visualizations can play a key role in making the various relationships transparent. This application paper is intended to inform the reader of the existence, functionality, and applicability of the toolbox. We present the DeltaProt Toolbox, a software toolbox that may be useful in importing, analyzing and visualizing data from multiple alignments of proteins. The toolbox has been written in MATLAB™ to provide an easy and user-friendly platform, including a graphical user interface, while ensuring good numerical performance. Problems in genome biology may be easily stated thanks to a compact input format. The toolbox also offers the possibility of utilizing structural information from the SABLE or other structure predictors. Different sequence plots can then be viewed and compared in order to find their similarities and differences. Detailed statistics are also calculated during the procedure. The DeltaProt package is open source and freely available for academic, non-commercial use. The latest version of DeltaProt can be obtained from http://services.cbu.uib.no/software/deltaprot/. The website also contains documentation, and the toolbox comes with real data sets that are intended for training in applying the models to carry out bioinformatical and statistical analyses of protein sequences.Equipped with the new algorithms proposed here, DeltaProt serves as an auxiliary analysis tool capable of visualizing and comparing orthologus protein sequences. The framework of the algorithms also enables easy incorporation of extra information on structure, if such data is available.


Haematological dynamics following treatment of visceral leishmaniasis: a protocol for systematic review and individual participant data (IPD) meta-analysis.
Visceral leishmaniasis (VL) is a parasitic disease with an estimated 30 000 new cases occurring annually. Despite anaemia being a common haematological manifestation of VL, the evolution of different haematological characteristics following treatment remains poorly understood. An individual participant data meta-analysis (IPD-MA) is planned to characterise the haematological dynamics in patients with VL. The Infectious Diseases Data Observatory (IDDO) VL data platform is a global repository of IPD from therapeutic studies identified through a systematic search of published literature (PROSPERO registration: CRD42021284622). The platform currently holds datasets from clinical trials standardised to a common data format. Corresponding authors and principal investigators of the studies indexed in the IDDO VL data platform meeting the eligibility criteria for inclusion were invited to be part of the collaborative IPD-MA. Mixed-effects multivariable regression models will be constructed to identify determinants of haematological parameters by taking clustering within study sites into account. This IPD-MA meets the criteria for waiver of ethical review as defined by the Oxford Tropical Research Ethics Committee (OxTREC) granted to IDDO, as the research consists of secondary analysis of existing anonymised data (exempt granted on 29 March 2023, OxTREC REF: IDDO). Ethics approval was granted by the ICMR-Rajendra Memorial Research Institute of Medical Sciences ethics committee (letter no.: RMRI/EC/30/2022) on 4 July 2022. The results of this analysis will be disseminated at conferences, the IDDO website and peer-reviewed publications in open-access journals. The findings of this research will be critically important for control programmes at regional and global levels, policymakers and groups developing new VL treatments. CRD42021284622.


Stimuli-responsive lipid-based magnetic nanovectors increase apoptosis in glioblastoma cells through synergic intracellular hyperthermia and chemotherapy.
In this study, taking into consideration the limitations of current treatments of glioblastoma multiforme, we fabricated a biomimetic lipid-based magnetic nanovector with a good loading capacity and a sustained release profile of the encapsulated chemotherapeutic drug, temozolomide. These nanostructures demonstrated an enhanced release after exposure to an alternating magnetic field, and a complete release of the encapsulated drug after the synergic effect of low pH (4.5), increased concentration of hydrogen peroxide (50 μM), and increased temperature due to the applied magnetic field. In addition, these nanovectors presented excellent specific absorption rate values (up to 1345 W g-1) considering the size of the magnetic component, rendering them suitable as potential hyperthermia agents. The presented nanovectors were progressively internalized in U-87 MG cells and in their acidic compartments (i.e., lysosomes and late endosomes) without affecting the viability of the cells, and their ability to cross the blood-brain barrier was preliminarily investigated using an in vitro brain endothelial cell-model. When stimulated with alternating magnetic fields (20 mT, 750 kHz), the nanovectors demonstrated their ability to induce mild hyperthermia (43 °C) and strong anticancer effects against U-87 MG cells (scarce survival of cells characterized by low proliferation rates and high apoptosis levels). The optimal anticancer effects resulted from the synergic combination of hyperthermia chronic stimulation and the controlled temozolomide release, highlighting the potential of the proposed drug-loaded lipid magnetic nanovectors for treatment of glioblastoma multiforme.


Examining the associations between HIV-related stigma and health outcomes in people living with HIV/AIDS: a series of meta-analyses.
To conduct a systematic review and series of meta-analyses on the association between HIV-related stigma and health among people living with HIV. A structured search was conducted on 6 electronic databases for journal articles reporting associations between HIV-related stigma and health-related outcomes published between 1996 and 2013. Controlled studies, cohort studies, case-control studies and cross-sectional studies in people living with HIV were considered for inclusion. Mental health (depressive symptoms, emotional and mental distress, anxiety), quality of life, physical health, social support, adherence to antiretroviral therapy, access to and usage of health/social services and risk behaviours. 64 studies were included in our meta-analyses. We found significant associations between HIV-related stigma and higher rates of depression, lower social support and lower levels of adherence to antiretroviral medications and access to and usage of health and social services. Weaker relationships were observed between HIV-related stigma and anxiety, quality of life, physical health, emotional and mental distress and sexual risk practices. While risk of bias assessments revealed overall good quality related to how HIV stigma and health outcomes were measured on the included studies, high risk of bias among individual studies was observed in terms of appropriate control for potential confounders. Additional research should focus on elucidating the mechanisms behind the negative relationship between stigma and health to better inform interventions to reduce the impact of stigma on the health and well-being of people with HIV. This systematic review and series of meta-analyses support the notion that HIV-related stigma has a detrimental impact on a variety of health-related outcomes in people with HIV. This review can inform the development of multifaceted, intersectoral interventions to reduce the impact of HIV-related stigma on the health and well-being of people living with HIV.


Monoclonal antibody BA-1 recognizes a novel human leukocyte cell surface sialoglycoprotein complex.
With the use of the monoclonal antibody BA-1, we have identified and characterized a unique molecular complex on the surface of human B lymphocytes. Despite the marked pronase sensitivity of the BA-1 antigen/epitope on the cell surface, repeated attempts to surface or biosynthetically radiolabel the antigen by using standard protein labeling techniques were unsuccessful. The antigen was identified by immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis after radiolabeling carbohydrate residues. Surface labeling of galactosyl residues by the neuraminidase/galactose oxidase/3HNaBH4 method revealed a three chain, nondisulfide-linked glycoprotein complex of 45, 55, and 65 kilodaltons (kDa), which we have designated gp45/55/65. Under nonreducing gel conditions there were shifts in the mobility of the 55- and 65-kDa components, consistent with the presence of intrachain disulfide linkages. Surface labeling of sialic acid residues by the sodium periodate/3HNaBH4 method revealed the presence of sialic acid residues on the 45- and 55-kDa components. Two-dimensional gel analysis indicated that the 55-kDa component had an acidic pI of approximately 4.0 and considerable charge heterogeneity, most likely attributable to sialic acid. In contrast, the 45-kDa component had a neutral pI of approximately 7.5. Despite the difficulty in radiolabeling amino acids in gp45/55/65, digestion with V8 protease and pronase clearly demonstrated the presence of protein cores in all three components. Consonant with prior serologic studies with the use of BA-1, we could identify gp45/55/65 on B lymphocytes, B cell precursor acute lymphoblastic leukemias, neutrophils, and eosinophils. This molecular complex has, to our knowledge, not been heretofore described on human B cells and is quite novel in its structure and labeling properties.


A mouse model of accelerated liver aging caused by a defect in DNA repair.
The liver changes with age, leading to an impaired ability to respond to hepatic insults and increased incidence of liver disease in the elderly. Therefore, there is critical need for rapid model systems to study aging-related liver changes. One potential opportunity is murine models of human progerias or diseases of accelerated aging. Ercc1(-/Δ) mice model a rare human progeroid syndrome caused by inherited defects in DNA repair. To determine whether hepatic changes that occur with normal aging occur prematurely in Ercc1(-/Δ) mice, we systematically compared liver from 5-month-old progeroid Ercc1(-/Δ) mice to old (24-36-month-old) wild-type (WT) mice. Both displayed areas of necrosis, foci of hepatocellular degeneration, and acute inflammation. Loss of hepatic architecture, fibrosis, steatosis, pseudocapillarization, and anisokaryosis were more dramatic in Ercc1(-/Δ) mice than in old WT mice. Liver enzymes were significantly elevated in serum of Ercc1(-/Δ) mice and old WT mice, whereas albumin was reduced, demonstrating liver damage and dysfunction. The regenerative capacity of Ercc1(-/Δ) liver after partial hepatectomy was significantly reduced. There was evidence of increased oxidative damage in Ercc1(-/Δ) and old WT liver, including lipofuscin, lipid hydroperoxides and acrolein, as well as increased hepatocellular senescence. There was a highly significant correlation in genome-wide transcriptional changes between old WT and 16-week-old, but not 5-week-old, Ercc1(-/Δ) mice, emphasizing that the Ercc1(-/Δ) mice acquire an aging profile in early adulthood. There are strong functional, regulatory, and histopathological parallels between accelerated aging driven by a DNA repair defect and normal aging. This supports a role for DNA damage in driving aging and validates a murine model for rapidly testing hypotheses about causes and treatment for aging-related hepatic changes.


A Profile of Pornography Users in Australia: Findings From the Second Australian Study of Health and Relationships.
There are societal concerns that looking at pornography has adverse consequences among those exposed. However, looking at sexually explicit material could have educative and relationship benefits. This article identifies factors associated with looking at pornography ever or within the past 12 months for men and women in Australia, and the extent to which reporting an "addiction" to pornography is associated with reported bad effects. Data from the Second Australian Study of Health and Relationships (ASHR2) were used: computer-assisted telephone interviews (CASIs) completed by a representative sample of 9,963 men and 10,131 women aged 16 to 69 years from all Australian states and territories, with an overall participation rate of 66%. Most men (84%) and half of the women (54%) had ever looked at pornographic material. Three-quarters of these men (76%) and more than one-third of these women (41%) had looked at pornographic material in the past year. Very few respondents reported that they were addicted to pornography (men 4%, women 1%), and of those who said they were addicted about half also reported that using pornography had had a bad effect on them. Looking at pornographic material appears to be reasonably common in Australia, with adverse effects reported by a small minority.


Lasing threshold control in two-dimensional photonic crystals with gain.
We demonstrate how the lasing threshold of a two dimensional photonic crystal containing a four-level gain medium is modified, as a result of the interplay between the group velocity and the modal reflectivity at the interface between the cavity and the exterior. Depending on their relative strength and the optical density of states, we show how the lasing threshold may be dramatically altered inside a band or, most importantly, close to the band edge. The idea is realized via self-consistent calculations based on a finite-difference time-domain method. The simulations are in good agreement with theoretical predictions.


Activation of the antitumor agent aminoflavone (NSC 686288) is mediated by induction of tumor cell cytochrome P450 1A1/1A2.
The present studies were performed to elucidate the mechanism of cytotoxicity of the aminoflavone analog (5-amino-2,3-fluorophenyl)-6,8-difluoro-7-methyl-4H-1-benzopyran-4-one (AF; NSC 686288), a novel flavone with potent in vitro and in vivo antiproliferative activity against a number of human tumor cell lines and with a unique pattern of antiproliferative activity in the National Cancer Institute tumor cell line screen. AF was extensively metabolized by cytochrome P450 (P450) 1A1 and 1A2 to several metabolites, one of which was identified by mass spectrometry as a potentially reactive hydroxylamine. Radiolabeled AF was converted by rat and human microsomes, by recombinant CYP1A1 and CYP1A2, and by sensitive human tumor cell lines to species that covalently bound macromolecules. Treatment of sensitive human MCF7 cells with AF resulted in increased CYP1A1 mRNA and CYP1A1/1A2 protein followed by covalent binding of an AF metabolite to DNA, phosphorylation and stabilization of p53, and increased expression of the p53 transcriptional target p21. Covalent binding of the AF metabolite was increased by pretreatment with the CYP1A inducer 3-methylcholanthrene and decreased by coincubation with the CYP1A inhibitor alpha-naphthoflavone. In contrast, induction of CYP1A1 and covalent binding of the AF metabolite did not occur in AF-resistant M14-MEL cells. These observations suggest that AF is uniquely able to induce its own metabolic activation via CYP1A1/1A2 in duction to cytotoxic DNA-damaging species directly in tumor cells. AF, and possibly other agents, may offer a treatment strategy for tumors responsive to CYP1A1/1A2 induction, such as breast, ovarian, and renal cancers.


High energy light scattering in the generalized eikonal approximation.
The generalized eikonal approximation method is applied to the study of light scattering by a dielectric medium. In this method, the propagation of light inside the medium is assumed to be rectilinear, as in the usual eikonal method, but with a parameterized propagator which is used to include the edge effect and ray optics behavior at the limit of very short wavelengths. The resulting formulas for the intensity and extinction efficiency factor are compared numerically and shown to agree excellently with the exact results for a homogeneous dielectric sphere.


Thoracic lymphadenopathy in Asians resident in the United Kingdom: role of mediastinoscopy in initial diagnosis.
Although the incidence of superficial glandular tuberculosis is high in Asian immigrants, a clinical diagnosis without biopsy has previously been shown to be inaccurate in 22% of cases. The role of diagnostic mediastinoscopy and biopsy in thoracic lymphadenopathy was therefore evaluated in 41 consecutive Asian patients. Tuberculosis was diagnosed by histological examination or culture (or both) of gland biopsy material in 24 (59%). A further 12 patients, however, also received antituberculous chemotherapy, with a response in 10 cases. If these are included, 34 (83%) were finally considered to have tuberculosis. The symptoms and ages of the patients with tuberculosis were similar to those typically seen in caucasians with sarcoidosis. Six had tuberculous bilateral hilar lymphadenopathy. In only four cases (10%) was a positive diagnosis other than tuberculosis established; in two (lymphoma and thymoma) mediastinoscopy confirmed preoperative suspicions, and saved only two more (with sarcoidosis and vascular anomaly) from unnecessary antituberculous treatment. Complications included severe haemorrhage (1) and chronic tuberculous sinus in the endoscopy tract (2). Mediastinoscopy is unlikely to change management in most patients, produces an appreciable amount of morbidity, and should be reserved for cases in which there is additional clinical doubt. Any future decline in the prevalence of tuberculosis in Asians may, however, require its further evaluation.


The basophil surface marker CD203c identifies Aspergillus species sensitization in patients with cystic fibrosis.
Colonization by Aspergillus fumigatus in patients with cystic fibrosis (CF) can cause A fumigatus sensitization and/or allergic bronchopulmonary aspergillosis (ABPA), which affects pulmonary function and clinical outcomes. Recent studies show that specific allergens upregulate the surface-expressed basophil marker CD203c in sensitized subjects, a response that can be readily measured by using flow cytometry. We sought to identify A fumigatus sensitization in patients with CF by using the basophil activation test (BAT). Patients with CF attending Beaumont Hospital were screened for study inclusion. BAT was used to identify A fumigatus sensitization. Serologic (total and A fumigatus-specific IgE), pulmonary function, and body mass index measurements were performed. The BAT discriminates A fumigatus-sensitized from nonsensitized patients with CF. Persistent isolation of A fumigatus in sputum is a significant risk factor for A fumigatus sensitization. Levels of the A fumigatus-stimulated basophil activation marker CD203c inversely correlated with pulmonary function and body mass index in A fumigatus-sensitized but not nonsensitized patients with CF. Total and A fumigatus-specific IgE, but not IgG, levels are increased in A fumigatus-sensitized patients with CF and ABPA when compared with those in A fumigatus-sensitized and nonsensitized patients with CF without ABPA. Itraconazole treatment did not affect A fumigatus sensitization. Combining the BAT with routine serologic testing allows classification of patients with CF into 3 groups: nonsensitized, A fumigatus-sensitized, and ABPA. Accurate and prompt identification of A fumigatus-associated clinical status might allow early and targeted therapeutic intervention, potentially improving clinical outcomes.


The Gatekeepers to Fitness: A Correspondence Study to Examine Disabling Practices Among Fitness Center Personnel.
Fitness centers may be an ideal setting for physical activity, yet qualitative findings suggest social-level barriers constrain access for people with disabilities. To further test this, I employed an online message correspondence study to investigate the effect of impairment status on the responsiveness of a national sample of fitness centers to requests for services. Email requests were sent to 800 fitness centers, of which 200 were tailored to each of the four investigative conditions (i.e., control, vision loss, spinal cord injury, or being autistic). The odds of receiving a positive response were 40.5% lower for individuals with vision loss (p = .011) and 33.3% lower for individuals with spinal cord injury (p = .055), as compared with individuals without an impairment. Specifically, the odds of receiving a positive response for personal training were 58.8% lower among individuals with vision loss (p = .003) and 41.1% lower for individuals with spinal cord injury (p = .065).


Use of odd and branched-chain fatty acids in rumen contents and milk as a potential microbial marker.
The objectives of this study were: 1) to determine if a correlation exists between rumen odd and branched-chain fatty acids (OBCFA, i.e., C(15:0), iso C(15:0), anteiso C(15:0), C(17:0), iso C(17:0), anteiso C(17:0), and C(17:1)), uracil, and purine bases (PB), 2) to evaluate the potential of milk OBCFA secretion to predict duodenal flow of microbial protein in lactating cows, 3) to evaluate the accuracy of the latter prediction equations using an independent data set, and 4) to determine whether these predictions were more accurate than predictions based on dry matter intake (DMI) and dietary characteristics. In the first experiment, 4 lactating dairy cows arranged in a 4 x 4 Latin square were offered diets based on grass silages of different botanical composition and a standard concentrate. The relationship between rumen pool size of OBCFA and microbial matter was investigated. Rumen pool size of microbial matter (g), determined 4, 12, and 17 h after feeding, using uracil and PB as microbial markers, was closely related to OBCFA (g) [r(2) = 0.716, root mean square error (RMSE) = 4.45]. To correct for differences in marker concentrations among strains of rumen microbes, C(17:0) was included in the regression equations, resulting in an increased predictive power (r(2) = 0.780, RMSE = 3.92). The relationship between microbial flow to the duodenum and milk OBCFA yield was evaluated in a second experiment with lactating dairy cows offered diets based on grass silage and concentrates differing in starch source. Similar to observations in the rumen, milk OBCFA yield was closely related to microbial flow to the duodenum (RMSE = 4.28), but predictive power of equations did not increase when straight-chain C(17)-fatty acids were included in the regression equations (RMSE = 4.92). Evaluation of the current prediction equations with 3 independent datasets resulted in a root mean square prediction error of 20.5 and 13.4% of the observed mean for equations based on milk secretion of total OBCFA and straight-chain C(17)-fatty acids, respectively. Comparison of the accuracy of the latter equations with 2 previously published equations based on DMI and dietary characteristics suggest the former to be more accurate. This first evaluation suggests that milk OBCFA could be used as a marker for duodenal flow of microbial matter, especially when accurate measurements of DMI are not available.


Coping with death and dying on a neurology inpatient service: death rounds as an educational initiative for residents.
Residents in neurology may feel unprepared to care for dying patients. We developed Death Rounds to provide emotional support and end-of-life care teaching for residents caring for dying patients on the inpatient neurology service. Death Rounds are monthly 1-hour clinical case discussions where residents identify issues through shared experiences. To survey neurology residents' perceptions of Death Rounds with respect to end-of-life care teaching and emotional support. Design, Setting, and We conducted an electronic survey of all (n = 26) neurology residents and recent residency graduates at the University of Washington 2 years after instituting monthly Death Rounds. Main Outcome Measure The survey consisted of 10 questions examining residents' perceptions of the extent to which Death Rounds provided emotional support and end-of-life care teaching. We dichotomized responses to statements about Death Rounds as agree or disagree. All 26 residents responded to the survey and attended at least 1 Death Rounds session. More than half of residents attended more than 3 sessions. Residents agreed that Death Rounds helped them cope with dying patients (17 residents [65%]), delivered closure for the team (16 residents [61%]), and provided emotional support, more for the team (18 residents [69%]) than the individual (10 residents [38%]). Most residents felt that Death Rounds provided useful teaching about end-of-life care (18 residents [69%]), and they were satisfied overall with Death Rounds (16 residents [61%]). Death Rounds afford an opportunity for physicians-in-training to process as a group their feelings, intense emotions, and insecurities while learning from the dying process. In our inpatient neurology service, most residents found it a rewarding and valuable experience.


Weight-Loss Cognitive-Behavioural Treatment and Essential Amino Acid Supplementation in a Patient with Spinal Muscular Atrophy and Obesity.
Spinal muscular atrophy is a genetic neuromuscular disease characterised by muscle atrophy, hypotonia, weakness, and progressive paralysis. Usually, these patients display increased fat mass deposition and reductions in fat-free mass and resting energy expenditure-an unfavourable condition that facilitates the development of obesity. However, weight management of these patients remains poorly described. Hence, the aim of this case report was to describe the clinical presentation and weight management of a 31-year-old male patient with spinal muscular atrophy type III, class I obesity, and metabolic syndrome treated for 1 year by means of a personalised multistep cognitive-behavioural treatment for obesity. The treatment produced a weight loss of 7.2 kg (7.1%), which was associated with a marked improvement in both the patient's self-reported general conditions and obesity-related cardiometabolic profile, and no adverse effects in terms of spinal muscular atrophy (i.e., reductions in fat-free mass or resting energy expenditure).


Clinical Updates in Women's Health Care Primary and Preventive Care Review Summary: Common Dermatologic Conditions.
The skin is the largest organ in the human body, and as such, cutaneous problems constitute a common component of visits to medical professionals. The skin functions as a physiologic barrier and a major organ of homeostasis. The practicing obstetrician-gynecologist can play an important role in identifying skin diseases and initiating management. Additionally, the skin often reflects internal disease states. An astute health care provider can identify systemic conditions early, with the goal of improving management. This monograph reviews common cutaneous conditions, both benign and malignant, hair and nail disorders, and skin conditions unique to the adult woman.


Acute regrowth and dissemination of a mature spinal cord teratoma after partial resection.
A 23-year-old man presented with difficulty walking and leg pain and numbness. MRI revealed a cystic mass at Th11-12 and a pineal-region tumour. The patient underwent surgery to resect the thoracic-level mass. The tumour adhered strongly to the neural tissue and could only be partially resected. On pathological examination, the resected tumour was diagnosed as a mature teratoma. The tumour regrew and disseminated within 3 months after resection. Both the spinal cord tumour and the tumour in the pineal region shrank significantly after chemotherapy and radiotherapy. Although the tumour was pathologically diagnosed as a mature teratoma, we suspect that the residual tumour contained an immature or malignant component. Thus, careful follow-up observation is mandatory after partial resection of a mature teratoma. In addition, because teratomas can disseminate in the central nervous system, the presence of teratoma should prompt an examination of both the spinal cord and brain.