Enumerating metabolic pathways for the production of heterologous target chemicals in chassis organisms.
We consider the possibility of engineering metabolic pathways in a chassis organism in order to synthesize novel target compounds that are heterologous to the chassis. For this purpose, we model metabolic networks through hypergraphs where reactions are represented by hyperarcs. Each hyperarc represents an enzyme-catalyzed reaction that transforms set of substrates compounds into product compounds. We follow a retrosynthetic approach in order to search in the metabolic space (hypergraphs) for pathways (hyperpaths) linking the target compounds to a source set of compounds. To select the best pathways to engineer, we have developed an objective function that computes the cost of inserting a heterologous pathway in a given chassis organism. In order to find minimum-cost pathways, we propose in this paper two methods based on steady state analysis and network topology that are to the best of our knowledge, the first to enumerate all possible heterologous pathways linking a target compounds to a source set of compounds. In the context of metabolic engineering, the source set is composed of all naturally produced chassis compounds (endogenuous chassis metabolites) and the target set can be any compound of the chemical space. We also provide an algorithm for identifying precursors which can be supplied to the growth media in order to increase the number of ways to synthesize specific target compounds. We find the topological approach to be faster by several orders of magnitude than the steady state approach. Yet both methods are generally scalable in time with the number of pathways in the metabolic network. Therefore this work provides a powerful tool for pathway enumeration with direct application to biosynthetic pathway design.


Immediate versus chronic tissue expansion.
A quantitative comparison of the effects on tissues is performed between chronic tissue expansion, intraoperative expansion, and load cycling in a guinea pig model. Intra-operative expansion, which was developed by Sasaki as a method of immediate tissue expansion for small- to medium-sized defects, and load cycling, which was described by Gibson as a method using intraoperative pull, are compared with chronic tissue expansion on the basis of the following four parameters: amount of skin produced, flap viability, intraoperative tissue pressures, and histological changes. The chronically expanded group, which included booster and nonbooster expansions, produced a 137% increase in surface area, or a 52% increase in flap arc length, whereas intraoperative expansion resulted in a 31% increase in surface area, or a 15% increase in flap arc length. The load-cycled group, however, resulted in an almost negligible amount of skin increase. All three techniques exhibit immediate postexpansion stretchback. Flap viability is not impaired by any of the three techniques, in spite of the elevated pressures observed during expansion. Therefore, intraoperative expansion is effective primarily for limited expansion of small defects, whereas chronic tissue expansion still provides the greatest amount of skin increase when compared with other techniques.


Early psychosocial exposures, hair cortisol levels, and disease risk.
Early psychosocial exposures are increasingly recognized as being crucial to health throughout life. A possible mechanism could be physiologic dysregulation due to stress. Cortisol in hair is a new biomarker assessing long-term hypothalamic-pituitary-adrenal axis activity. The objective was to investigate whether early-life adverse psychosocial circumstances influence infant cortisol levels in hair and health outcomes in children prospectively until age 10. A cohort study in the general community using a questionnaire covering 11 psychosocial items in the family during pregnancy and the cumulative incidence of diagnoses until age 10 years in 1876 children. Cortisol levels in hair were measured by using a radioimmunoassay in those with sufficient hair samples at age 1, yielding a subsample of n = 209. Children with added psychosocial exposures had higher infant cortisol levels in hair (B = 0.40, P < .0001, adjusted for gender and size for gestational age) in a cumulative manner and were significantly more often affected by 12 of the 14 most common childhood diseases, with a general pattern of increasing odds ratios. The findings support the model of physiologic dysregulation as a plausible mechanism by which the duration and number of early detrimental psychosocial exposures determine health outcomes. The model indicates that the multiplicity of adversities should be targeted in future interventions and could help to identify children who are at high risk of poor health. Furthermore, given the prolonged nature of exposure to a stressful social environment, the novel biomarker of cortisol in hair could be of major importance.


Motoric Cognitive Risk Syndrome Subtypes and Cognitive Profiles.
The motoric cognitive risk (MCR) syndrome, characterized by slow gait and cognitive complaints, is a simple and easily accessible clinical approach to identify older adults at high risk for transitioning to dementia. This study aims to define subtypes of MCR based on individual quantitative gait variables and to compare their neuropsychological profiles and risk factors as well risk for incident cognitive impairment. MCR was diagnosed in 314 community-residing, nondemented, older adults aged 65 and older (56% women) based on the presence of cognitive complaints and slow gait velocity (MCRv). Four new subtypes of MCR were defined by substituting slow gait with short stride length (MCRsl), slow swing time (MCRsw), high stride length variability (MCRslv), and high swing time variability (MCRswv). MCR subtypes were not mutually exclusive. A total of 25 participants (8%) met criteria for MCRv, 20 for MCRsl (6.4%), 15 for MCRsw (4.8%), 16 for MCRslv (5.1%), 12 for MCRswv (3.8%), and 266 participants (84.7%) did not meet criteria for any MCR subtype. At baseline, MCRv was associated with deficits in attention and language as well as in overall cognitive status. MCRswv was associated with deficits in all cognitive domains including memory. Obesity and sedentariness were risk factors of MCRv, MCRsl, and MCRsw. MCRv status predicted incident cognitive impairment in global cognition (odds ratio: 3.59, p = .016), whereas MCRswv status predicted incident cognitive impairment in memory (odds ratio: 4.24, p = .048). MCR subtypes based on individual gait parameters show commonalities and differences in cognitive profiles and risk factors. Future studies should investigate whether the MCR subtypes predict different subtypes of dementia.


Morphological characterization of adult Fascioloides magna (Trematoda: Fasciolidae): first SEM report.
Five adult Fascioloides magna specimens were recovered from the livers of naturally infected calves from Texas, USA. Scanning electron microscopy was used to study the morphological characteristics of the trematodes. These mature flukes measured 35-100 mm in length by 15-25 mm in width and had an oval dorsoventrally flattened body, with no anterior cone. The tegument was armed with sharp spines. Around the oral and ventral suckers, some of the spines were small, with a sharp point, while others had serrated edges with 15-22 sharp points. The surface of the oral sucker was covered by an interesting pattern of tegument, small dome-shaped and ciliated papillae. The ventral sucker showed a smooth surface and two unknown spine-like structures. There were fewer spines at the base of the genital pore than on other parts of the anterior end of the worm. At the anterior end of the ventral side, well-developed spines were observed, while at the posterior end of the ventral side, the spines were small, mostly with one or three points and blunted edges. At the posterior end of the dorsal side, the spines became progressively fewer, smaller, and shorter. Around the excretory pore, the tegument was folded, with no spines, and small groups of dome-shaped and ciliated papillae were present. The cirrus organ showed a smooth surface, with small pores on the dorsal side and small groups of tiny spines between the folds. The eggs measured 168 × 101 μm and had a protoplasmic appendage at the pole opposite the operculum. At the posterior end of the dorsal side, and toward the right, a pore with a very thin rim was present, which could be the terminus of Laurer's canal.


Effect of distal embolization on myocardial perfusion reserve after percutaneous coronary intervention: a quantitative magnetic resonance perfusion study.
Studies have shown that a subset of patients demonstrate persistent impairment in microcirculatory function after percutaneous coronary intervention (PCI). Distal embolization of plaque contents has been postulated as the main mechanism for this. We sought to investigate this further by evaluating PCI-induced changes in myocardial perfusion reserve index (MPRI) over time in segments with "distal-type" procedure-related myonecrosis using high-resolution quantitative cardiovascular magnetic resonance imaging. Forty patients undergoing PCI were studied with pre-PCI and 24-hour post-PCI delayed-enhancement magnetic resonance imaging and first-pass perfusion magnetic resonance imaging at rest and stress. Twenty patients underwent a third magnetic resonance imaging scan at 6 months. For perfusion imaging, 3 short-axis images were acquired during every heartbeat with a T1-weighted turboFLASH sequence. MPRI was calculated as the ratio of hyperemic to resting myocardial blood flow and subdivided according to the presence and location of new delayed hyperenhancement. Twenty-one patients demonstrated new distal hyperenhancement after PCI. Mean MPRI in revascularized myocardial segments not demonstrating new HE was significantly increased after the procedure (2.06 [95% CI, 1.99 to 2.13] before PCI and 2.52 [95% CI, 2.42 to 2.62] after PCI; P<0.001). In contrast, MPRI in segments with distal hyperenhancement was reduced after PCI (2.16 [95% CI, 1.95 to 2.37] before PCI; 2.00 [95% CI, 1.82 to 2.19] after PCI; mixed-model z=-4.82; P<0.001). Changes in mean MPRI 24 hours after PCI in segments upstream to new injury were not significantly different compared with perfusion changes in remote myocardium (z=-0.68; P=0.50). At 6 months after the procedure, mean MPRI in segments with new injury improved significantly compared with MPRI measured in these segments at 24 hours after PCI. MPRI is reduced in myocardial segments that demonstrate new distal irreversible injury at 24 hours after PCI. These reductions are confined to the segments with injury and do not affect the entire supply territory of the culprit vessel.


Exosomes as Theranostics for Lung Cancer.
Extensive research in genetics and genomics has revealed that lung cancer is a physiologically complex and genetically heterogeneous disease. Although molecular targets that can yield favorable response have been identified, those targets cannot be exploited due to the lack of suitable drug carriers. Furthermore, lung cancer often is diagnosed at an advanced stage when the disease has metastasized. Conventional treatments are not effective for treating metastatic lung cancer. Targeted therapeutics while beneficial has challenges that include poor tumor-targeting, off-target effects, and development of resistance to therapy. Therefore, improved drug delivery systems that can deliver drugs specifically to tumor will produce improved treatment outcomes. Exosomes have a natural ability to carry functional biomolecules, such as small RNAs, DNAs, and proteins, in their lumen. This property makes exosomes attractive for use in drug delivery and molecular diagnosis. Moreover, exosomes can be attached to nanoparticles and used for high precision imaging. Exosomes are now considered an important component in liquid biopsy assessments, which are useful for detecting cancers, including lung cancer. Several studies are currently underway to develop methods of exploiting exosomes for use as efficient drug delivery vehicles and to develop novel diagnostic modalities. This chapter summarizes the current status of exosome studies with regard to their use as theranostics in lung cancer. Examples from other cancers have also been cited to illustrate the extensive applicability of exosomes to therapy and diagnosis.


Opioid receptor agonistic characteristics of mitragynine pseudoindoxyl in comparison with mitragynine derived from Thai medicinal plant Mitragyna speciosa.
We have previously elucidated the opiate-like action of mitragynine, an active principle isolated from the Thai medicinal plant Mitragyna speciosa. In the present study, effects of the related compound, mitragynine pseudoindoxyl on electrically stimulated contraction in guinea pig ileum and mouse vas deferens, and on its binding affinity in the guinea pig brain membranes were studied. Mitragynine pseudoindoxyl inhibited the electrically stimulated ileum and mouse vas deferens contractions in a concentration-dependent manner. In the ileum, the effective concentration is in an nM order, being nearly equivalent to reported concentrations of the micro-opioid receptor agonist [D-Ala2, Met-Phe4, Gly-ol5] enkephalin (DAMGO), and is 100- and 20-fold smaller than those of mitragynine and morphine, respectively. In the vas deferens, it is 35-fold smaller than that of morphine. The inhibitory action of mitragynine pseudoindoxyl in the ileum was antagonized by the non-selective opioid receptor antagonist naloxone and the micro-receptor antagonist naloxonazine. It was also antagonized by the delta-receptor antagonist naltrindole in the vas deferens. Mitragynine pseudoindoxyl showed a similar binding affinity to DAMGO and naltrindole at micro- and delta-receptors, respectively. However, the affinity at kappa-receptors was negligible. The present study demonstrates that mitragynine pseudoindoxyl, a novel alkaloid structurally different from other opioid agonists, acts on opioid receptors, leading to a potent inhibition of electrically stimulated contraction in the ileum through the micro-receptors and in mouse vas deferens through delta-receptors.


Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study.
'Long COVID' describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. Patients with fatigue-dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical-based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two-week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. Between December 15th 2021, and May 23th 2022, 60 participants were screened, and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] -4.30, 95% confidence interval (95% CI) -7.14, -1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious or led to treatment discontinuation. Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there were significant improvements in fatigue-based symptoms among patients living with Long COVID following a four-week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. Axcella Therapeutics.


Role of muscle stem cells in sarcopenia.
The review is an update on recent research investigating the role of skeletal muscle stem cells (also known as satellite cells) during muscle fiber regeneration and growth in animal and human skeletal muscle, with an emphasis on their role in age-related sarcopenia. Studies indicate clear impairments in satellite cell function with aging, resulting in an impaired muscle fiber regenerative response. The autophagy-mediated switch to an irreversible presenescent state of geriatric satellite cells appears to play a key role in age-related impaired satellite cell function. In addition, inadequate muscle fiber vascularization may be a crucial factor underlying impaired regulation of satellite cells in older adults. Controversy remains on the actual contribution of satellite cells to the development of sarcopenia in later life, this clearly requires further research. Nevertheless, exercise training remains to be a potent intervention strategy, mediated through satellite cells or not, to counteract the ill effects of sarcopenia. Although important strides are made investigating the importance of satellite cells in the development and/or treatment of sarcopenia, the idea that satellite cell function is a therapeutic target to treat sarcopenia remains controversial.


Variability and Costs of Low-Value Preoperative Testing for Carpal Tunnel Release Surgery.
The American Society of Anesthesiologists (ASA) Choosing Wisely Top-5 list of activities to avoid includes "Don't obtain baseline laboratory studies in patients without significant systemic disease (ASA I or II) undergoing low-risk surgery - specifically complete blood count, basic or comprehensive metabolic panel, coagulation studies when blood loss (or fluid shifts) is/are expected to be minimal." Accordingly, we define low-value preoperative tests (LVTs) as those performed before minor surgery in patients without significant systemic disease. The objective of the current study was to examine the extent, variability, drivers, and costs of LVTs before carpal tunnel release (CTR) surgeries in the US Veterans Health Administration (VHA). Using fiscal year (FY) 2015-2017 data derived from the VHA Corporate Data Warehouse (CDW), we determined the overall national and facility-level rates and associated costs of receiving any of 8 common LVTs in the 30 days before CTR in ASA physical status (PS) I-II patients. We also examined the patient, procedure, and facility factors associated with receiving ≥1 LVT with mixed-effects logistic regression and the number of tests received with mixed-effects negative binomial regression. From FY15-17, 10,000 ASA class I-II patients received a CTR by 699 surgeons in 125 VHA facilities. Overall, 47.0% of patients had a CTR that was preceded by ≥1 LVT, with substantial variability between facilities (range = 0%-100%; interquartile range = 36.3%), representing $339,717 in costs. Older age and female sex were associated with higher odds of receiving ≥1 LVT. Local versus other modes of anesthesia were associated with lower odds of receiving ≥1 LVT. Several facilities experienced large (>25%) increases or decreases from FY15 to FY17 in the proportion of patients receiving ≥1 LVT. Counter to guidance from the ASA, we found that almost half of CTRs performed on ASA class I-II VHA patients were preceded by ≥1 LVT. Although the total cost of these tests is relatively modest, CTR is just one of many low-risk procedures (eg, trigger finger release, cataract surgery) that may involve similar preoperative testing practices. These results will inform site selection for qualitative investigation of the drivers of low-value testing and the development of interventions to improve preoperative testing practice, especially in locations where rates of LVT are high.


A genomic biomarker signature can predict skin sensitizers using a cell-based in vitro alternative to animal tests.
Allergic contact dermatitis is an inflammatory skin disease that affects a significant proportion of the population. This disease is caused by an adverse immune response towards chemical haptens, and leads to a substantial economic burden for society. Current test of sensitizing chemicals rely on animal experimentation. New legislations on the registration and use of chemicals within pharmaceutical and cosmetic industries have stimulated significant research efforts to develop alternative, human cell-based assays for the prediction of sensitization. The aim is to replace animal experiments with in vitro tests displaying a higher predictive power. We have developed a novel cell-based assay for the prediction of sensitizing chemicals. By analyzing the transcriptome of the human cell line MUTZ-3 after 24 h stimulation, using 20 different sensitizing chemicals, 20 non-sensitizing chemicals and vehicle controls, we have identified a biomarker signature of 200 genes with potent discriminatory ability. Using a Support Vector Machine for supervised classification, the prediction performance of the assay revealed an area under the ROC curve of 0.98. In addition, categorizing the chemicals according to the LLNA assay, this gene signature could also predict sensitizing potency. The identified markers are involved in biological pathways with immunological relevant functions, which can shed light on the process of human sensitization. A gene signature predicting sensitization, using a human cell line in vitro, has been identified. This simple and robust cell-based assay has the potential to completely replace or drastically reduce the utilization of test systems based on experimental animals. Being based on human biology, the assay is proposed to be more accurate for predicting sensitization in humans, than the traditional animal-based tests.


Placental amino acids transport in intrauterine growth restriction.
The placenta represents a key organ for fetal growth as it acts as an interface between mother and fetus, regulating the fetal-maternal exchange of nutrients, gases, and waste products. During pregnancy, amino acids represent one of the major nutrients for fetal life, and both maternal and fetal concentrations are significantly different in pregnancies with intrauterine growth restriction when compared to uncomplicated pregnancies. The transport of amino acids across the placenta is a complex process that includes the influx of neutral, anionic, and cationic amino acids across the microvilluos plasma membrane of the syncytiotrophoblast, the passage through the cytoplasm of the trophoblasts, and the transfer outside the trophoblasts across the basal membrane into the fetal circulation. In this paper, we review the transport mechanisms of amino acids across the placenta in normal pregnancies and in pregnancies complicated by intrauterine growth restriction.


Enhanced functional connectivity involving the ventromedial hypothalamus following methamphetamine exposure.
Methamphetamine (MA) consumption causes disruption of many biological rhythms including the sleep-wake cycle. This circadian effect is seen shortly following MA exposure and later in life following developmental MA exposure. MA phase shifts, entrains the circadian clock and can also alter the entraining effect of light by currently unknown mechanisms. We analyzed and compared immunoreactivity of the immediate early gene c-Fos, a marker of neuronal activity, to assess neuronal activation 2 h following MA exposure in the light and dark phases. We used network analyses of correlation patterns derived from global brain immunoreactivity patterns of c-Fos, to infer functional connectivity between brain regions. There were five distinct patterns of neuronal activation. In several brain areas, neuronal activation following exposure to MA was stronger in the light than the dark phase, highlighting the importance of considering circadian periods of increased effects of MA in defining experimental conditions and understanding the mechanisms underlying detrimental effects of MA exposure to brain function. Functional connectivity between the ventromedial hypothalamus (VMH) and other brain areas, including the paraventricular nucleus of the hypothalamus and basolateral and medial amygdala, was enhanced following MA exposure, suggesting a role for the VMH in the effects of MA on the brain.


Epidemiology of Kaposi's sarcoma.
The AIDS epidemic drew attention to KS, a previously rare and little studied condition. The epidemiological evidence summarized here strongly suggests that the disease is caused by a transmissible agent, in addition to HIV. Sexual contact is the most important mode of transmission of the agent, although transmission by blood and perinatally may also occur (Beral et al, 1990).


Temperature dependent red luminescence from a distorted Mn4+ site in CaAl4O7:Mn4+.
Thermal luminescence quenching behavior of a phosphor is essential for application in phosphor converted white light emitting diodes (pc-WLEDs) because the phosphor layer can be heated up to 473K in a working high power WLEDs. Here, we have confirmed indeed a red luminescence of Mn(4+) substituting for calcium sites rather than tetrahedral aluminum sites in CaAl(4)O(7):Mn which can be synthesized in pure phase even with boron acid as flux, and examined the low and high temperature luminescent properties in the range of 10 to 500K. We have revealed as well as thermal quenching mechanism that distorted octahedral Mn(4+) sites suffer severe thermal quenching. This work, thus, hints a strategy to find a new Mn(4+) phosphor with better resistance to thermal impact in the future.


Cancer incidence in British Indians and British whites in Leicester, 2001-2006.
Incidence rates for many cancers are lower in India than in Britain and it is therefore of interest to compare rates in British Indians to British whites, as well as to rates in India. We present estimates for Leicester, which has the largest population of Indian origin in Britain, and also has virtually complete, self-assigned, ethnicity data. We obtained data on all cancer registrations from 2001 to 2006 for Leicester with ethnicity data obtained by linkage to the Hospital Episode Statistics database. Age-standardised incidence rates were calculated for British Indians and British whites as well as incidence rate ratios, adjusted for age and income. Incidence rate ratios for British Indians compared with British whites were significantly less than 1.0 for all cancers combined (0.65) and for cancer of the breast (0.72), prostate (0.76), colon (0.46), lung (0.30), kidney (0.36), stomach (0.54), bladder (0.48) and oesophagus (0.64), but higher than 1.0 for liver cancer (1.95). These results are likely to be the most accurate estimate of cancer incidence in British Indians to date and confirm that cancer incidence in British Indians is lower than in British whites in Leicester, particularly for cancer of the breast, prostate, colon and lung (and other smoking-related cancers), but much higher than in India.


Forage preservation (grazing vs. hay) fed to ewes affects the fatty acid profile of milk and CPT1B gene expression in the sheep mammary gland.
Alterations in lipid metabolism occur when animals are exposed to different feeding systems. In the last few decades, the characterisation of genes involved in fat metabolism and technological advances have enabled the study of the effect of diet on the milk fatty acid (FA) profile in the mammary gland and aided in the elucidation of the mechanisms of the response to diet. The aim of this study was to evaluate the effect of different forage diets (grazing vs. hay) near the time of ewe parturition on the relationship between the fatty acid profile and gene expression in the mammary gland of the Churra Tensina sheep breed. In this study, the forage type affected the C18:2 cis-9 trans-11 (CLA) and long-chain saturated fatty acid (LCFA) content, with higher percentages during grazing than during hay feeding. This may suggest that these FAs act as regulatory factors for the transcriptional control of the carnitine palmitoyltransferase 1B (CPT1B) gene, which was more highly expressed in the grazing group (GRE). The most highly expressed gene in the mammary gland at the fifth week of lactation is CAAT/ enhancer- binding protein beta (CEBPB), possibly due to its role in milk fat synthesis in the mammary gland. More stable housekeeping genes in the ovine mammary gland that would be appropriate for use in gene expression studies were ribosomal protein L19 (RPL19) and glyceraldehyde- 3- phosphate dehydrogenase (GAPDH). Small changes in diet, such as the forage preservation (grazing vs. hay), can affect the milk fatty acid profile and the expression of the CPT1B gene, which is associated with the oxidation of fatty acids. When compared to hay fed indoors, grazing fresh low mountain pastures stimulates the milk content of CLA and LCFA via mammary uptake. In this sense, LCFA in milk may be acting as a regulatory factor for transcriptional control of the CPT1B gene, which was more highly expressed in the grazing group.


Using the mouse grimace scale to assess pain associated with routine ear notching and the effect of analgesia in laboratory mice.
Social housing is recommended where possible for laboratory mice. In order to achieve this, mice must be individually identifiable. Although, various methods are available, permanent identification is often required, such as ear notching. This method is likely to be painful and to date there is limited literature on pain assessment and alleviation for this routine husbandry practice. Here we aimed to determine if the mouse grimace scale (MGS) could be used to assess pain in C57BL/6 mice following routine ear notching. Langford et al. found that very acute noxious stimuli (i.e. < 10 min in duration) did not produce a change in MGS score in comparison to baseline. Here, no significant difference was found between MGS scores at baseline and immediately post ear notching, potentially indicating that the pain associated with ear notching is either too acute to assess using the MGS tool or the practice is not painful. Studies in other species indicate that ear notching is painful, therefore, unless we can confidently conclude that the process of ear notching is not painful, we should err on the side of caution and assume it is painful due to the large number of mice ear-notched and potential welfare consequences. Alternative methods of assessing pain following this routine practice should be used in order to assess both the potential pain in mice, and the effectiveness of analgesics or local anaesthetics to relieve any associated pain.


An automatic system for the analysis and classification of human atrial fibrillation patterns from intracardiac electrograms.
This paper presents an automatic system for the analysis and classification of atrial fibrillation (AF) patterns from bipolar intracardiac signals. The system is made up of: 1) a feature-extraction module that defines and extracts a set of measures potentially useful for characterizing AF types on the basis of their degree of organization; 2) a feature-selection module (based on the Jeffries-Matusita distance and a branch and bound search algorithm) identifying the best subset of features for discriminating different AF types; and 3) a support vector machine technique-based classification module that automatically discriminates the AF types according to the Wells' criteria. The automatic system was applied on 100 intracardiac AF signal strips and on a selection of 11 representative features, demonstrating: a) the possibility to properly identify the most significant features for the discrimination of AF types; b) higher accuracy (97.7% using the seven most informative features) than the traditional maximum likelihood classifier; and c) effectiveness in AF classification also with few training samples (accuracy = 88.3% with only five training signals). Finally, the system identifies a combination of indices characterizing changes of morphology of atrial activation waves and perturbation of the isoelectric line as the most effective in separating the AF types.


Changing patterns in competing causes of death in men with prostate cancer: a population based study.
We examined trends in hospitalization and death in men with prostate cancer to determine whether outcomes have changed with time in men diagnosed and treated for this disorder. A population based cohort study of 180973 patients with prostate cancer in the 1979 to 1996 Surveillance, Epidemiology and End Results cancer registry and 450448 admissions in the 1987 to 1996 Surveillance, Epidemiology and End Results-Medicare linked database were analyzed. ORs derived from logistic regression were used to assess time trends in mortality and hospitalization. Multinominal logistic regression was used to obtain the adjusted proportions of deaths due to various causes in different years. In men with prostate cancer the risk of death from cancer was 39.7% (OR = 0.61, 95% CI = 0.56 to 0.66), which was lower in 1995 to 1996 than in 1979 to 1980. Decreases in prostate cancer death were greater than those in cardiovascular disorders (OR = 0.85, 95% CI = 0.78 to 0.92) and evident even in men with nonlocalized disease. Overall nonprostate cancer causes of mortality increased (OR = 1.65, 95% CI = 1.52 to 1.79) and ultimately exceeded that due to prostate cancer. By 1995 to 1996 the proportion of prostate cancer deaths was similar to that of cardiovascular disorders (27.7% and 26.6%, respectively) and substantially less than that of all other sources combined (45.7%). Similar effects were observed for prostate cancer (OR = 0.40, 95% CI = 0.37 to 0.42) and nonprostate cancer (OR = 2.51, 95% CI = 2.36 to 2.68) hospitalizations. In men with prostate cancer decreases in prostate cancer hospitalization and mortality have been greater than those in competing diseases with time. Most deaths in patients with prostate cancer, including those with nonlocalized disease, are now due to nonprostate cancer causes.


Lower body positive-pressure exercise after knee surgery.
Lower body positive pressure allows unloading of the lower extremities during exercise in a pressurized treadmill chamber. This study assessed the preliminary feasibility of lower body positive pressure exercise as a rehabilitation technique by examining its effects on gait mechanics and pain, postoperatively. Fifteen patients who had arthroscopic meniscectomy or anterior cruciate ligament reconstruction participated in this study. Patients exercised for 5 minutes at 2.0 mph under three body weight conditions (normal body weight, 60% body weight, and 20% body weight) in random order. Bilateral ground reaction force, electromyographs, and dynamic knee range of motion were collected, and pain was assessed using a visual analog scale. Ground reaction forces for surgically treated and contralateral extremities were reduced 42% and 79% from normal body weight conditions when ambulating at 60% and 20% body weight, respectively. After meniscectomy, ambulatory knee range of motion decreased only at 20% body weight (37 degrees), compared with normal body weight conditions (49 degrees). Peak electromyographic activity of the biceps was maintained at all body weight conditions, whereas that of the vastus medialis was reduced at 20% body weight. Pain relief was significant with lower body positive pressure ambulation after anterior cruciate ligament reconstruction. This study showed that lower body positive pressure exercise is effective at reducing ground reaction forces, while safely facilitating gait postoperatively.


X-linked lymphoproliferative disease: prenatal detection of an unaffected histocompatible male.
Chorionic Villous Biopsy (CVS) for diagnosis of XLP was undertaken at 10 weeks gestation in an obligate carrier. The fetus was found to be male by cytogenetic analysis. XLP (Xq25-q26) is closely linked to the RFLP markers DXS10, DXS37 and DXS42, but only DXS10 (distal to XLP) was informative for prenatal diagnosis in this family. RFLP analysis using this marker gave a 7% risk that the fetus was affected, based on the known recombination frequency between DXS10 and XLP. Further investigation was then undertaken to obtain a rapid and more accurate diagnosis using the three highly polymorphic PCR based markers. These were the AC repeat markers DXS424 (XL5A) and DXS425 (XL90A3) and the tetramer repeat marker within HPRT. DX425 is approximately 10 cM proximal to DXS10 and HPRT but is not known with certainty to map proximal or distal to XLP. DXS424 is proximal to DXS10 and HPRT and was inferred to be proximal to XLP on the basis of map distance from HPRT estimated by linkage analysis of data from CEPH pedigrees. This was confirmed by a recombinant in the XLP family between DXS424 and DXS425, placing DXS424 proximal to XLP. Diagnosis by linkage using DXS424 and DXS425, at least one of which is proximal to XLP, and distal markers DXS10 and HPRT, increased the accuracy of diagnosis using flanking marker analysis to greater than 99% that the fetus was unaffected. HLA DR typing of the CVS showed that the fetus was DR identical to a male sibling with XLP. HLA compatibility was confirmed at delivery by full HLA typing and MLC.(ABSTRACT TRUNCATED AT 250 WORDS)


Behavioural insights to support increased consumption of quality protein maize by young children: a cluster randomised trial in Ethiopia.
Biofortified crops have tremendous potential to improve child nutrition. We tested whether complementing the distribution of quality protein maize (QPM) with a package of interventions informed by behavioural insights could support greater consumption of QPM by young children and translate into improved growth. We conducted a cluster-randomised trial in Oromia, Ethiopia. Clusters of households with a child between 6 and 35 months were randomised into an arm receiving QPM seed only (320 households, 203 clusters) or an arm receiving QPM seed and a child consumption targeting intervention (290 households, 183 clusters). The intervention package included tools to help caregivers keep QPM separate from conventional maize and to earmark QPM specifically for child consumption, as well as encouragement regarding cooking QPM specifically for young children. We analysed the impact of the intervention on food storage, cooking and consumption behaviours and on anthropometric measures (weight-for-age, height-for-age z scores). The consumption targeting intervention increased the probability of child consumption of QPM in the past week by 17.3 percentage points (pp) (95% CI 9.4 pp to 25.1 pp; p<0.01), increased the probability that QPM flour was stored separately from conventional maize by 46.5 pp (95% CI 38.3 pp to 54.7 pp; p<0.01) and increased the probability that caregivers cooked QPM specifically for young children in the past week by 14.4 pp (95% CI 7.9 pp to 20.9 pp; p<0.01). These effects persisted, but were attenuated, 10 months postintervention. No significant effects on anthropometric outcomes were found. Enhancing the distribution of new, biofortified crop varieties with a consumption targeting campaign can change storage, cooking and consumption behaviours. However, these improved behaviours did not translate into increased growth in this setting. NCT02710760 and AEARCTR0000786.


Structure-activity relationships for inhibition of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone lung tumorigenesis by arylalkyl isothiocyanates in A/J mice.
Phenethyl isothiocyanate (PEITC), 3-phenylpropyl isothiocyanate (PPITC), 4-phenylbutyl isothiocyanate (PBITC), and the newly synthesized 5-phenylpentyl isothiocyanate (PPeITC), 6-phenylhexyl isothiocyanate (PHITC), and 4-(3-pyridyl)butyl isothiocyanate (PyBITC) were tested for their abilities to inhibit tumorigenicity and DNA methylation induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) in the lungs of A/J mice. Mice were administered isothiocyanates by gavage for 4 consecutive days at doses of 5, 1, or 0.2 mumol/day prior to administration of 10 mumol of NNK by i.p. injection. Mice were sacrificed 16 weeks after NNK administration and pulmonary adenomas were quantitated, PEITC effectively inhibited NNK-induced lung tumors at a dose of 5 mumol/day but was not inhibitory at doses of 1 or 0.2 mumol/day. PPITC, PBITC, PPeITC, and PHITC were all considerably more potent inhibitors of NNK lung tumorigenesis than PEITC. While virtually no differences in inhibitory activity could be ascertained for PPITC, PBITC, and PPeITC, PHITC appeared to be the most potent tumor inhibitor of all of the compounds. At a dose of 0.2 mumol/day, PHITC pretreatment reduced tumor multiplicity by 85%. PyBITC, an analogue of both NNK and PBITC, was ineffective as an inhibitor. Using the same protocol, the compounds were found to have qualitatively similar inhibitory effects on NNK-induced DNA methylation when administered at 1 mumol/day. These results extend our previous findings that increased alkyl chain length enhances the inhibitory activity of an arylalkyl isothiocyanate toward NNK lung tumorigenesis and demonstrate the exceptional chemopreventive potentials of two new isothiocyanates, PPeITC and PHITC.


Links between depressive symptoms and unmet health and social care needs among older prisoners.
absolute numbers of older prisoners and their proportion of the total prison population are increasing. They have multiple health and social care needs that are prominent on entry into prison. No previous studies have identified older prisoners' health and social care needs at this crucial point. to examine unmet health and social care needs among older men entering prison and their links with depressive symptoms. a cross-sectional survey across nine prisons in the North of England was completed. One hundred male prisoners aged between 60 and 81 were interviewed, using the Camberwell Assessment of Need-Forensic short version (CANFOR-S) and Geriatric Depression Scale-Short Form (GDS-15). Descriptive statistics were generated and χ(2) tests performed. participants reported high levels of unmet needs as measured with the CANFOR-S, notably in the domains of knowledge about their condition and treatment (38%); psychological distress (34%); daytime activities (29%); benefits (28%); food (22%) and physical health (21%). The mean total number of unmet needs was 2.74, with a median of 2.0. More than half the sample (56%, 95% CI 45-66%) exhibited clinical signs of depression. A significant association between depressive symptomology and an unmet physical health need, as measured by the CANFOR-S, was detected (χ(2) = 6.76, df = 1, P < 0.01). high levels of depressive symptoms were experienced by older prisoners on entry into prison. Personalised health and social care needs assessment and discrete depression screening are required on prison entry to facilitate effective management of unmet needs.


The measurement of disability.
The frequent occurrence of desynchrony between psychiatric symptoms and disability makes it necessary to measure disability/ functional impairment in addition to psychiatric symptoms when tracking treatment outcome. Existing disability measures in psychiatry are comprehensive but lengthy. There is a need for short, simple, cost-effective, sensitive measures of disability and functional impairment in psychiatric disorders. We developed a discretized analog disability scale (DISS) which uses visual-spatial, numeric and verbal descriptive anchors to assess disability across three domains: work, social life and family life. The DISS has proved to be very sensitive to change in drug treatment studies in psychiatry. The usefulness of the DISS in assessing disability in terms of work, social and family relationships is discussed.


Myogenic response and wall mechanics of arterioles.
The magnitude of the arteriolar response to altered intraluminal pressure was assessed in isolated, cannulated vessels of the hamster cheek pouch. Microvessels were studied during various levels of smooth muscle activation, either occurring spontaneously, or resulting from the application of exogenous agonists including potassium (35 or 70 mM) and phenylephrine (1.25 or 2.50 x 10(-6) M). Diameter-pressure curves were obtained by lowering intraluminal pressure from 60 to 0 mmHg in seven steps at 3-min intervals. At an intraluminal pressure of 40 mmHg, spontaneous tone produced an average constriction to 34 +/- 2% of the maximum diameter. Step reductions in pressure typically led to reductions in the level of activation of the muscle, which resulted in a net dilation over a significant pressure range. This "myogenic response" was more effective in modifying spontaneous tone than in modifying exogenous tone. In fact, the data suggest that reduction of the intraluminal pressure to zero can result in complete inactivation of spontaneous tone. Complete inactivation was not observed when contractions were induced by exogenous agonists, however. The magnitude of the myogenic response in arterioles was consistent with a role in autoregulation, which is 2.5-fold greater than that previously reported for small arteries. The data demonstrate that in the analysis of the mechanics of submaximally activated blood vessels one must include considerations of two phenomenon: the classical stress-length behavior as determined under conditions of maximal activation, and a superimposed modification of the activation level induced by stress- or length-dependent processes. Furthermore, the findings indicate substantial differences in response when tone is spontaneous compared with the case when tone is induced by exogenous agonists.


DiffAni: visualizing dynamic graphs with a hybrid of difference maps and animation.
Visualization of dynamically changing networks (graphs) is a significant challenge for researchers. Previous work has experimentally compared animation, small multiples, and other techniques, and found trade-offs between these. One potential way to avoid such trade-offs is to combine previous techniques in a hybrid visualization. We present two taxonomies of visualizations of dynamic graphs: one of non-hybrid techniques, and one of hybrid techniques. We also describe a prototype, called DiffAni, that allows a graph to be visualized as a sequence of three kinds of tiles: diff tiles that show difference maps over some time interval, animation tiles that show the evolution of the graph over some time interval, and small multiple tiles that show the graph state at an individual time slice. This sequence of tiles is ordered by time and covers all time slices in the data. An experimental evaluation of DiffAni shows that our hybrid approach has advantages over non-hybrid techniques in certain cases.


Future technologies for monitoring HIV drug resistance and cure.
Sensitive, scalable and affordable assays are critically needed for monitoring the success of interventions for preventing, treating and attempting to cure HIV infection. This review evaluates current and emerging technologies that are applicable for both surveillance of HIV drug resistance (HIVDR) and characterization of HIV reservoirs that persist despite antiretroviral therapy and are obstacles to curing HIV infection. Next-generation sequencing (NGS) has the potential to be adapted into high-throughput, cost-efficient approaches for HIVDR surveillance and monitoring during continued scale-up of antiretroviral therapy and rollout of preexposure prophylaxis. Similarly, improvements in PCR and NGS are resulting in higher throughput single genome sequencing to detect intact proviruses and to characterize HIV integration sites and clonal expansions of infected cells. Current population genotyping methods for resistance monitoring are high cost and low throughput. NGS, combined with simpler sample collection and storage matrices (e.g. dried blood spots), has considerable potential to broaden global surveillance and patient monitoring for HIVDR. Recent adaptions of NGS to identify integration sites of HIV in the human genome and to characterize the integrated HIV proviruses are likely to facilitate investigations of the impact of experimental 'curative' interventions on HIV reservoirs.


Activation of corticotropin-releasing factor in the limbic system during cannabinoid withdrawal.
Corticotropin-releasing factor (CRF) has been implicated in the mediation of the stress-like and negative affective consequences of withdrawal from drugs of abuse, such as alcohol, cocaine, and opiates. This study sought to determine whether brain CRF systems also have a role in cannabinoid dependence. Rats were treated daily for 2 weeks with the potent synthetic cannabinoid HU-210. Withdrawal, induced by the cannabinoid antagonist SR 141716A, was accompanied by a marked elevation in extracellular CRF concentration and a distinct pattern of Fos activation in the central nucleus of the amygdala. Maximal increases in CRF corresponded to the time when behavioral signs resulting from cannabinoid withdrawal were at a maximum. These data suggest that long-term cannabinoid administration alters CRF function in the limbic system of the brain, in a manner similar to that observed with other drugs of abuse, and also induces neuroadaptive processes that may result in future vulnerability to drug dependence.


Profiling hospitals based on emergency readmission: a multilevel transition modelling approach.
Emergency readmission is seen as an important part of the United Kingdom government policy to improve the quality of care that patients receive. In this context, patients and the public have the right to know how well different health organizations are performing. Most methods for profiling estimate the expected numbers of adverse outcomes (e.g. readmission, mortality) for each organization. A number of statistical concerns have been raised, such as the differences in hospital sizes and the unavailability of relevant data for risk adjustment. Having recognized these statistical concerns, a new framework known as the multilevel transition model is developed. Hospital specific propensities of the first, second and further readmissions are considered to be measures of performance, where these measures are used to define a new performance index. During the period 1997 and 2004, the national (English) hospital episodes statistics dataset comprise more than 5 million patient readmissions. Implementing a multilevel model using the complete population dataset could possibly take weeks to estimate the parameters. To resolve the problem, we extract 1000 random samples from the original data, where each random sample is likely to lead to differing hospital performance measures. For computational efficiency a Grid implementation of the model is developed. Analysing the output from the full 1000 sample, we noticed that 4 out of the 5 worst performing hospitals treating cancer patients were in London. These hospitals are known to be the leading NHS Trusts in England, providing diverse range of services to complex patients, and therefore it is inevitable to expect higher numbers of emergency readmissions.


Personality traits and career choices among physicians in Finland: employment sector, clinical patient contact, specialty and change of specialty.
Personality influences an individual's adaptation to a specific job or organization. Little is known about personality trait differences between medical career and specialty choices after graduating from medical school when actually practicing different medical specialties. Moreover, whether personality traits contribute to important career choices such as choosing to work in the private or public sector or with clinical patient contact, as well as change of specialty, have remained largely unexplored. In a nationally representative sample of Finnish physicians (N = 2837) we examined how personality traits are associated with medical career choices after graduating from medical school, in terms of employment sector, patient contact, medical specialty and change of specialty. Personality was assessed using the shortened version of the Big Five Inventory (S-BFI). An analysis of covariance with posthoc tests for pairwise comparisons was conducted, adjusted for gender and age with confounders (employment sector, clinical patient contact and medical specialty). Higher openness was associated with working in the private sector, specializing in psychiatry, changing specialty and not practicing with patients. Lower openness was associated with a high amount of patient contact and specializing in general practice as well as ophthalmology and otorhinolaryngology. Higher conscientiousness was associated with a high amount of patient contact and specializing in surgery and other internal medicine specialties. Lower conscientiousness was associated with specializing in psychiatry and hospital service specialties. Higher agreeableness was associated with working in the private sector and specializing in general practice and occupational health. Lower agreeableness and neuroticism were associated with specializing in surgery. Higher extraversion was associated with specializing in pediatrics and change of specialty. Lower extraversion was associated with not practicing with patients. The results showed distinctive personality traits to be associated with physicians' career and specialty choices after medical school independent of known confounding factors. Openness was the most consistent personality trait associated with physicians' career choices in terms of employment sector, amount of clinical patient contact, specialty choice and change of specialty. Personality-conscious medical career counseling and career guidance during and after medical education might enhance the person-job fit among physicians.


Dosimetric comparisons of three-dimensional conformal radiotherapy, intensity-modulated radiotherapy, and helical tomotherapy in whole abdominopelvic radiotherapy for gynecologic malignancy.
The goal of this study was to dosimetrically compare 3-dimensional radiotherapy (3DCRT), intensity-modulated radiotherapy (IMRT), and helical tomotherapy (TOMO) plans for whole abdominopelvic radiotherapy (WART) in patients with gynecologic cancer. Ten patients were selected for WART planning. Doses were prescribed to planning target volumes (PTVs) as the followings: 30 Gy to PTV-whole abdominopelvis (PTV-WA), 40 Gy to PTV-para-aortic lymph node (PTV-PALN), 44 Gy to PTV-pelvis, and 50 Gy to gross target volume (GTV) in 20 fractions. Dose to whole liver, both kidneys, and spinal cord were constrained below each tissue tolerance, and bone marrow (BM)-sparing technique was adopted in IMRT and TOMO. Dosimetric parameters and treatment times were compared among plans. Calculated doses in TOMO came most closely to the prescribed dose for coverage of PTV-WA, PTV-PALN, PTV-pelvis, and GTV compared to 3DCRT, and IMRT. In normal organs, TOMO had significantly better dosimetric profiles compared to IMRT and 3DCRT. TOMO significantly reduced V(20Gy), and mean dose of whole liver, both kidneys, and spinal cord. The use of BM-sparing technique (BMS) did not impair coverage of target volume in IMRT and TOMO. While IMRT showed no differences of irradiated BM dose using BMS, TOMO with BMS reduced half V(20Gy) of BM compared to TOMO without BMS. TOMO showed dosimetric superiority in target coverage, sparing BM, and other normal organs compared to 3DCRT and IMRT. Clinical experiences will be needed for evaluation of feasibility of WART using TOMO in patients with gynecologic cancer.


Phase I study of infusional paclitaxel in combination with the P-glycoprotein antagonist PSC 833.
PSC 833 (valspodar) is a second-generation P-glycoprotein (Pgp) antagonist developed to reverse multidrug resistance. We conducted a phase I study of a 7-day oral administration of PSC 833 in combination with paclitaxel, administered as a 96-hour continuous infusion. Fifty patients with advanced cancer were enrolled onto the trial. PSC 833 was administered orally for 7 days, beginning 72 hours before the start of the paclitaxel infusion. Paclitaxel dose reductions were planned because of the pharmacokinetic interactions known to occur with PSC 833. In combination with PSC 833, maximum-tolerated doses were defined as paclitaxel 13.1 mg/m(2)/d continuous intravenous infusion (CIVI) for 4 days without filgrastim, and paclitaxel 17.5 mg/m(2)/d CIVI for 4 days with filgrastim support. Dose-limiting toxicity for the combination was neutropenia. Statistical analysis of cohorts revealed similar mean steady-state concentrations (C(pss)) and areas under the concentration-versus-time curve (AUCs) when patients received paclitaxel doses of 13.1 or 17.5 mg/m(2)/d for 4 days with PSC 833, as when they received a paclitaxel dose of 35 mg/m(2)/d for 4 days without PSC 833. However, the effect of PSC 833 on paclitaxel pharmacokinetics varied greatly among individual patients, although a surrogate assay using CD56+ cells suggested inhibition of Pgp was complete or nearly complete at low concentrations of PSC 833. Responses occurred in three of four patients with non-small-cell lung cancer, and clinical benefit occurred in five of 10 patients with ovarian carcinoma. PSC 833 in combination with paclitaxel can be administered safely to patients provided the paclitaxel dose is reduced to compensate for the pharmacokinetic interaction. Surrogate studies with CD56+ cells indicate that the maximum-tolerated dose for PSC 833 gives serum levels much higher than those required to block Pgp. The variability in paclitaxel pharmacokinetics, despite complete inhibition of Pgp in the surrogate assay, suggests that other mechanisms, most likely related to P450, contribute to the pharmacokinetic interaction. Future development of combinations such as this should include strategies to predict pharmacokinetics of the chemotherapeutic agent. This in turn will facilitate dosing to achieve comparable CPss and AUCs.


The laminar organization of optic nerve fibres in the tectum of goldfish.
Potentials in the tectum of large (12--20 cm) goldfish, evoked by stimulation of the optic nerve, were recorded extracellularly with double-barrelled electrodes (d.c., saline and a.c., Woods metal--Pt). Four fibre groups (E, M1, M2, M3) were recorded at latencies of approximately 2, 3, 5 and 8 ms after stimulation (conduction velocities of approximately 7, 5, 3 and 2 m/s). The same four groups were recorded from the optic nerve when the tectum was stimulated. The fastest fibre groups (E) did not give rise to a postsynaptic wave. Fibre groups M1, M2 and M3 gave rise to postsynaptic potentials which, following computation of their second spatial derivatives with depth, were found to have current sinks at depths of approximately 100-150 micrometers, 150--200 micrometers and 250--350 micrometers respectively. Thus the fastest conducting retinotectal fibres make their synapses most superficially, the opposite of the arrangement in the frog tectum. These postsynaptic waves fatigued at repetitive stimulus rates of 20--50 per second, and in twin pulses at interstimulus intervals of 10--15 ms; and they were reversibly blocked by topical application of pentobarbitol. The fibre potentials, however, were virtually undecremented under these conditions. To compare these electrophysiological findings with the anatomy, the cobalt procedure was used to visualize the profiles of the optic fibres in the various tectal laminae. A thick dense projection filled the superficial grey and white (s.g.w.) layer, and there was a thin satellite band just superficial to it. In addition, there were two deeper bands of sparse innervation, in the middle of the central grey zone (c.g.) and in the deep white (d.w.) layer. These bands were associated with the field potential sinks through lesions made with recording electrodes. The two deep bands correspond to the M3 fibre group. The dense s.g.w. innervation contains both the M1 and M2 fibre groups, the M1 just superficial to the M2. The fastest fibre group, E, which had no postsynaptic wave associated with it, persisted at least six weeks after retinal removal, and probably represents efferent cells with fibres projecting back through the optic nerve to the retina. Filled cell profiles could not be positively identified with the cobalt technique, but could be seen with the HRP technique, when the optic afferents were first allowed to degenerate. The filled cells were the pyramidals of the s.g.w. layer.


Shoulder arthrodesis for treatment of flail shoulder in children with polio.
Poliomyelitis in children can cause paralysis of shoulder girdle muscles leading to a flail shoulder. Shoulder arthrodesis is indicated as a possible treatment for these children in order to stabilize the shoulder. This retrospective study reviewed all shoulder arthrodesis surgeries owing to complications of polio performed at a major medical institution between 1981 and 1996 to assess position of fusion, radiographic evidence of fusion, complications, and patient satisfaction. A review of medical records identified 11 patients undergoing 13 shoulder arthrodesis procedures, with a mean age of 14.7 years at the time of the procedure. Internal fixation was achieved with large cancellous screws in 8 patients and a Dynamic Compression Plate (DCP) plate in 5 procedures. Average follow-up period was 41 months. Eight patients were placed into a spica cast and 5 used a sling postoperatively. Shoulder arthrodesis surgery in this cohort resulted in an average position of fusion with 42.3 degrees of abduction, 23.8 degrees of flexion, and 26.2 degrees of internal rotation. Twelve of the 13 procedures assessed for radiographic union demonstrated fusion. The most common complications were malrotation and nonunion. Of the 13 procedures, 2 underwent humeral osteotomies for malrotation, and 1 with 6.5 mm cancellous screws required revision with a DCP plate owing to nonunion. Six patients underwent hardware removal, 3 of which were specifically owing to complaints of painful hardware. At final follow-up, no patient reported pain and all expressed satisfaction with their results and improved shoulder function after repair. This study is the largest series of shoulder arthrodesis surgeries for treatment of patients with a flail shoulder from polio to date, providing a more thorough analysis of its efficacy as an indicated treatment. Level III-Retrospective Comparative Study.


Impact of tobacco-control legislation.
Oncology nurses should be aware of smoking-related public health legislation and tobacco use prevention resources as well as increase their knowledge of psycho-education materials, medications, and products available to aid smoking cessation. Smoking is the leading cause of preventable death; one out of five deaths in the United States is attributed to smoking. Each day, almost 4,000 Americans younger than age 18 try their first cigarette, and 1,000 of those youths will become regular smokers. In 2009, House Resolution 1256: The Family Smoking Prevention and Tobacco Control Act gave the U.S. Food and Drug Administration the authority to regulate tobacco products with emphasis placed on prevention of the use by youth through graphic health warnings. Most states and many countries have enacted bans on smoking in all enclosed public places; however, some still allow smoking in adult-specific venues, such as bars, and some have not enacted any general statewide ban on smoking in any nongovernment-owned spaces. Oncology nurses can be instrumental in advocating for tobacco control legislation as well as providing and supporting services focused on smoking cessation and the prevention of tobacco use.


Diagnostic tests for hyperthyroidism in cats.
The diagnosis of hyperthyroidism, one of the most common disorders affecting elderly cats, is usually straightforward and considered routine by most practitioners. Nowadays, however, most cats suffering from hyperthyroidism tend to be diagnosed earlier and at a milder stage of the disease than those cats diagnosed 10 to 25 years ago. There are, in fact, a growing number of cats with clinical signs of hyperthyroidism and palpably large thyroid glands whose baseline serum total thyroid hormone concentrations are within the normal or borderline range, making diagnosis problematic. This paper reviews the available tests used to confirm a diagnosis of hyperthyroidism in cats and discusses their overall usefulness.


No Escaping the Rat Race: Simulated Night Shift Work Alters the Time-of-Day Variation in BMAL1 Translational Activity in the Prefrontal Cortex.
Millions of people worldwide work during the night, resulting in disturbed circadian rhythms and sleep loss. This may cause deficits in cognitive functions, impaired alertness and increased risk of errors and accidents. Disturbed circadian rhythmicity resulting from night shift work could impair brain function and cognition through disrupted synthesis of proteins involved in synaptic plasticity and neuronal function. Recently, the circadian transcription factor brain-and-muscle arnt-like protein 1 (BMAL1) has been identified as a promoter of mRNA translation initiation, the most highly regulated step in protein synthesis, through binding to the mRNA "cap". In this study we investigated the effects of simulated shift work on protein synthesis markers. Male rats (n = 40) were exposed to forced activity, either in their rest phase (simulated night shift work) or in their active phase (simulated day shift work) for 3 days. Following the third work shift, experimental animals and time-matched undisturbed controls were euthanized (rest work at ZT12; active work at ZT0). Tissue lysates from two brain regions (prefrontal cortex, PFC and hippocampus) implicated in cognition and sleep loss, were analyzed with m7GTP (cap) pull-down to examine time-of-day variation and effects of simulated shift work on cap-bound protein translation. The results show time-of-day variation of protein synthesis markers in PFC, with increased protein synthesis at ZT12. In the hippocampus there was little difference between ZT0 and ZT12. Active phase work did not induce statistically significant changes in protein synthesis markers at ZT0 compared to time-matched undisturbed controls. Rest work, however, resulted in distinct brain-region specific changes of protein synthesis markers compared to time-matched controls at ZT12. While no changes were observed in the hippocampus, phosphorylation of cap-bound BMAL1 and its regulator S6 kinase beta-1 (S6K1) was significantly reduced in the PFC, together with significant reduction in the synaptic plasticity associated protein activity-regulatedcytoskeleton-associated protein (Arc). Our results indicate considerable time-of-day and brain-region specific variation in cap-dependent translation initiation. We concludethat simulated night shift work in rats disrupts the pathways regulating the circadian component of the translation of mRNA in the PFC, and that this may partly explain impaired waking function during night shift work.


Self-assembly of three-dimensional ensembles of magnetic particles with laterally shifted dipoles.
We consider a model of colloidal spherical particles carrying a permanent dipole moment which is laterally shifted out of the particles' geometrical centres, i.e. the dipole vector is oriented perpendicular to the radius of the particles. Varying the shift δ from the centre, we analyse ground state structures for two, three and four hard spheres, using a simulated annealing procedure. We also compare earlier ground state results. We then consider a bulk system at finite temperatures and different densities. Using molecular dynamics simulations, we examine the equilibrium self-assembly properties for several shifts. Our results show that the shift of the dipole moment has a crucial impact on both the ground state configurations as well as the self-assembled structures at finite temperatures.


Stereoselective sulfoxidation by human flavin-containing monooxygenase. Evidence for catalytic diversity between hepatic, renal, and fetal forms.
The stereoselective formation of p-tolyl methyl sulfoxide from the corresponding sulfide has been examined in detergent-solubilized human adult liver, adult kidney, and fetal liver microsomes, in order to compare the functional activities of human flavin-containing monooxygenase(s). Solubilization with detergent was performed to eradicate the contribution that cytochrome P-450 would make to the net stereochemistry. Consistent with studies in experimental animal livers, solubilized human fetal liver and adult kidney microsomes formed (R)-p-tolyl methyl sulfoxide in greater than 86% enantiomeric excess. These enzyme activities were sensitive to methimazole inhibition and were markedly thermolabile in the absence of NADPH, attributes that are consistent with a flavin-containing monooxygenase-mediated process. However, solubilized adult human liver microsomes displayed little stereoselectivity (0-40% enantiomeric excess) for the formation of (R)-p-tolyl methyl sulfoxide, although this reaction also displayed several of the characteristics of a flavin-containing monooxygenase-dependent process, including sensitivity to methimazole inhibition and NADPH protection against heat inactivation. Furthermore, this lack of stereoselectivity was not attenuated by the inclusion of activated oxygen scavengers in reaction mixtures. Human tissue metabolite profiling was further studied by using the ethyl, propyl, and isopropyl p-tolyl sulfides. Parallel changes in product stereochemistry as a function of increasing steric bulk were observed with the fetal liver and adult kidney tissue, whereas an anomalous profile was again observed with adult human liver. These data are consistent with the presence of functionally discrete complements of the flavin-containing monooxygenase in detergent-solubilized adult and fetal human liver microsomes.


Energy transfer-based biodetection using optical nanomaterials.
Energy transfer-based biosensing is one of the most effective methods for fast and accurate biodetection. By designing appropriate energy transfer pairs as optical probes, a large diversity of analytes, ranging from small molecules to viruses, can be detected with high sensitivity and selectivity. Particularly, the development of optical nanoprobes has greatly improved the capability of energy transfer-based biosensing systems. By controlling the composition and structure of nanomaterials, both their optical characteristics and energy transfer pathways can be rationally manipulated, thereby enabling novel sensing processes. In this article, we focus on various nanomaterials as components of energy transfer probes, and review recent advances in biodetection using optical nanoprobes in different biological settings.


Possible use of repeated cold stress for reducing fatigue in chronic fatigue syndrome: a hypothesis.
Physiological fatigue can be defined as a reduction in the force output and/or energy-generating capacity of skeletal muscle after exertion, which may manifest itself as an inability to continue exercise or usual activities at the same intensity. A typical example of a fatigue-related disorder is chronic fatigue syndrome (CFS), a disabling condition of unknown etiology and with uncertain therapeutic options. Recent advances in elucidating pathophysiology of this disorder revealed hypofunction of the hypothalamic-pituitary-adrenal axis and that fatigue in CFS patients appears to be associated with reduced motor neurotransmission in the central nervous system (CNS) and to a smaller extent with increased fatigability of skeletal muscle. There is also some limited evidence that CFS patients may have excessive serotonergic activity in the brain and low opioid tone. This work hypothesizes that repeated cold stress may reduce fatigue in CFS because brief exposure to cold may transiently reverse some physiological changes associated with this illness. For example, exposure to cold can activate components of the reticular activating system such as raphe nuclei and locus ceruleus, which can result in activation of behavior and increased capacity of the CNS to recruit motoneurons. Cold stress has also been shown to reduce the level of serotonin in most regions of the brain (except brainstem), which would be consistent with reduced fatigue according to animal models of exercise-related fatigue. Finally, exposure to cold increases metabolic rate and transiently activates the hypothalamic-pituitary-adrenal axis as evidenced by a temporary increase in the plasma levels of adrenocorticotropic hormone, beta-endorphin and a modest increase in cortisol. The increased opioid tone and high metabolic rate could diminish fatigue by reducing muscle pain and accelerating recovery of fatigued muscle, respectively. To test the hypothesis, a treatment is proposed that consists of adapted cold showers (20 degrees Celsius, 3 minutes, preceded by a 5-minute gradual adaptation to make the procedure more comfortable) used twice daily. If testing supports the proposed hypothesis, this could advance our understanding of the mechanisms of fatigue in CFS.


Adult plant development in triticale (× triticosecale wittmack) is controlled by dynamic genetic patterns of regulation.
Many biologically and agronomically important traits are dynamic and show temporal variation. In this study, we used triticale (× Triticosecale Wittmack) as a model crop to assess the genetic dynamics underlying phenotypic plasticity of adult plant development. To this end, a large mapping population with 647 doubled haploid lines derived from four partially connected families from crosses among six parents was scored for developmental stage at three different time points. Using genome-wide association mapping, we identified main effect and epistatic quantitative trait loci (QTL) at all three time points. Interestingly, some of these QTL were identified at all time points, whereas others appear to only contribute to the genetic architecture at certain developmental stages. Our results illustrate the temporal contribution of QTL to the genetic control of adult plant development and more generally, the temporal genetic patterns of regulation that underlie dynamic traits.


Phylogeny of the Simbu serogroup of the genus Bunyavirus.
The Simbu serogroup of the genus Bunyavirus, family Bunyaviridae contains 25 viruses. Previous serological studies provided important information regarding some but not all of the relationships among Simbu serogroup viruses. This report describes the nucleotide sequence determination of the nucleocapsid (N) gene of the small genomic segment of 14 Simbu serogroup viruses and partial nucleotide sequence determination of the G2 glycoprotein-coding region (encoded by the medium RNA segment) of 19 viruses. The overall phylogeny of the Simbu serogroup inferred from analyses of the N gene was similar to that inferred from analyses of the G2 protein-coding region. Both analyses revealed that the Simbu serogroup viruses have evolved into at least five major phylogenetic lineages. In general, these phylogenetic lineages were consistent with the previous serological data, but provided a more detailed understanding of the relatedness amongst many viruses. In comparison to previous phylogenetic studies on the California and Bunyamwera serogroups of the Bunyavirus genus, the Simbu serogroup displays much larger genetic variation in the N gene (up to 40% amino acid sequence divergence).


Antibiotic interactions that select against resistance.
Multidrug combinations are increasingly important in combating the spread of antibiotic-resistance in bacterial pathogens. On a broader scale, such combinations are also important in understanding microbial ecology and evolution. Although the effects of multidrug combinations on bacterial growth have been studied extensively, relatively little is known about their impact on the differential selection between sensitive and resistant bacterial populations. Normally, the presence of a drug confers an advantage on its resistant mutants in competition with the sensitive wild-type population. Here we show, by using a direct competition assay between doxycycline-resistant and doxycycline-sensitive Escherichia coli, that this differential selection can be inverted in a hyper-antagonistic class of drug combinations. Used in such a combination, a drug can render the combined treatment selective against the drug's own resistance allele. Further, this inversion of selection seems largely insensitive to the underlying resistance mechanism and occurs, at sublethal concentrations, while maintaining inhibition of the wild type. These seemingly paradoxical results can be rationalized in terms of a simple geometric argument. Our findings demonstrate a previously unappreciated feature of the fitness landscape for the evolution of resistance and point to a trade-off between the effect of drug interactions on absolute potency and the relative competitive selection that they impose on emerging resistant populations.


Characterization of oligomeric assembly of colonization factor CS6 from enterotoxigenic Escherichia coli.
The widely distributed colonization factor (CF) CS6 of enterotoxigenic Escherichia coli (ETEC) has gained importance over the years in terms of its structure and function. CS6 is an afimbrial assembly in contrast to the other ETEC CFs, which are mostly fimbrial. A recent study predicted a linear fibre model for recombinant chimeric CS6 and formation of oligomers in solution. In this study, we characterized the oligomeric assembly of CS6, purified from a clinical ETEC isolate and identified its existence in the WT strain. We found that purified CS6 forms a continuous array of higher order oligomers composed of two tightly associated subunits, CssA and CssB in an equal (1:1) stoichiometry. This oligomerization occurs by formation of (CssA-CssB)n complex where 'n' increases with the concentration. The diameter of CS6 oligomers also proportionally increases with concentration. More significantly, we showed CS6 oligomers to be spherical in shape instead of being linear fibres as predicted earlier and this was further confirmed by electron microscopy. We also showed CS6 assembled on the bacterial surface in the form of an oligomeric complex. This process depends on the expression of properly folded CssA and CssB together, guided by the chaperone CssC and usher CssD. In conclusion, our results provide evidence for the existence of concentration-dependent, spherical oligomers of CS6 comprising both the structural subunits in equal stoichiometry and the CS6 oligomeric complex on the ETEC surface.


Large-scale implementation of disease control programmes: a cost-effectiveness analysis of long-lasting insecticide-treated bed net distribution channels in a malaria-endemic area of western Kenya-a study protocol.
Historically, Kenya has used various distribution models for long-lasting insecticide-treated bed nets (LLINs) with variable results in population coverage. The models presently vary widely in scale, target population and strategy. There is limited information to determine the best combination of distribution models, which will lead to sustained high coverage and are operationally efficient and cost-effective. Standardised cost information is needed in combination with programme effectiveness estimates to judge the efficiency of LLIN distribution models and options for improvement in implementing malaria control programmes. The study aims to address the information gap, estimating distribution cost and the effectiveness of different LLIN distribution models, and comparing them in an economic evaluation. Evaluation of cost and coverage will be determined for 5 different distribution models in Busia County, an area of perennial malaria transmission in western Kenya. Cost data will be collected retrospectively from health facilities, the Ministry of Health, donors and distributors. Programme-effectiveness data, defined as the number of people with access to an LLIN per 1000 population, will be collected through triangulation of data from a nationally representative, cross-sectional malaria survey, a cross-sectional survey administered to a subsample of beneficiaries in Busia County and LLIN distributors' records. Descriptive statistics and regression analysis will be used for the evaluation. A cost-effectiveness analysis will be performed from a health-systems perspective, and cost-effectiveness ratios will be calculated using bootstrapping techniques. The study has been evaluated and approved by Kenya Medical Research Institute, Scientific and Ethical Review Unit (SERU number 2997). All participants will provide written informed consent. The findings of this economic evaluation will be disseminated through peer-reviewed publications.


Steroidogenic enzyme activities, morphology, and receptor studies of a testicular adrenal rest in a patient with congenital adrenal hyperplasia.
Steroid-secreting tumors of the testis have generally been considered to be of Leydig cell origin. Testicular tumors in patients with congenital adrenal hyperplasia have been thought to be adrenal rests, but no conclusive evidence supporting the hypothesis has been presented. We report a morphological and biochemical analysis of a patient with 21-hydroxylase deficiency who developed bilateral nodular hyperplasia of steroid-secreting tissue within the testis, despite suppression therapy with both exogenous glucocorticoids and testosterone. The tissue was formed of confluent nodules of homogenous cells. Electron microscopy showed the cells to have abundant smooth endoplasmic reticulum, well developed Golgi apparatus, and mitochondria with predominantly tubular cristae, features characteristic of steroid-secreting cells of adrenocortical origin. Crystals of Reinke were not observed. Functional studies in vivo showed a marked response to ACTH infusion, with 17-hydroxyprogesterone rising from 56 to 13,500 ng/mL, cortisol from less than 2 to 19 micrograms/dL, and testosterone from 369 to 629 ng/dL, with an attendant increase in testicular size and pain over 48 h. Receptor studies in vitro revealed no gonadotropin receptors, but abundant angiotensin-II receptors. Enzyme activity analysis in vitro showed undetectable 21-hydroxylase activity and an enzyme profile consistent with adrenocortical cells rather than Leydig cells. Based on these morphological and biochemical findings, we conclude that the nodular steroidogenic tissue that replaced this patient's testes was of adrenal origin. The study documents for the first time the development of adrenocortical tumors from adrenal rest tissue within the testis.


The GLP-1 Receptor Agonist Exendin-4 and Diazepam Differentially Regulate GABAA Receptor-Mediated Tonic Currents in Rat Hippocampal CA3 Pyramidal Neurons.
Glucagon-like peptide-1 (GLP-1) is a metabolic hormone that is secreted in a glucose-dependent manner and enhances insulin secretion. GLP-1 receptors are also found in the brain where their signalling affects neuronal activity. We have previously shown that the GLP-1 receptor agonists, GLP-1 and exendin-4 enhanced GABA-activated synaptic and tonic currents in rat hippocampal CA3 pyramidal neurons. The hippocampus is the centre for memory and learning and is important for cognition. Here we examined if exendin-4 similarly enhanced the GABA-activated currents in the presence of the benzodiazepine diazepam. In whole-cell recordings in rat brain slices, diazepam (1 μM), an allosteric positive modulator of GABAA receptors, alone enhanced the spontaneous inhibitory postsynaptic current (sIPSC) amplitude and frequency by a factor of 1.3 and 1.6, respectively, and doubled the tonic GABAA current normally recorded in the CA3 pyramidal cells. Importantly, in the presence of exendin-4 (10 nM) plus diazepam (1 μM), only the tonic but not the sIPSC currents transiently increased as compared to currents recorded in the presence of diazepam alone. The results suggest that exendin-4 potentiates a subpopulation of extrasynaptic GABAA receptors in the CA3 pyramidal neurons.


The effect of peripheral blood values on prognosis of patients with locally advanced gastric cancer before treatment.
We aimed to investigate the prognostic significance of neutrophil, lymphocyte, platelet, mean platelet value (MPV), platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in patients with locally advanced gastric cancer (LAGC). One hundred sixty-eight patients with LAGC who had been followed-up between 2004 and 2008 were included in present study. The results of hematological (platelet, lymphocyte, neutrophil and MPV) and biochemical (uric acid and LDH) parameters were evaluated before treatment. NLR was divided into two groups as <2.56 and ≥2.57 and PLR was also divided into two groups as ≤160 and >160. Platelet counts and lymphocyte counts were also divided into two groups; ≤300.000/mm3 and >300.000/mm3, and <1,500/mm3 and ≥1,500/mm3, respectively. Results were evaluated with Kaplan-Meier and Long-rank tests. The mean age of patients at diagnosis was 60.1±12.1 and 114 of patients (67.8%) were male. For 168 patients, 48 months overall survival (OS) rate was 45.2% and the median OS was 39 months (range 33-44). In patients whose PLR was less than 160 (n=54), the median OS was 45 months (range 38-52) and also for cases whose PRL was greater than 160 (n=114), the median OS was 27 months (range 22-32) (p=0.006). While for fifty patients whose lymphocyte counts were less than 1,500, the median OS was 27 months (range 21-33), in cases with high lymphocyte counts (≥1,500) (n=118), it was 41 months (range 35-48) (p=0.03). The median OS was 41 (range 34-48) and 30 (range 23-37) months in two platelets groups, respectively (p=0.24). However, in the patients whose NLR was less than 2.56 (n=107), median OS was better than with cases whose NLR was greater than or equal to 2.56 (42 vs. 27 months). Routine peripheral blood counts may be useful prognostic factor for evaluating the accuracy of risk stratification in patients with radically resected gastric cancer Our results need to be confirmed by study including larger sample size in future.


Combined use of remifentanil and propofol to limit patient movement during retinal detachment surgery under local anesthesia.
One of the drawbacks of performing ophthalmic surgery under local anesthesia is patient movement, which might affect optimal surgical outcome. The study aims to evaluate the efficacy of the combined use of propofol and remifentanil as a sedative technique in comparison with the use of propofol alone to limit patient discomfort and movement during local anesthesia for vitreo-retinal surgery lasting for more than two hours. A total of 140 patients scheduled for vitreo-retinal surgery under local anesthesia, with an expected surgical time of more than two hours, were included in the study. Patients were divided randomly into two equal groups: group I where patients were given propofol and remifentanil by continuous infusion and group II where patients were given propofol alone by continuous infusion. The two groups were comparable with regard to age, weight, gender, ASA physical status and duration of surgery. There was a significant decrease in heart rate and mean arterial blood pressure (MABP) in each group 10 minutes after the start of sedation compared with pre-sedation data and continued all through the procedure. There was an insignificant difference between the two groups with regard to changes in heart rate and MABP all through surgical procedure. There was no significant difference between the two groups with regard to the incidence of complications except for an increased incidence of breakthrough pain and discomfort which necessitated the use of fentanyl as a rescue treatment in the propofol group P<0.001. There were no instances of movements with a major effect on the surgical field, which could have affected surgical outcome, in the two groups. The number of patients who did not move was significantly higher, 56 (80%), in group I compared with 38 (54.29%) in group II with P<0.001. The ophthalmologist satisfaction scale was significantly higher in group I (4.5±0.63) compared with group II (3.7±1.04) with P=0.0016. The combined use of propofol and remifentanil as a continuous infusion before performance of the block and during lengthy vitreo-retinal surgery was associated with a lower incidence of patient discomfort, breakthrough pain, and patient movement along with high degree of surgeons' satisfaction and hemodynamic stability.


Injuries from non-retention in gillnet fisheries suppress reproductive maturation in escaped fish.
Exploitation of fisheries resources has unintended consequences, not only in the bycatch and discard of non-target organisms, but also in damage to targeted fish that are injured by gear but not landed (non-retention). Delayed mortality due to non-retention represents lost reproductive potential in exploited stocks, while not contributing to harvest. Our study examined the physiological mechanisms by which delayed mortality occurs and the extent to which injuries related to disentanglement from commercial gear compromise reproductive success in spawning stocks of Pacific salmon (Oncorhynchus spp.). We found evidence for elevated stress in fish injured via non-retention in gillnet fisheries. Plasma cortisol levels correlated with the severity of disentanglement injury and were elevated in fish that developed infections related to disentanglement injuries. We also analyzed sex steroid concentrations in females (estradiol-17β and 17,20β-dihydroxy-4-pregnen-3-one) to determine whether non-retention impairs reproductive potential in escaped individuals. We demonstrate evidence for delayed or inhibited maturation in fish with disentanglement injuries. These findings have important implications for effective conservation and management of exploited fish stocks and suggest means to improve spawning success in such stocks if retention in commercial fisheries is improved and incidental mortality reduced.


Pre- and post-test evaluation of a project to facilitate research development in practice in a hospital setting.
This paper describes a project designed to facilitate the use of research in nursing practice in one acute hospital. A university team worked in collaboration with staff from the hospital to develop and evaluate the impact of development work designed to enhance knowledge and use of research in practice. A research utilization questionnaire was administered as a pre-test (stage 1); a development phase was implemented (stage 2) and a post-test survey (stage 3) was administered to evaluate the impact of the development work. In stage 1, the total population of nursing and midwifery staff in the hospital (n=473) were targeted and 235 returned the questionnaire, giving a response rate of 50%. Data from the pre-test and focus group discussions with staff were used to plan stage 2 of the project. The development stage involved an educational strand in which open learning research materials were made available to staff, who were also offered tutorial support in their learning. A second strand supported the development of clinical research projects and funds were identified for clinical staff to apply for project development awards to enable them to develop skills in research and development activity under the supervision of a research fellow. Stage 3 involved a post-test survey of staff who had completed the questionnaire in stage 1 (n=81). There were no significant differences in findings between the pre-test and post-test. Qualitative data from those involved in the clinical projects in stage 2 indicated factors impacting on the feasibility of undertaking research in practice.


Withholding/withdrawing treatment from neonates: legislation and official guidelines across Europe.
Representatives from eight European countries compared the legal, ethical and professional settings within which decision making for neonates takes place. When it comes to limiting treatment there is general agreement across all countries that overly aggressive treatment is to be discouraged. Nevertheless, strong emphasis has been placed on the need for compassionate care even where cure is not possible. Where a child will die irrespective of medical intervention, there is widespread acceptance of the practice of limiting aggressive treatment or alleviating suffering even if death may be hastened as a result. Where the infant could be saved but the future outlook is bleak there is more debate, but only two countries have tested the courts with such cases. When it comes to the active intentional ending of life, the legal position is standard across Europe; it is prohibited. However, recognising those intractable situations where death may be lingering and unpleasant, Dutch paediatricians have reported that they do sometimes assist babies to die with parental consent. Two cases have been tried through the courts and recent official recommendations have set out standards by which such actions may be assessed.


Unraveling cellular phenotypes of novel TorsinA/TOR1A mutations.
A three-nucleotide (GAG) deletion (ΔE) in TorsinA (TOR1A) has been identified as the most common cause of dominantly inherited early-onset torsion dystonia (DYT1). TOR1A encodes a chaperone-like AAA+-protein localized in the endoplasmic reticulum. Currently, only three additional, likely mutations have been reported in single dystonia patients. Here, we report two new, putative TOR1A mutations (p.A14_P15del and p.E121K) that we examined functionally in comparison with wild-type (WT) protein and two known mutations (ΔE and p.R288Q). While inclusion formation is a characteristic feature for ΔE TOR1A, elevated levels of aggregates for other mutations were not observed when compared with WT TOR1A. WT and mutant TOR1A showed preferred degradation through the autophagy-lysosome pathway, which is most pronounced for p.A14_P15del, p.R288Q, and ΔE TOR1A. Notably, blocking of the autophagy pathway with bafilomycin resulted in a significant increase in inclusion formation in p.E121K TOR1A. In addition, all variants had an influence on protein stability. Although the p.A14_P15del mutation affects the proposed oligomerization domain of TOR1A, this mutation did not disturb the ability to dimerize. Our findings demonstrate functional changes for all four mutations on different levels. Thus, both diagnostic and research genetic screening of dystonia patients should not be limited to testing for the ∆E mutation.


The health and wellbeing of Australian lesbian, gay and bisexual people: a systematic assessment using a longitudinal national sample.
This study revisits disparities in health and wellbeing by sexual identity in Australia, identifying which domains demand priority policy intervention, documenting differences between gay/lesbian vs. bisexual populations, and examining change over time in the relative health and wellbeing of sexual minorities. I fitted multivariable ordinary least squares and random-effect panel regression models on 20 outcomes to compare the health and wellbeing of heterosexual, gay/lesbian and bisexual people, using 2012/2016 data from a national probability sample - the Household, Income and Labour Dynamics in Australia (HILDA) Survey. I found strong associations between sexual minority identities and most health and wellbeing outcomes. These were comparatively larger for: role-emotional health, mental health and general health; bisexual compared to gay/lesbian people; and minority women compared to minority men. I found no change over time in the relative health and wellbeing outcomes of gay/lesbian people, but evidence of worsening circumstances among bisexual people. There are important disparities in the health and wellbeing profiles of different sexual minority populations in Australia, based on sex (male vs. female), sexual identity (gay/lesbian vs. bisexual), and observation time (2012 vs. 2016). Implications for public health: Sexual identity remains an important marker of risk for health and wellbeing outcomes within Australia, underscoring the importance of fully integrating sexual identity in health policy and practice.