The martian surface.
With the scarcity of factual data and the difficulty of applying crucial tests, many of the properties of the Martian surface remain a mystery; the planet may become a source of great surprises in the future. In the following, the conclusions are enumerated more or less in the order of their reliability, the more certain ones first, conjectures or ambiguous interpretations coming last. Even if they prove to be wrong, they may serve as a stimulus for further investigation. Impact craters on Mars, from collisions with nearby asteroids and other stray bodies, were predicted 16 years ago (5-7) and are now verified by the Mariner IV pictures. The kink in the frequency curve of Martian crater diameters indicates that those larger than 20 kilometers could have survived aeolian erosion since the "beginning." They indicate an erosion rate 30 times slower than that in terrestrial deserts and 70 times faster than micrometeorite erosion on the moon. The observed number, per unit area, of Martian craters larger than 20 kilometers exceeds 4 times that calculated from the statistical theory of interplanetary collisions with the present population of stray bodies and for a time interval of 4500 million years, even when allowance is made for the depletion of the Martian group of asteroids, which were more numerous in the past. This, and the low eroded rims of the Martian craters suggest that many of the craters have survived almost since the formation of the crust. Therefore, Mars could not have possessed a dense atmosphere for any length of time. If there was abundant water for the first 100 million years or so, before it escaped it could have occurred only in the solid state as ice and snow, with but traces of vapor in the atmosphere, on account of the low temperature caused by the high reflectivity of clouds and snow. For Martian life there is thus the dilemma: with water, it is too cold; without, too dry. The crater density on Mars, though twice that in lunar maria, is much smaller than the "saturation density" of lunar highlands. Many primeval craters, those from the last impacts which formed the planet, must have become erased, either by late impacts of preferentially surviving large asteroids or by a primeval atmosphere which rapidly escaped. The tenuous Martian atmosphere may have originated entirely from outgassing of surface rocks by asteroidal impacts, which also could have produced some molten lava. The role of genuine volcanism on Mars must have been insignificant, if any. The large amplitude in temperature indicates that the Martian upper soil, equally in the bright and the dark areas, is of a porous unconsolidated structure, with a thermal conductivity as low as that of atmospheric air. Limb darkening at full phase in green, yellow, and red light indicates absorption by atmospheric haze, aerosols, and dust. The loss of contrast in the blue and violet is caused by stronger absorptivity of the haze, which is almost as dark as soot, and not by a true decrease in contrast of the surface markings. Photometric measurementsin the blue reveal a residual contrast of 5 to 7 percent between the markings in 1958, invisible to the eye at a time when there was no "blue clearing." The surface brightness of the maria was surprisingly uniform in 1958 (late summer in the southern hemisphere), while the continentes showed considerable variation. In view of the spotty microstructure of the Martian surface as revealed by Mariner IV, and the lack of a sharp border between a mare and a continens, it seems that all the difference consists in the relative number of small dark and bright areas in the surface mosaic. If there is vegetation on Mars, it should be concentrated in the darkarea elements, measuring 10 to 100 kilometers. Vegetation is the best hypothesis to account for seasonal changes in the maria and for the persistence of these formations despite dust storms of global extent. Survival of vegetation in the extreme dryness of the Martian climate could depend on the low night-time temperature and deposition of hoarfrost, which could melt into droplets after sunrise, before evaporating. If not vegetation, it must be something thing specifically Martian; no other hypothesis hitherto proposed is able to account for the facts. However, the infrared bands which at one time were thought to be associated with the presence of organic matter, belong to heavy water in the terrestrial atmosphere. The conversion of a former bright area into a dark one in 1954, over some 1 million square kilometers, is the largest recorded change of this kind. Even on the vegetation hypothesis, it eludes satisfactory explanation. Relatively bright areas observed in the blue and violet in polar regions and elsewhere on the limb can be explained by a greater transparency of the atmosphere,its dust content being decreased by a downward (anticyclonic) current. The surface, of a greater reflecting power than the atmospheric smoke, then becomes visible. The sudden explosion-like occurrence of yellow or gray clouds, reducing atmospheric transparency and surface contrast, could be due to impacts of asteroids; in such a case, however, the number of unobservable small asteroids, down to 30 to 40 meters in diameter, should greatly exceed the number extrapolated from the larger members of the group. A "meteoritic" increment in numbers, instead of the asteroidal one, would be required. special observations with large Schmidt telescopes could settle this crucial question. The Martian "oases," centers of "canal" systems, could be impact creters. The canals may be real formations, without sharp borders and 100 to 200 kilometers wide, due to a systematic alignment. of the dark surface elements. They may indicate cracks in the planet's crust, radiating from the point of impact.


Longitudinal assessment of neuroanatomical and cognitive differences in young children with type 1 diabetes: association with hyperglycemia.
Significant regional differences in gray and white matter volume and subtle cognitive differences between young diabetic and nondiabetic children have been observed. Here, we assessed whether these differences change over time and the relation with dysglycemia. Children ages 4 to <10 years with (n = 144) and without (n = 72) type 1 diabetes (T1D) had high-resolution structural MRI and comprehensive neurocognitive tests at baseline and 18 months and continuous glucose monitoring and HbA1c performed quarterly for 18 months. There were no differences in cognitive and executive function scores between groups at 18 months. However, children with diabetes had slower total gray and white matter growth than control subjects. Gray matter regions (left precuneus, right temporal, frontal, and parietal lobes and right medial-frontal cortex) showed lesser growth in diabetes, as did white matter areas (splenium of the corpus callosum, bilateral superior-parietal lobe, bilateral anterior forceps, and inferior-frontal fasciculus). These changes were associated with higher cumulative hyperglycemia and glucose variability but not with hypoglycemia. Young children with T1D have significant differences in total and regional gray and white matter growth in brain regions involved in complex sensorimotor processing and cognition compared with age-matched control subjects over 18 months, suggesting that chronic hyperglycemia may be detrimental to the developing brain.


Renal lymphoma: MR appearance with diffusion-weighted imaging.
Imaging of renal lymphoma on magnetic resonance imaging and diffusion-weighted imaging is not well documented in the literature. We present a case of renal lymphoma in a 61-year-old patient with computed tomography and magnetic resonance imaging correlation. The lymphomatous lesions demonstrate mild enhancement and restricted diffusion. Differential considerations for hypoenhancing masses include papillary or chromophobe renal cell carcinoma, lymphoma, urothelial tumor, or metastasis, all of which have different management pathways. Apparent diffusion coefficient values can be obtained using diffusion-weighted imaging, and may be useful in identifying focal renal lesions, especially on noncontrast imaging. Apparent diffusion coefficient values may be helpful in differentiating between some of these lesions, although more investigation is needed.


Elevated alcohol consumption among geriatric psychiatric in-patients.
Although a clear relationship has been established between elevated alcohol consumption and psychiatric problems in old age, there are few descriptions of the prevalence of elevated alcohol consumption in older adults who have been referred to geriatric psychiatric treatment. To describe the prevalence of self-reported elevated alcohol consumption in men and women referred to geriatric psychiatry wards in Norway, and to explore factors associated with elevated alcohol consumption. This cross-sectional study includes data from a registry of geriatric psychiatry patients aged ≥ 65 years from December 2016 until December 2018. The outcome measure was reported elevated alcohol consumption assessed with the short version of the Alcohol Use Disorders Identification Test (AUDIT-C). The analyses used demographic data as well as a measure of cognitive function, psychiatric diagnosis and use of psychotropic drugs. In total, 367 patients (131, 35.7% men) with a mean (SD) age of 74.7 (7.6) years were included. Of these patients, 27% scored above the pre-set cut-off for elevated alcohol consumption according to AUDIT-C (≥ 3 and 4 for women and men, respectively). The prevalence of elevated alcohol did not differ by gender. In adjusted logistic regression analysis, older age, living with someone and use of antidepressants were associated with reduced odds for reporting elevated alcohol consumption (OR 0.93, 95% CI 0.89-0.96; OR 0.54, 95% CI 0.31-0.97; and 0.54, 95% CI 0.32-0.92, respectively). A relatively high proportion of psychiatric patients aged 65 years or older reported elevated alcohol consumption, regardless of diagnosis. Older age, living with someone and use of antidepressants were associated with lower odds for elevated alcohol consumption.


Early repolarization of surface ECG predicts fatal ventricular arrhythmias in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy and symptomatic ventricular arrhythmias.
The clinical characteristics and prognostic value of early repolarization (ER) in patients with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) and symptomatic ventricular arrhythmias remain unclear. We investigated the prevalence, clinical features, and cardiovascular outcomes of patients with symptomatic ARVD/C and ER. A total of 59 consecutive ARVD/C patients hospitalized for catheter ablation, presenting with and without J-point elevations of ≥0.1mV in at least 2 inferior leads or lateral leads were enrolled. Clinical characteristics, electrophysiological study, substrate mapping, catheter ablation, and future clinical outcomes in a prospective patient registry were investigated. ER was observed in 38 patients (64.4%). Among these patients, ER was found in the inferior leads in 18 patients (47.4%), in the lateral leads in 2 patients (5.3%), and in both inferior and lateral leads in 18 patients (47.4%). Patients exhibiting ER were commonly men, had lower right ventricular ejection fraction, had higher incidence of clinical ventricular fibrillation or aborted sudden cardiac death, had more defibrillator implantations, had higher the need of epicardial ablation, and had more major criteria according to the task force criteria. Significant higher incidence of induced ventricular fibrillation and shorter tachycardia cycle length of induced ventricular tachycardia were found during procedure. The recurrence rate of ventricular arrhythmias did not differ between patients with and without ER after catheter ablation. A high prevalence of electrocardiographic ER was found among symptomatic ARVD/C patients undergoing catheter ablation. ER in 12-lead ECG is associated with an increased risk of clinical fatal ventricular arrhythmias.


GUS and PMM1 as suitable reference genes for gene expression analysis in the liver tissue of patients with chronic hepatitis.
The proper application of quantitative real-time reverse transcription polymerase chain reaction (RT-PCR) for the relative quantification of a target gene in gene profiling studies requires reference genes to normalize sample variations. Stable housekeeping genes for this purpose have never been investigated in the liver tissue of patients with chronic hepatitis. Expression profiles of six functionally distinct housekeeping genes (ACTB, CYCC, GUS, HPRT1, PMM1, POLR2L) were examined by RT-PCR in liver specimens from 12 individuals with chronic hepatitis C or B. Two software programs, geNorm and NormFinder, were used to assess the expression stability of the studied genes. Crossing-point values of the candidate reference genes were recorded between 22 and 28. In three groups of patients (all patients, HCV patients, HBV patients) both programs identified GUS as the most stably expressed housekeeping gene (stability values: 0.275-0.360 and 0.095-0.107 determined by geNorm and NormFinder, respectively), followed by PMM1 (0.275-0.360 and 0.168-0.227), and POLR2L (0.347-0.397 and 0.319-0.388). The genes GUS and PMM1 are recommended for normalization purposes in gene expression studies of liver tissue from patients with chronic hepatitis C or B. Using these genes in combination will ensure very reliable results.


Iron-ion radiation accelerates atherosclerosis in apolipoprotein E-deficient mice.
Radiation exposure from a number of terrestrial sources is associated with an increased risk for atherosclerosis. Recently, concern over whether exposure to cosmic radiation might pose a similar risk for astronauts has increased. To address this question, we examined the effect of 2 to 5 Gy iron ions ((56)Fe), a particularly damaging component of cosmic radiation, targeted to specific arterial sites in male apolipoprotein E-deficient (apoE(-/-)) mice. Radiation accelerated the development of atherosclerosis in irradiated portions of the aorta independent of any systemic effects on plasma lipid profiles or circulating leukocytes. Further, radiation exposure resulted in a more rapid progression of advanced aortic root lesions, characterized by larger necrotic cores associated with greater numbers of apoptotic macrophages and reduced lesional collagen compared to sham-treated mice. Intima media thickening of the carotid arteries was also exacerbated. Exposure to (56)Fe ions can therefore accelerate the development of atherosclerotic lesions and promote their progression to an advanced stage characterized by compositional changes indicative of increased thrombogenicity and instability. We conclude that the potential consequences of radiation exposure for astronauts on prolonged deep-space missions are a major concern. Knowledge gained from further studies with animal models should lead to a better understanding of the pathophysiological effects of accelerated ion radiation to better estimate atherogenic risk and develop appropriate countermeasures to mitigate its damaging effects.


Hyponatraemia, rhabdomyolysis, alterations in blood pressure and persistent mydriasis in patients envenomed by Malayan kraits (Bungarus candidus) in southern Viet Nam.
Between 1998 and 2007, 42 patients admitted to Choray hospital, Ho Chi Minh City, and to two hospitals in adjacent regions in southern Viet Nam brought the Malayan kraits (Bungarus candidus) that had been responsible for biting them. Half of the patients had been bitten while they were asleep. Fang marks and numbness were the only local features of the bites. Common signs of neurotoxic envenoming included bilateral ptosis, persistently dilated pupils, limb weakness, breathlessness, hypersalivation, dysphonia and dysphagia. Thirty patients (71.4%) required endotracheal intubation of whom all but one were mechanically ventilated. Fourteen patients (33.3%) developed hypertension, 13 (31.0%) shock, 31 (73.8%) hyponatraemia (plasma sodium concentration < 130 mEq/l) and 30 (71.4%) showed evidence of mild rhabdomyolysis (peak plasma creatine kinase concentration 1375 +/- 140 micro/l). None developed acute kidney injury. All the patients were treated with a new monospecific B. candidus antivenom. There were no fatalities. Hyponatraemia has been reported previously in victims of Chinese kraits (Bungarus multicinctus) in northern Viet Nam and rhabdomyolysis in patients envenomed by B. niger in Bangladesh. These features of envenoming pose new problems for the management of krait bite cases in South east Asia and should stimulate a search for the causative venom toxins.


Bone mineral density in patients with type 1 and type 2 diabetes.
To assess the effect of type 1 and type 2 diabetes and insulin treatment on bone mineral density (BMD) in middle-aged and elderly men and women. We measured BMD and evaluated known determinants of osteoporosis in 56 type 1 and 68 type 2 diabetic patients and 498 nondiabetic community control subjects. All patients, aged 52-72 years, developed diabetes after the age of 30 years (i.e., after achievement of peak bone mass) and were treated with insulin. BMD was measured at the proximal femur with dual-energy X-ray absorptiometry. Among both sexes, BMD values were significantly lower in type 1 diabetic patients than in type 2 diabetic patients or the control subjects. When adjusted for age and BMI, the differences between type 1 diabetic patients and control subjects remained essentially unchanged in both sexes, whereas the differences between type 1 and type 2 diabetic subjects were significant only in men. After further adjustments for confounding factors, the average BMD values were still lower in type 1 diabetic subjects than in type 2 diabetic subjects although with lesser significance. Past low-energy fractures were more common in type 1 diabetic women than in type 2 diabetic women. The lower BMD in type 1 versus type 2 diabetic patients and control subjects probably results from more rapid bone loss after the onset of type 1 diabetes. This cannot be explained by insulin treatment, which was prescribed for both types of patients. Because the causes of low BMD in type 1 diabetes are unknown, these patients should be evaluated for the risk of osteoporosis and related fractures and offered appropriate preventive measures.


Cultural differences in conceptual models of depression.
Members of ethnic minority groups are less likely than white middle class people to seek professional treatment for depression and other mental health problems. One explanation is that the former conceptualize depressive symptoms as social problems or emotional reactions to situations, while the latter are more apt to view depression as a disease requiring professional treatment. Though considerable evidence supports this hypothesis, it is rarely explored directly through cross-cultural comparisons. The present study compares conceptual models of depressive symptoms in two diverse cultural groups in New York City (USA): 36 South Asian (SA) immigrants and 37 European Americans (EA) were presented with a vignette describing depressive symptoms and participated in a semi-structured interview designed to elicit representational models of the symptoms. Results indicate pervasive differences in representational models across the two groups. SA participants identified the "problem" in the vignette in largely social and moral terms. Suggestions for management and health seeking in this group emphasized self-management and lay referral strategies. EAs, by contrast, often proposed alternate, sometimes contradictory, explanatory models for the depressive symptoms. One model emphasized biological explanations ranging from "hormonal imbalance" to "neurological problem." The second model resembled the "situational stress" or "life problem" model described by SAs. The implications of these findings, and directions for future research, are discussed.


Apple Polysaccharide inhibits microbial dysbiosis and chronic inflammation and modulates gut permeability in HFD-fed rats.
The saying "An apple a day keeps the doctor away" has been known for over 150 years, and numerous studies have shown that apple consumption is closely associated with reduced risks of chronic diseases. It has been well accepted that dysbiosis is the reflection of various chronic diseases. Therefore, this study investigates the effects of apple polysaccharides (AP) on gut dysbiosis. High-fat diet (HFD) fed rats were treated for 14 weeks with AP. The microbiota composition, microbiota-generated short chain fatty acids (SCFAs), gut permeability and chronic inflammation were analyzed. AP treatment showed higher abundance of Bacteroidetes and Lactobacillus while lower Firmicutes and Fusobacteium. AP significantly increased total SCFAs level that contributed by acetic acid and isobutyric acid. Moreover, AP dramatically alleviated dysbiosis-associated gut permeability and chronic inflammation with decreased plasma LBP, up-regulation of Occludin, down-regulation of tumor necrosis factor a (TNF-a), monocyte chemotactic protein 1 (MCP-1), chemokine ligand 1 (CXCL-1) and interleukin 1 beta (IL-1β). The potential mechanism is due to the fact that AP reduces gut permeability, which involves the induction of autophagy in goblet cells. Therefore, AP exerts health benefits through inhibiting gut dysbiosis and chronic inflammation and modulating gut permeability in HFD-induced dysbiosis rats.


The theoretical and political framing of the population factor in development.
The silence about population growth in recent decades has hindered the ability of those concerned with ecological change, resource scarcity, health and educational systems, national security, and other global challenges to look with maximum objectivity at the problems they confront. Two central questions about population--(1) is population growth a problem? and (2) what causes fertility decline?--are often intertwined; if people think the second question implies possible coercion, or fear of upsetting cultures, they can be reluctant to talk about the first. The classic and economic theories explaining the demographic transition assume that couples want many children and they make decisions to have a smaller family when some socio-economic change occurs. However, there are numerous anomalies to this explanation. This paper suggests that the societal changes are neither necessary nor sufficient for family size to fall. Many barriers of non-evidence-based restrictive medical rules, cost, misinformation and social traditions exist between women and the fertility regulation methods and correct information they need to manage their family size. When these barriers are reduced, birth rates tend to decline. Many of the barriers reflect a patriarchal desire to control women, which can be largely explained by evolutionary biology. The theoretical explanations of fertility should (i) attach more weight to the many barriers to voluntary fertility regulation, (ii) recognize that a latent desire to control fertility may be far more prevalent among women than previously understood, and (iii) appreciate that women implicitly and rationally make benefit-cost analyses based on the information they have, wanting modern family planning only after they understand it is a safe option. Once it is understood that fertility can be lowered by purely voluntary means, comfort with talking about the population factor in development will rise.


Prediction of Pig Trade Movements in Different European Production Systems Using Exponential Random Graph Models.
In most European countries, data regarding movements of live animals are routinely collected and can greatly aid predictive epidemic modeling. However, the use of complete movements' dataset to conduct policy-relevant predictions has been so far limited by the massive amount of data that have to be processed (e.g., in intensive commercial systems) or the restricted availability of timely and updated records on animal movements (e.g., in areas where small-scale or extensive production is predominant). The aim of this study was to use exponential random graph models (ERGMs) to reproduce, understand, and predict pig trade networks in different European production systems. Three trade networks were built by aggregating movements of pig batches among premises (farms and trade operators) over 2011 in Bulgaria, Extremadura (Spain), and Côtes-d'Armor (France), where small-scale, extensive, and intensive pig production are predominant, respectively. Three ERGMs were fitted to each network with various demographic and geographic attributes of the nodes as well as six internal network configurations. Several statistical and graphical diagnostic methods were applied to assess the goodness of fit of the models. For all systems, both exogenous (attribute-based) and endogenous (network-based) processes appeared to govern the structure of pig trade network, and neither alone were capable of capturing all aspects of the network structure. Geographic mixing patterns strongly structured pig trade organization in the small-scale production system, whereas belonging to the same company or keeping pigs in the same housing system appeared to be key drivers of pig trade, in intensive and extensive production systems, respectively. Heterogeneous mixing between types of production also explained a part of network structure, whichever production system considered. Limited information is thus needed to capture most of the global structure of pig trade networks. Such findings will be useful to simplify trade networks analysis and better inform European policy makers on risk-based and more cost-effective prevention and control against swine diseases such as African swine fever, classical swine fever, or porcine reproductive and respiratory syndrome.


Different neural networks are involved in audiovisual speech perception depending on the context.
How are we able to easily and accurately recognize speech sounds despite the lack of acoustic invariance? One proposed solution is the existence of a neural representation of speech syllable perception that transcends its sensory properties. In the present fMRI study, we used two different audiovisual speech contexts both intended to identify brain areas whose levels of activation would be conditioned by the speech percept independent from its sensory source information. We exploited McGurk audiovisual fusion to obtain short oddball sequences of syllables that were either (a) acoustically different but perceived as similar or (b) acoustically identical but perceived as different. We reasoned that, if there is a single network of brain areas representing abstract speech perception, this network would show a reduction of activity when presented with syllables that are acoustically different but perceived as similar and an increase in activity when presented with syllables that are acoustically similar but perceived as distinct. Consistent with the long-standing idea that speech production areas may be involved in speech perception, we found that frontal areas were part of the neural network that showed reduced activity for sequences of perceptually similar syllables. Another network was revealed, however, when focusing on areas that exhibited increased activity for perceptually different but acoustically identical syllables. This alternative network included auditory areas but no left frontal activations. In addition, our findings point to the importance of subcortical structures much less often considered when addressing issues pertaining to perceptual representations.


Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide.
Longitudinal bone growth is determined by the process of endochondral ossification in the cartilaginous growth plate, which is located at both ends of vertebrae and long bones and involves many systemic hormones and local regulators. Natriuretic peptides organize a family of three structurally related peptides: atrial natriuretic peptide, brain natriuretic peptide (BNP), and C-type natriuretic peptide. Atrial natriuretic peptide and BNP are cardiac hormones that are produced predominantly by the atrium and ventricle, respectively. C-type natriuretic peptide occurs in a wide variety of tissues, where it acts as a local regulator. These peptides can influence body fluid homeostasis and blood pressure control through the activation of two guanylyl cyclase (GC)-coupled natriuretic peptide receptor subtypes-GC-A and GC-B. We report here marked skeletal overgrowth in transgenic mice that overexpress BNP. Transgenic mice with elevated plasma BNP concentrations exhibited deformed bony skeletons characterized by kyphosis, elongated limbs and paws, and crooked tails. Bone abnormalities resulted from a high turnover of endochondral ossification accompanied by overgrowth of the growth plate. Studies using an in vitro organ culture of embryonic mouse tibias revealed that BNP increases the height of cartilaginous primordium directly, thereby stimulating the total longitudinal bone growth. The present study demonstrates that natriuretic peptides can affect the process of endochondral ossification.


Targeting the mercapturic acid pathway and vicenin-2 for prevention of prostate cancer.
Prostate cancer (CaP) is often androgen-sensitive malignancy and regresses upon inhibition of androgen signaling. However, CaP, nearly always develops androgen resistance and progresses to aggressive and lethal androgen-independent CaP, which lacks satisfactory therapy. For metastatic CaP, patients are often treated with Taxotere (docetaxel), a cytoskeleton-targeted chemotherapy drug, that provides transient palliative benefit but to which patients rapidly develop drug-resistance. Combination chemotherapy may be used instead, but is more toxic and adds little clinically relevant benefit over docetaxel. Therefore, novel strategies to enhance docetaxel efficacy are needed to effectively treat patients with metastatic CaP. The mercapturic acid pathway, which metabolizes genotoxic and pro-apoptotic toxins, is over-expressed in CaP and plays an important role in carcinogenesis, metastasis and therapy-resistance of CaP. Vicenin-2, a flavonoid derived from Tulsi (holy basil) as an active compound, inhibits the growth of CaP and increases the anti-tumor activity of docetaxel in-vitro and in-vivo. Taken together, the combination of vicenin-2 and docetaxel could be highly effective in the treatment of advanced and metastatic CaP due to their multi-targeting anti-tumor potential.


Use of Chinese hamster ovary cells with altered glycosylation patterns to define the carbohydrate specificity of Entamoeba histolytica adhesion.
We compared the adherence of E. histolytica trophozoites with a panel of lectin-resistant CHO mutants with altered glycosylation patterns. Our results coupled with data from saccharide inhibition studies indicate that terminal N-acetyllactosamine units on Asn-linked complex type oligosaccharides provide the major determinants on the cellular receptor for E. histolytica adhesion.


Providing recurrence risk counselling for parents after diagnosis of a serious genetic condition caused by an apparently de novo mutation in their child: a qualitative investigation of the PREGCARE strategy with UK clinical genetics practitioners.
Diagnosis of a child with a genetic condition leads to parents asking whether there is a risk the condition could occur again with future pregnancies. If the cause is identified as an apparent de novo mutation (DNM), couples are currently given a generic, population average, recurrence risk of ~1%-2%, depending on the condition. Although DNMs usually arise as one-off events, they can also originate through the process of mosaicism in either parent; in this instance, the DNM is present in multiple germ cells and the actual recurrence risk could theoretically be as high as 50%. Our qualitative interview study examined the views and reflections on current practice provided by UK practitioners working in clinical genetics (n=20) regarding the potential impact of PREcision Genetic Counselling And REproduction (PREGCARE)-a new preconception personalised recurrence risk assessment strategy. Those interviewed regarded PREGCARE as a very useful addition to risk management, especially for cases where it revised the risk downwards or clarified that a couple's personalised recurrence risk meets National Health Service thresholds for non-invasive prenatal testing, otherwise inaccessible based on the generic DNM recurrence risk. Participants said it could release some couples requiring reassurance from undergoing unnecessary invasive testing in future pregnancies. However, they regarded mosaicism and PREGCARE as complex concepts to communicate, requiring further training and additional appointment time for pre-test genetic counselling to prepare couples for all the possible outcomes of a personalised risk assessment, including potentially identifying the parental origin of the DNM, and to ensure informed consent.


Genetic influences in the aetiology of femoroacetabular impingement: a sibling study.
Femoroacetabular impingement causes pain in the hip in young adults and may predispose to the development of osteoarthritis. Genetic factors are important in the aetiology of osteoarthritis of the hip and may have a role in that of femoroacetabular impingement. We compared 96 siblings of 64 patients treated for primary impingement with a spouse control group of 77 individuals. All the subjects were screened clinically and radiologically using a standardised protocol for the presence of cam and pincer deformities and osteoarthritis. The siblings of those patients with a cam deformity had a relative risk of 2.8 of having the same deformity (66 of 160 siblings hips versus 23 of 154 control hips, p < 0.00001). The siblings of those patients with a pincer deformity had a relative risk of 2.0 of having the same deformity (43 of 116 sibling hips versus 29 of 154 control hips, p = 0.001). Bilateral deformity occurred more often in the siblings (42 of 96 siblings versus 13 of 77 control subjects, relative risk 2.6, p = 0.0002). The prevalence of clinical features in those hips with abnormal morphology was also greater in the sibling group compared with the control group (41 of 109 sibling hips versus 7 of 46 control hips, relative risk 2.5, p = 0.007). In 11 sibling hips there was grade-2 osteoarthritis according to Kellgren and Lawrence versus none in the control group (p = 0.002). Genetic influences are important in the aetiology of primary femoroacetabular impingement. This risk appears to be manifested through not only abnormal joint morphology, but also through other factors which may modulate progression of the disease.


Influence of anesthetics on metabolic, functional and pathological responses to regional cerebral ischemia.
Regional cerebral ischemia was produced by common carotid artery occlusion in gerbils and by middle cerebral artery occlusion in dogs, cats, and squirrel monkeys. Anesthesia was induced with either pentobarbital or halothane and maintained for two to three hours after vessel occlusion. In acute studies, the effect of regional cerebral ischemia on cerebral concentrations of ATP, phosphocreatine, lactate, and pyruvate was determined at the end of this period in gerbils, cats, and squirrel monkeys. In chronic studies, the degree of neurological deficit and size of cerebral infarction were determined 48 hours after a two-hour to three-hour period of vessel occlusion in cats and squirrel monkeys and permanent occlusion in dogs. In gerbils, dogs, and cats, there were no differences in the metabolis, functional, or pathological effects of anesthesia with pentobarbital or halothane. However, in the squirrel monkey, in acute studies the metabolic alterations were significantly less with pentobarbital, and in chronic studies the frequency and magnitude of functional deficits and cerebral infarction were significantly less. We conclude that pentobarbital does provide a degree of protection during regional cerebral ischemia but that such effects are only consistently demonstrable in primates. In nonprimates, we assume that variability in the collateral circulation renders demonstration of significant differences difficult or impossible.


Multidimensional endotypes of asthma: topological data analysis of cross-sectional clinical, pathological, and immunological data.
Incomplete understanding of mechanisms and clinicopathobiological heterogeneity in asthma hinders research progress. Pathogenic roles for T-helper-type 17 (Th17) cells and invariant T cells implied by murine data have yet to be assessed in man. We aimed to investigate the role of Th17 and mucosal associated invariant T (MAIT) cells in airway inflammation; to characterise associations between diverse clinical and immunological features of asthma; and to identify novel multidimensional asthma endotypes. In this single-centre, cross-sectional observational study in the UK, we assessed volunteers with mild-to-severe asthma and healthy non-atopic controls using clinical and physiological assessment and immunological sampling of blood, induced sputum, endobronchial biopsy, and bronchoalveolar lavage for flow cytometry and multiplex-electrochemiluminescence assays. Primary outcomes were changes in frequencies of Th17 and MAIT cells between health and asthma using Mann-Whitney U tests and the Jonckheere-Terpstra test (linear trend across ranked groups). The study had 80% power to detect 60% differences in T-cell frequencies at p<0·05. Bayesian Network Analysis (BNA) was used to explore associations between parameters. Topological Data Analysis (TDA) was used to identify multidimensional endotypes. The study had local research ethics approval. All participants provided informed consent. Participants were 84 male and female volunteers (60 with mild-to-severe asthma and 24 healthy, non-atopic controls) aged 18-70 years recruited from clinics and research cohorts. Th17 cells and γδ17 cells were not associated with asthma, even in severe neutrophilic forms. MAIT-cell frequencies were strikingly reduced in asthma compared with health (median frequency in blood 0·9% of CD3+ cells [IQR 0·3-1·8] in asthma vs 1·6 [1·2-2·6] in health, p=0·005; in sputum 1·1 [0·7-2·0] vs 1·8 [1·6-2·3], p=0·002; and in biopsy samples 1·3 [0·7-2·3] vs 3·9% [1·3-5·3%], p=0·02), especially in severe asthma where BAL regulatory T cells were also reduced compared with those in health (4·4, 3·1-6·1, vs 8·1, 5·6-10; p=0·02). BNA and TDA identified six novel clinicopathobiological clusters of underlying disease mechanisms, with elevated mast cell mediators tryptase (p<0·0001), chymase (p=0·02), and carboxypeptidase A3 (p=0·02) in severe asthma. This study suggests that Th17 cells do not have a major pathogenic role in human asthma. We describe a novel deficiency of MAIT cells in severe asthma. We also provide proof of concept for application of TDA to identification of multidimensional clinicopathobiological endotypes. Endotypes will require validation in further cohorts. Wellcome Trust.


The Effects of the PLAYTOD Program on Children's Physical Activity at Preschool Playgrounds in a Deprived Urban Area: A Randomized Controlled Trial.
Interventions to improve children's physical activity in Early Childhood Education and Care (ECEC) settings are needed. This randomized controlled trial examines the effects of a preschool-based playground program for ECEC teachers in a deprived urban area. On intervention preschools, the PLAYgrounds for TODdlers program (PLAYTOD) was performed. It focused on teacher's knowledge and skills in order to create a challenging outdoor environment in which young children (2.5 to 4 years old) are able to practice their motor skills. Observations were performed before and after the program with a modified version of the SOPLAY protocol. The activating role of teachers (score from 0 = inactive to 4 = participating), the number of different physical activities, and the quality of children's physical activity on playgrounds were observed. The latter included the number of performed fundamental movement skills and the estimated physical activity intensity (score from 0 = sedentary to 3 = vigorous). Descriptive statistics and linear regression analyses were used to evaluate the effects of PLAYTOD. After the program, the activating role of teachers on intervention playgrounds improved. Moreover, the program and consecutively the changes made by teachers had a positive effect on the number of different activities and the quality of children's physical activity. The results emphasize an important role for ECEC teachers in improving physical activity in young children.


Dynamic regulation of endosymbiotic organelles by ubiquitination.
Recent work has revealed that mitochondria and chloroplasts are subject to direct control by the ubiquitin-proteasome system (UPS). Ubiquitin E3 ligases are present at the outer membrane of both organelles where they mediate ubiquitination and turnover of other organellar proteins. Both organelles exhibit remarkable structural dynamism and UPS control is particularly concerned with these properties. In mitochondria, the UPS targets factors involved in organellar fission and fusion, with significant impacts upon organellar morphology, mitophagy, and apoptosis. In chloroplasts (and other plastids), the UPS targets components of the protein import machinery, facilitating reorganization of the organellar proteome to determine organellar development and functions. Acquisition of such regulatory control during evolution is perhaps linked to the dynamic characteristics of the two organelles, which are not paralleled in their prokaryotic relatives. Here we discuss our current understanding of the role of the UPS in the regulation of endosymbiotic organelles.


Contraceptive use among HIV infected women attending Comprehensive Care Centre.
To determine contraceptive use among HIV infected women attending Comprehensive Care Centre at Kenyatta National Hospital. Hospital based cross-sectional descriptive study. Comprehensive Care Centre (CCC), Kenyatta National Hospital. The study group was non-pregnant HIV positive women on follow up at the CCC. A total of 94 HIV infected women were interviewed between May 2006 and August 2006 through a pretested interviewer administered questionnaire. Consecutive women willing to participate in the study were interviewed. Current contraceptive use, contraceptive methods, source of contraception, reproductive intention and unmet need of family planning. The mean age of the respondents was 34 years, 47.9% were married, all had formal education and 74.6% were employed. Eighty six percent of the respondents did not have reproduction intentions in the next two years; however, only 44.2% of the respondents were using contraception. Condoms were the most popular (81.5%) contraceptive method. Female condom was used by 10.5% of the respondents. Norplant was the only long-term contraceptive method and was used by only 2.6%. Dual method of contraception was practiced by 13.5% of the respondents. Majority of the respondents obtained contraceptives from private sector (42.9%) with less than 10% getting them from CCC. The unmet need for family planning among the study group was 30%. Marital status and regular sexual partner were significantly associated with contraceptive use. Although majority of respondents did not have reproduction intentions in the next two years, use of contraception was low with only 44% being on a method. Use of long-term contraceptive methods was low among respondents. Majority of the respondents obtained contraceptives away from CCC. The unmet need for family planning was high at 30%.


Beta-amyloid sequelae in the eye: a critical review on its diagnostic significance and clinical relevance in Alzheimer's disease.
Alzheimer's disease (AD) is a progressive and fatal neurodegenerative disorder. There is no test for its definitive diagnosis in routine clinical practice. Although phase III clinical trials have failed, only symptomatic treatment is currently available; a possible reason for these failed trials is that intervention commenced at an advanced stage of the disease. The hallmarks of an AD brain include plaques comprising of extracellular beta-amyloid (Aβ) protein aggregates and intracellular hyperphosphorylated neurofibrillary tangles of tau. Research into the preclinical diagnosis of AD has provided considerable evidence regarding early neuropathological changes using brain Aβ imaging and the cerebrospinal fluid biomarkers, Aβ and tau. Both these approaches have limitations that are expensive, invasive or time consuming and thus preclude them from screening at-risk population. Recent studies have demonstrated the presence of Aβ plaques in the eyes of AD subjects, which is positively associated with their brain Aβ burden. Thus ocular biomarkers point to a potential avenue for an earlier, relatively low-cost diagnosis in order for therapeutic interventions to be effective. Here we review the literature that spans the investigation for the presence of Aβ in aging eyes and the significance of its deposition in relation to AD pathology. We discuss clinical studies investigating in vivo imaging of Aβ in the eye and its association with brain Aβ burden and therapies that target ocular Aβ. Finally, we focus on the need to characterize AD-specific retinal Aβ to differentiate Aβ found in some eye diseases. Based on the current evidence, we conclude that integration of ocular biomarkers that can correctly predict brain Aβ burden would have an important role as a non-invasive, yet economical surrogate marker in the diagnostic process of AD.


Water access points and hydration pathways in CLC H+/Cl- transporters.
CLC transporters catalyze transmembrane exchange of chloride for protons. Although a putative pathway for Cl(-) has been established, the pathway of H(+) translocation remains obscure. Through a highly concerted computational and experimental approach, we characterize microscopic details essential to understanding H(+)-translocation. An extended (0.4 µs) equilibrium molecular dynamics simulation of membrane-embedded, dimeric ClC-ec1, a CLC from Escherichia coli, reveals transient but frequent hydration of the central hydrophobic region by water molecules from the intracellular bulk phase via the interface between the two subunits. We characterize a portal region lined by E202, E203, and A404 as the main gateway for hydration. Supporting this mechanism, site-specific mutagenesis experiments show that ClC-ec1 ion transport rates decrease as the size of the portal residue at position 404 is increased. Beyond the portal, water wires form spontaneously and repeatedly to span the 15-Å hydrophobic region between the two known H(+) transport sites [E148 (Glu(ex)) and E203 (Glu(in))]. Our finding that the formation of these water wires requires the presence of Cl(-) explains the previously mystifying fact that Cl(-) occupancy correlates with the ability to transport protons. To further validate the idea that these water wires are central to the H(+) transport mechanism, we identified I109 as the residue that exhibits the greatest conformational coupling to water wire formation and experimentally tested the effects of mutating this residue. The results, by providing a detailed microscopic view of the dynamics of water wire formation and confirming the involvement of specific protein residues, offer a mechanism for the coupled transport of H(+) and Cl(-) ions in CLC transporters.


Jointly Modelling Economics and Epidemiology to Support Public Policy Decisions for the COVID-19 Response: A Review of UK Studies.
COVID-19 in the UK has had a profound impact on population health and other socially important outcomes, including on education and the economy. Although a range of evidence has guided policy, epidemiological models have been central. It is less clear whether models to support decision making have sought to integrate COVID-19 epidemiology with a consideration of broader health, wellbeing and economic implications. We report on a rapid review of studies seeking to integrate epidemiological and economic modelling to assess the impacts of alternative policies. Overall, our results suggest that few studies have explored broader impacts of different COVID-19 policies in the UK. Three studies looked only at health, capturing impacts on individuals with and without COVID-19, with various methods used to model the latter. Four models considered health and wider impacts on individuals' economic outcomes, such as wages. However, these models made no attempt to consider the dynamic impacts on economic outcomes of others and the wider economy. The most complex analyses sought to link epidemiological and dynamic economic models. Studies compared a wide range of policies, although most were defined in general terms with minimal consideration of their granular specifications. There was minimal exploration of uncertainty, with no consideration in half the studies. Selecting appropriate models to inform decisions requires careful thought of factors relevant to the decision options under consideration such as the outcomes of interest, sectors likely to be impacted and causal pathways. In summary, better linking epidemiological and economic modelling would help to inform COVID-19 policy.


Current approaches to the treatment of advanced-stage Hodgkin's disease.
Combination chemotherapy (CT) has been the mainstay of treatment of advanced-stage Hodgkin's disease since the late 1960s. Although treatment with MOPP (nitrogen mustard, vincristine sulfate [Oncovin], procarbazine and prednisone) has resulted in long-term disease-free survival rates exceeding 50%, newer approaches have been studied to improve on this success rate and to reduce the toxic effects associated with MOPP. Prognostic factors have now been defined that identify patients who may require more aggressive treatment; they include age greater than 40 years, presence of B symptoms and more advanced (especially extranodal) disease. A small number of patients with pathological stage III disease may still be successfully treated with extensive radiotherapy (RT) alone. Among patients with advanced-stage disease, significantly better therapeutic results are being obtained with newer treatment approaches than with MOPP, particularly in patients with factors that predict a poor outcome. These newer approaches include combination CT plus RT, alternating cycles of two non-cross-resistant CT regimens and hybrid regimens, which combine agents from two different CT regimens in one cycle. The prognosis of patients who suffer relapse after combination CT remains poor, even with newer drug regimens. The newer treatment approaches may well lead to better cure rates and fewer short-term and long-term toxic effects.


Does Telehealth Delivery of a Dyadic Dementia Care Program Provide a Noninferior Alternative to Face-To-Face Delivery of the Same Program? A Randomized, Controlled Trial.
This study aimed to determine whether delivery of a dyadic intervention using telehealth was noninferior to delivery of the same program using traditional face-to-face delivery through home visits. We conducted a noninferiority randomized controlled trial. Participants had a diagnosis of dementia, were living in the community, and had an informal caregiver who reported difficulties in managing activities of daily living or behavioral symptoms. Participants were randomized to receive either telehealth or home visit delivery of the same intervention program. The primary outcome was the Caregiving Mastery Index, secondary outcomes included caregiver's perceptions of change, activities of daily living function, and type and frequency of behavioral symptoms of persons living with dementia. Therapists delivering the intervention recorded the time spent delivering the intervention as well as travel time. Sixty-three dyads were recruited and randomized. Both groups reported improvements for the primary outcome, however, these were not statistically significant. There were no significant differences between groups for the primary outcome (mean difference 0.09 (95% confidence interval -1.26 to 1.45) or the secondary outcomes at 4 months. Both groups reported significant improvements in caregiver's perceptions of change. The amount of time spent delivering the content of the program was similar between groups, however offering the intervention via telehealth significantly reduced travel time (mean 255.9 minutes versus mean 77.2 minutes, p <0.0001). It is feasible to offer dyadic interventions via telehealth and doing so reduces travel time and results in similar benefits for families.


Terahertz surface plasmon sensor for distinguishing gasolines.
Gasolines of two different octane numbers are experimentally distinguished using a thin metal sheet perforated with a periodic hole array terahertz surface plasmon (SP) sensor. This sensor is proved to be very sensitive to the change in permittivities of analytes. The differences between the gasolines 93# and 97# in composition lead to various refractive indices, permittivities, and absorption coefficients, thus varying their interactions with surface waves on the sensor, which enables a distinction of 6 GHz between the two octane numbers in the transmission peaks. The freestanding SP sensor is effective and reliable and can be simply employed in analyte distinction, which has potential applications in the petroleum industry.


The pollen dispersal kernel and mating system of an insect-pollinated tropical palm, Oenocarpus bataua.
Pollen dispersal shapes the local genetic structure of plant populations and determines the opportunity for local selection and genetic drift, but has been well studied in few animal-pollinated plants in tropical rainforests. Here, we characterise pollen movement for an insect-pollinated Neotropical canopy palm, Oenocarpus bataua, and relate these data to adult mating system and population genetic structure. The study covers a 130-ha parcel in which all adult trees (n=185) were mapped and genotyped at 12 microsatellite loci, allowing us to positively identify the source tree for 90% of pollination events (n=287 of 318 events). Mating system analysis showed O. bataua was effectively outcrossed (t(m)=1.02) with little biparental inbreeding (t(m)-t(s)=-0.005) and an average of 5.4 effective pollen donors (N(ep)) per female. Dispersal distances were relatively large for an insect-pollinated species (mean=303 m, max=1263 m), and far exceeded nearest-neighbour distances. Dispersal kernel modelling indicated a thin-tailed Weibull distribution offered the best fit to the genetic data, which contrasts with the fat-tailed kernels typically reported for pollen dispersal in trees. Preliminary analyses suggest that our findings may be explained, at least in part, by a relatively diffuse spatial and temporal distribution of flowering trees. Comparison with previously reported estimates of seed movement for O. bataua suggests that pollen and seed dispersal distances may be similar. These findings add to the growing body of information on dispersal in insect-pollinated trees, but underscore the need for continued research on tropical systems in general, and palms in particular.


The identification of Naegleria fowleri from water and soil samples by nested PCR.
Naegleria fowleri is the causative agent of primary amebic meningoencephalitis (PAM), a disease of the central nervous system. Healthy humans sporadically become infected with N. fowleri and develop fatal PAM after recreational or work exposure to freshwater; accordingly, there is a need for monitoring the presence of pathogenic ameboflagellates in public freshwater. The present study was conducted to determine whether a nested PCR assay could be used for the detection of N. fowleri in freshwater habitats. Water samples were collected in Virginia, since Naegleria has been isolated previously in this state. Additionally, the occurrence of N. fowleri in samples from Connecticut was investigated since neither N. fowleri nor PAM has been reported from this region. PCR analysis demonstrated that two of four samples from Virginia were positive for N. fowleri without intervening culture while 15 of 86 samples from Connecticut were positive that had been enriched by culture. This constitutes the first report of N. fowleri from Connecticut waters. These results indicate that the PCR assay can be utilized to detect N. fowleri in water and soil collected from the environment.


Tissue-specific regulation of low density lipoprotein receptor gene expression.
LDL receptor mRNA levels are increased by mitogenic stimulation of PBMC and are less effectively regulated by exogenous LDL in the activated cells. Enhanced LDL receptor mRNA levels reflect increased rates of gene transcription and not stabilization of mRNA. The alteration of LDL-mediated regulation of LDL receptor gene expression in mitogen-activated PBMC is not the result of cellular proliferation alone and occurs without apparent changes in measurable regulatory pools of cholesterol. These results indicate that signals transduced during mitogenic stimulation, as well as ambient LDL concentration, play a major role in regulating LDL receptor gene transcription. Fibroblasts apparently differ from PBMC in the effect of modulatory proteins on LDL receptor mRNA levels. In fibroblasts, LDL receptor gene transcription appears to be down-regulated by a short-lived protein whereas the dominant regulatory influence in PBMC appears to be a short-lived protein with a positive effect on transcription. Differences in the expression of specific transcription factors may contribute to cell-specific alterations in the regulation of LDL receptor gene expression by lipids.


Redox regulation of ischemic limb neovascularization - What we have learned from animal studies.
Mouse hindlimb ischemia has been widely used as a model to study peripheral artery disease. Genetic modulation of the enzymatic source of oxidants or components of the antioxidant system reveal that physiological levels of oxidants are essential to promote the process of arteriogenesis and angiogenesis after femoral artery occlusion, although mice with diabetes or atherosclerosis may have higher deleterious levels of oxidants. Therefore, fine control of oxidants is required to stimulate vascularization in the limb muscle. Oxidants transduce cellular signaling through oxidative modifications of redox sensitive cysteine thiols. Of particular importance, the reversible modification with abundant glutathione, called S-glutathionylation (or GSH adducts), is relatively stable and alters protein function including signaling, transcription, and cytoskeletal arrangement. Glutaredoxin-1 (Glrx) is an enzyme which catalyzes reversal of GSH adducts, and does not scavenge oxidants itself. Glrx may control redox signaling under fluctuation of oxidants levels. In ischemic muscle increased GSH adducts through Glrx deletion improves in vivo limb revascularization, indicating endogenous Glrx has anti-angiogenic roles. In accordance, Glrx overexpression attenuates VEGF signaling in vitro and ischemic vascularization in vivo. There are several Glrx targets including HIF-1α which may contribute to inhibition of vascularization by reducing GSH adducts. These animal studies provide a caution that excess antioxidants may be counter-productive for treatment of ischemic limbs, and highlights Glrx as a potential therapeutic target to improve ischemic limb vascularization.


Association between ADHD and smoking in adolescence: shared genetic, environmental and psychopathological factors.
The present study aimed to examine the extent to which the co-occurrence of ADHD and smoking in adolescents could be attributed to common genetic, environmental and psychopathological factors. Data are from an ongoing prospective study of the outcome of early risk factors. At age 15 years, 305 adolescents completed self-report questionnaires measuring tobacco consumption and deviant peer affiliations. Lifetime psychiatric diagnoses were obtained using standardized interviews. DNA was genotyped for the dopamine D4 receptor (DRD4) gene exon III polymorphism. Adolescents with a lifetime diagnosis of ADHD displayed significantly higher smoking activity than non-ADHD controls. A major component of this association could be accounted for by deviant peer affiliations and the comorbidity with oppositional-defiant and conduct disorder, while a minor part was attributable to DRD4 in males but not in females. These findings suggest that the association of ADHD with smoking relies on risk factors shared by the two behaviors.


Increase of muscle activities in hemiplegic lower extremity during driving a cycling wheelchair.
For the patients with severe hemiplegia, long-time wheelchair sitting is unavoidable, which however increases a risk of secondary impairments due to non-use of the affected leg. A cycling wheelchair (C-W/C) has a possibility to activate paretic muscle through self-locomotion with bilateral pedaling. We therefore measured driving speed of C-W/C and electromyogram (EMG) in both legs during driving in the healthy adults and severe hemiplegic patients. Ten healthy volunteers (mean age 32.8, 26-45 years) and ten non-ambulatory post-stroke patients (mean age 69.0, 55-81 years) with complete or semi-complete hemiplegia participated in this study. EMG was recorded from the key muscles for cycling during isometric movement as baseline and during driving a C-W/C straightforward. All of the patients could drive a C-W/C with mean maximum driving speed of 46.6 (31.7-61.7) m/min, which was about half of that in the healthy subjects and within practical level. Root mean square of EMG (R-EMG) as a parameter reflecting muscle activity was compared between baseline and C-W/C driving. There was no increase in most of the values of R-EMG during driving in the healthy subjects and in the intact side of the hemiplegic patients. In contrast, significant increase was found during driving in several paretic muscles, despite that EMG of the paretic leg showed almost silent at baseline. These results suggest C-W/C can induce muscle activities of the paretic leg and provide a chance of practical locomotion even for the severe hemiplegics. Daily use of a C-W/C may contribute to restore paretic leg function.


A randomized phase II trial investigating the effect of platelet function inhibition on circulating tumor cells in patients with metastatic breast cancer.
Blockade of platelet activation and aggregation can inhibit metastasis in preclinical models and is associated with cancer prevention. To test whether disruption of platelet function with clopidogrel and aspirin would decrease the number of circulating tumor cells (CTCs) in patients with metastatic breast cancer, a randomized phase II study was performed. Patients with metastatic breast cancer who were not currently receiving cytotoxic chemotherapy were eligible. Patients were randomized to receive either clopidogrel and aspirin or to a control group receiving no treatment. Phlebotomy was performed at baseline, at 2 and 4 weeks, and monthly thereafter to obtain specimens to assess CTC, platelet aggregation, and thrombin activity. The primary end point was the proportion of patients with detectable CTCs at 1 month. Forty-eight patients were enrolled and 42 were evaluable at 1 month. Baseline CTC numbers were ≥ 5 in 13% and ≥ 1 in 65% of patients. Despite adequate platelet function inhibition in the treatment group, the proportion of patients with detectable CTCs was similar between the clopidogrel/aspirin and control groups at baseline (P = .21) and 4 weeks (P = .75), showing no treatment effect. Measured endogenous thrombin potential did not correlate with CTC number. No bleeding-related serious adverse events (SAEs) occurred. The baseline CTC numbers were lower than expected, decreasing the ability to detect an impact of platelet inhibition on CTCs. Clopidogrel and aspirin were well tolerated. Future studies evaluating the potential therapeutic role of antiplatelet therapy in breast cancer remain of interest, and they may be informed by these results.


p53 in Bronchial Club Cells Facilitates Chronic Lung Inflammation by Promoting Senescence.
The tumor suppressor p53 limits tumorigenesis by inducing apoptosis, cell cycle arrest, and senescence. Although p53 is known to limit inflammation during tumor development, its role in regulating chronic lung inflammation is less well understood. To elucidate the function of airway epithelial p53 in such inflammation, we subjected genetically modified mice, whose bronchial epithelial club cells lack p53, to repetitive inhalations of lipopolysaccharide (LPS), an exposure that leads to severe chronic bronchitis and airway senescence in wild-type mice. Surprisingly, the club cell p53 knockout mice exhibited reduced airway senescence and bronchitis in response to chronic LPS exposure and were significantly protected from global lung destruction. Furthermore, pharmacological elimination of senescent cells also protected wild-type mice from chronic LPS-induced bronchitis. Our results implicate p53 in induction of club-cell senescence and correlate epithelial cell senescence of chronic airway inflammation and lung destruction.


Excessive White Matter Hyperintensity Increases Susceptibility to Poor Functional Outcomes After Acute Ischemic Stroke.
Objective: To personalize the prognostication of post-stroke outcome using MRI-detected cerebrovascular pathology, we sought to investigate the association between the excessive white matter hyperintensity (WMH) burden unaccounted for by the traditional stroke risk profile of individual patients and their long-term functional outcomes after a stroke. Methods: We included 890 patients who survived after an acute ischemic stroke from the MRI-Genetics Interface Exploration (MRI-GENIE) study, for whom data on vascular risk factors (VRFs), including age, sex, atrial fibrillation, diabetes mellitus, hypertension, coronary artery disease, smoking, prior stroke history, as well as acute stroke severity, 3- to-6-month modified Rankin Scale score (mRS), WMH, and brain volumes, were available. We defined the unaccounted WMH (uWMH) burden via modeling of expected WMH burden based on the VRF profile of each individual patient. The association of uWMH and mRS score was analyzed by linear regression analysis. The odds ratios of patients who achieved full functional independence (mRS < 2) in between trichotomized uWMH burden groups were calculated by pair-wise comparisons. Results: The expected WMH volume was estimated with respect to known VRFs. The uWMH burden was associated with a long-term functional outcome (β = 0.104, p < 0.01). Excessive uWMH burden significantly reduced the odds of achieving full functional independence after a stroke compared to the low and average uWMH burden [OR = 0.4, 95% CI: (0.25, 0.63), p < 0.01 and OR = 0.61, 95% CI: (0.42, 0.87), p < 0.01, respectively]. Conclusion: The excessive amount of uWMH burden unaccounted for by the traditional VRF profile was associated with worse post-stroke functional outcomes. Further studies are needed to evaluate a lifetime brain injury reflected in WMH unrelated to the VRF profile of a patient as an important factor for stroke recovery and a plausible indicator of brain health.


Rating of perceived exertion - a valid method for monitoring light to vigorous exercise intensity in individuals with subjective and mild cognitive impairment?
In rehabilitation settings, exercise intensity is often monitored with Borg's rating of perceived exertion (RPE). However, previous studies showed that severe cognitive impairment may limit the usability of the RPE. The aim of this study was to assess the relationship between RPE and heart rate (HR), and to establish whether a target RPE can be used to achieve exercise intensity based on an individual's HR-RPE in people with early cognitive impairment. 97 participants (74.7 ± 6 years) with early cognitive impairment completed an incremental exercise test. Of these, 54 were tested during a single, RPE guided exercise session. RPE and HR were monitored throughout. Correlations between HR and RPE were assessed using Spearman's correlation. Mean differences between measured HR and target HR were calculated and compared using a two-way ANOVA with factors cognition and exercise mode. Bland-Altman plots were constructed to analyse the agreement between target and measured HR. HR and RPE correlated moderately with each other (p < 0.001; r = 0.555) and no differences between target and measured HR were observed. Bland-Altman plots revealed a mean difference of 1.2 bpm and a 95% level of agreement was between 24.4 and -22.1 bpm. No differences in rating accuracy were observed between different cognitive impairment levels nor between different exercise modes. Bland-Altman plots revealed some variance between the participants with almost half of them missing target HR by 10bpm or more. Therefore, the RPE should only be applied with caution and, if possible, with other measurements (e.g. heart rate monitors) to ensure that target intensity is reached.


Pyruvate controls the checkpoint inhibitor PD-L1 and suppresses T cell immunity.
Patients with coronary artery disease (CAD) are at high risk for reactivation of the varicella zoster virus (VZV) and development of herpes zoster (HZ). Here, we found that macrophages from patients with CAD actively suppress T cell activation and expansion, leading to defective VZV-specific T cell immunity. Monocyte-derived and plaque-infiltrating macrophages from patients with CAD spontaneously expressed high surface density of the immunoinhibitory ligand programmed death ligand-1 (PD-L1), thereby providing negative signals to programmed death-1+ (PD-1+) T cells. We determined that aberrant PD-L1 expression in patient-derived macrophages was metabolically controlled. Oversupply of the glycolytic intermediate pyruvate in mitochondria from CAD macrophages promoted expression of PD-L1 via induction of the bone morphogenetic protein 4/phosphorylated SMAD1/5/IFN regulatory factor 1 (BMP4/p-SMAD1/5/IRF1) signaling pathway. Thus, CAD macrophages respond to nutrient excess by activating the immunoinhibitory PD-1/PD-L1 checkpoint, leading to impaired T cell immunity. This finding indicates that metabolite-based immunotherapy may be a potential strategy for restoring adaptive immunity in CAD.


Non-cell-autonomous Effects of Autophagy Inhibition in Tumor Cells Promote Growth of Drug-resistant Cells.
Autophagy, the mechanism by which cells deliver material to the lysosome, has been associated with resistance to anticancer drugs, leading autophagy inhibition to be widely studied as a potential chemosensitization strategy for cancer cells. This strategy is based on the idea that inhibition of autophagy will increase drug sensitivity and kill more cancer cells. Here we report an unintended negative effect of this strategy. When modeling the effect of drug resistance in a heterogeneous cancer cell population, we found that autophagy inhibition in drug-sensitive tumor cells causes increased growth of drug-resistant cells in the population through a mechanism involving caspase activation and prostaglandin E2 signaling. These results emphasize the importance of understanding how autophagy manipulation in a tumor cell can have both cell-autonomous and nonautonomous effects and suggest that attempts to chemosensitize by inhibiting autophagy could be enhanced by adopting methods aimed at reducing tumor repopulation.


Women, cardiac syndrome X, and microvascular heart disease.
New data suggest that persistent chest pain, despite normal coronary angiography, is less benign than previously thought. It has long been recognized that cardiac syndrome X (CSX) is associated with significant suffering, disability, and health care costs, but the biggest shift in thinking comes in terms of long-term risk. It is now recognized that the prognosis is not benign and that a significant proportion of patients are at increased cardiovascular disease risk. Of major debate is the question of whether the mechanisms that explain this chest pain are cardiac vs noncardiac. The most current definition of CSX is the triad of angina, ischemia, and normal coronary arteries, which is associated with an increased cardiovascular risk. This paper provides a review of CSX, epidemiology of the problem, proposed explanatory mechanisms, and important next steps in research. Central to this review is the proposition that new insights into CSX will be fostered by both clinical and scientific collaboration between cardiovascular and pain scientists.


Trends in Testicular Injury in Korea, 1986-2015.
The objectives of this study were to investigate patients treated for scrotal trauma at our institute for the last three decades to describe our experience with an emphasis on the etiologies and ultrasonographic findings in these patients. We reviewed medical records of patients who underwent scrotal ultrasonography for evaluation of testicular trauma at our institutes from 1986 to 2015. Trends regarding the etiology of scrotal trauma were evaluated during each decade. The echo pattern and contour definition of the testicular parenchyma and the pattern of hematoma development were recorded to evaluate radiographic findings of testicular injury. The correlation between ultrasonographic and intraoperative findings was assessed. A total of 115 patients were analyzed. Most patients (92.2%) presented with blunt trauma. The most common etiology of testicular trauma was assault during the first and second decades, while injury related to a fall was most common during the third decade. Of the 77 patients (67.0%) who underwent urgent exploration, 46 patients (59.7%) had testicular rupture. Loss of contour definition, heterogeneous echo pattern of the testicular parenchyma, and testicular hematoma showed a moderate to strong degree of correlation with testicular rupture (Spearman correlation co-efficient: 0.5-0.8). Over the past 30 years, the etiology of testicular injury changed from assault to falls or athletic injury and the severity of injury has decreased. Our findings demonstrate the importance of ultrasonography for determining an appropriate management strategy in scrotal trauma. Surgical exploration should be considered in patients with abnormal ultrasonographic findings.


An in vivo doxycycline-controlled expression system for functional studies of the retina.
Transgenic mice were developed that express tetracycline-controlled transactivator 1 (tTA1) specifically in photoreceptor cells. In these mice the transcription of the gene of interest can be easily inactivated in the retina in a short time frame. A construct was prepared containing tTA1 under control of the murine rhodopsin regulatory region. This construct was used for the generation of transgenic mice. In situ hybridization was performed to study the distribution of the transactivator in the retina. The activity of the transactivator was analyzed by mating the lines with a luciferase reporter transgenic mouse. tTA1 activity and doxycycline's ability to block it were analyzed by luciferase assay. The effects of tTA1 on the retina were assessed by histology and electrophysiology. Two transgenic lines were developed that specifically express tTA1 in photoreceptor cells. The time course of transgene expression replicated transcription of endogenous rhodopsin. tTA1 was not toxic to the retina. Transactivator activity was blocked readily by doxycycline. An expression system for photoreceptor cells was generated to drive transcription in a cell-specific and time-controllable manner. This system is suitable for the study of factors involved in retinal biology and of mutant forms of genes involved in retinal diseases.


Single-particle fusion of influenza viruses reveals complex interactions with target membranes.
The first step in infection of influenza A virus is contact with the host cell membrane, with which it later fuses. The composition of the target bilayer exerts a complex influence on both fusion efficiency and time. Here, an in vitro, single-particle approach is used to study this effect. Using total internal reflection fluorescence (TIRF) microscopy and a microfluidic flow cell, the hemifusion of single virions is visualized. Hemifusion efficiency and kinetics are studied while altering target bilayer cholesterol content and sialic-acid donor. Cholesterol ratios tested were 0%, 10%, 20%, and 40%. Sialic-acid donors GD1a and GYPA were used. Both cholesterol ratio and sialic-acid donors proved to have a significant effect on hemifusion efficiency. Furthermore, comparison between GD1a and GYPA conditions shows that the cholesterol dependence of the hemifusion time is severely affected by the sialic-acid donor. Only GD1a shows a clear increasing trend in hemifusion efficiency and time with increasing cholesterol concentration of the target bilayer with maximum rates for GD1A and 40% cholesterol. Overall our results show that sialic acid donor and target bilayer composition should be carefully chosen, depending on the desired hemifusion time and efficiency in the experiment.


Four-dimensional diffusion-weighted MR imaging (4D-DWI): a feasibility study.
Diffusion-weighted Magnetic Resonance Imaging (DWI) has been shown to be a powerful tool for cancer detection with high tumor-to-tissue contrast. This study aims to investigate the feasibility of developing a four-dimensional DWI technique (4D-DWI) for imaging respiratory motion for radiation therapy applications. Image acquisition was performed by repeatedly imaging a volume of interest (VOI) using an interleaved multislice single-shot echo-planar imaging (EPI) 2D-DWI sequence in the axial plane. Each 2D-DWI image was acquired with an intermediately low b-value (b = 500 s/mm2 ) and with diffusion-encoding gradients in x, y, and z diffusion directions. Respiratory motion was simultaneously recorded using a respiratory bellow, and the synchronized respiratory signal was used to retrospectively sort the 2D images to generate 4D-DWI. Cine MRI using steady-state free precession was also acquired as a motion reference. As a preliminary feasibility study, this technique was implemented on a 4D digital human phantom (XCAT) with a simulated pancreas tumor. The respiratory motion of the phantom was controlled by regular sinusoidal motion profile. 4D-DWI tumor motion trajectories were extracted and compared with the input breathing curve. The mean absolute amplitude differences (D) were calculated in superior-inferior (SI) direction and anterior-posterior (AP) direction. The technique was then evaluated on two healthy volunteers. Finally, the effects of 4D-DWI on apparent diffusion coefficient (ADC) measurements were investigated for hypothetical heterogeneous tumors via simulations. Tumor trajectories extracted from XCAT 4D-DWI were consistent with the input signal: the average D value was 1.9 mm (SI) and 0.4 mm (AP). The average D value was 2.6 mm (SI) and 1.7 mm (AP) for the two healthy volunteers. A 4D-DWI technique has been developed and evaluated on digital phantom and human subjects. 4D-DWI can lead to more accurate respiratory motion measurement. This has a great potential to improve the visualization and delineation of cancer tumors for radiotherapy.


MicroRNA-204-5p-Mediated Regulation of SIRT1 Contributes to the Delay of Epithelial Cell Cycle Traversal in Diabetic Corneas.
We investigated how the microRNA (miRNA) modifies the expression of silent mating type information regulation 2 homolog 1 (SIRT1) in diabetic corneas. The bioinformatic assay was used to predict which miRNAs might regulate the expression of SIRT1. A lipid transfection protocol was used to upregulate or knockdown the miRNA expression in TKE2 cells. Adenovirus-expressing short interfering RNA was used to knockdown the expression of SIRT1 in TKE2 cells and Ins2(Akita/+) mice were used to evaluate how miRNA promotes diabetic corneal epithelial wound healing. Cell cycle status was determined by flow cytometry assay and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was used to analyze the cell viability. Nine miRNAs were selected for quantitative PCR (qPCR) detection after bioinformatics analysis. The miR-204-5p merited further investigation, because it was increased almost 5-fold in diabetic corneal epithelia compared to nondiabetic control corneal epithelia. Using luciferase activity assay, we identified SIRT1 was a direct target of miR-204-5p. The results of flow cytometry and MTT assay demonstrated that downregulation of miR-204-5p increased TKE2 cell growth and restored cell cycle progression in high glucose (HG) conditions by the regulation of Cyclin D1 and p16. Furthermore, we showed downregulation of miR-204-5p promoted HG attenuation of corneal epithelial wound healing via upregulation of SIRT1 in Ins2(Akita/+) mice. Our data provide firm evidence of a role for miR-204-5p in the direct regulation of SIRT1 in diabetic corneas and identified the miR-204-5p-mediated regulation of SIRT1 contributes to the delay of epithelial cell cycle traversal in diabetic keratopathy. : Chinese Abstract.


Pressure effects revealed by small angle neutron scattering on block copolymer gels.
We study the effects of hydrostatic pressure (P) on aqueous solutions and gels of the block copolymer B(20)E(610) (E, oxyethylene; B, oxybutylene; subscripts, number of repeats), by performing simultaneous small angle neutron scattering/pressure experiments. Micellar cubic gels were studied for 9.5 and 4.5 wt % B(20)E(610) at T = 20-80 and 35-55 degrees C, respectively, while micellar isotropic solutions where studied for 4.5 wt % B(20)E(610) at T > 55 degrees C. We observed that the interplanar distance d 110 (cubic unit cell parameter a = [see text for formula]) decreases while the correlation length of the cubic order (delta) increases, upon increasing P at a fixed T for 9.5 wt % B(20)E(610). The construction of master curves for d(110) and delta corresponding to 9.5 wt % B(20)E(610) proved the correlation between changes in T and P. Neither d(110) and delta nor the cubic-isotropic phase transition temperature was affected by the applied pressure for 4.5 wt % B(20)E(610). The dramatic contrast between the pressure-induced behavior observed for 9.5 and 4.5 wt % B(20)E(610) suggests that pressure induced effects might be more effectively transmitted through samples that present wider domains of cubic structure order (9.5 wt % compared to 4.5 wt % B(20)E(610)).


A Bidirectional Label Propagation Based Computational Model for Potential Microbe-Disease Association Prediction.
A growing number of clinical observations have indicated that microbes are involved in a variety of important human diseases. It is obvious that in-depth investigation of correlations between microbes and diseases will benefit the prevention, early diagnosis, and prognosis of diseases greatly. Hence, in this paper, based on known microbe-disease associations, a prediction model called NBLPIHMDA was proposed to infer potential microbe-disease associations. Specifically, two kinds of networks including the disease similarity network and the microbe similarity network were first constructed based on the Gaussian interaction profile kernel similarity. The bidirectional label propagation was then applied on these two kinds of networks to predict potential microbe-disease associations. We applied NBLPIHMDA on Human Microbe-Disease Association database (HMDAD), and compared it with 3 other recent published methods including LRLSHMDA, BiRWMP, and KATZHMDA based on the leave-one-out cross validation and 5-fold cross validation, respectively. As a result, the area under the receiver operating characteristic curves (AUCs) achieved by NBLPIHMDA were 0.8777 and 0.8958 ± 0.0027, respectively, outperforming the compared methods. In addition, in case studies of asthma, colorectal carcinoma, and Chronic obstructive pulmonary disease, simulation results illustrated that there are 10, 10, and 8 out of the top 10 predicted microbes having been confirmed by published documentary evidences, which further demonstrated that NBLPIHMDA is promising in predicting novel associations between diseases and microbes as well.


In silico prediction of hERG potassium channel blockage by chemical category approaches.
The human ether-a-go-go related gene (hERG) plays an important role in cardiac action potential. It encodes an ion channel protein named Kv11.1, which is related to long QT syndrome and may cause avoidable sudden cardiac death. Therefore, it is important to assess the hERG channel blockage of lead compounds in an early drug discovery process. In this study, we collected a large data set containing 1163 diverse compounds with IC50 values determined by the patch clamp method on mammalian cell lines. The whole data set was divided into 80% as the training set and 20% as the test set. Then, five machine learning methods were applied to build a series of binary classification models based on 13 molecular descriptors, five fingerprints and molecular descriptors combining fingerprints at four IC50 thresholds to discriminate hERG blockers from nonblockers, respectively. Models built by molecular descriptors combining fingerprints were validated by using an external validation set containing 407 compounds collected from the hERGCentral database. The performance indicated that the model built by molecular descriptors combining fingerprints yielded the best results and each threshold had its best suitable method, which means that hERG blockage assessment might depend on threshold values. Meanwhile, kNN and SVM methods were better than the others for model building. Furthermore, six privileged substructures were identified using information gain and frequency analysis methods, which could be regarded as structural alerts of cardiac toxicity mediated by hERG channel blockage.


[Cooperation between regional and central hospitals--how to achieve the best results?].
The authors reviews a recent governmental analysis of cooperation between third-line university clinics and local and central hospitals. The hospitals are owned by the government (mainly by the counties), and the various Acts and regulation permit the central authorities to make decisions on all aspects of highly specialized medicine. The analysis concludes that a limited number of problems should be solved by decision of the central government, but only those where national concerns are involved. The counties within a health region should cooperate within a Regional Health Policy Board, to create plans for flow of patients through the health care system, specified for each field of medicine. When such plans have been approved by the Regional Health Policy Board, each county should be willing to accept them. In the event of local disagreement, the central government should decide.


3D in vitro Model of Vascular Medial Thickening in Pulmonary Arterial Hypertension.
In pulmonary arterial hypertension (PAH), excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) causes vascular medial thickening. Medial thickening is a histopathological hallmark of pulmonary vascular remodeling, the central disease process driving PAH progression. Pulmonary vascular remodeling causes stenosis and/or obstruction of small pulmonary arteries. This leads to increased pulmonary vascular resistance, elevated pulmonary arterial pressure, and ultimately right heart failure. To improve the survival of PAH patients, which remains at approximately 60% at 3 years after diagnosis, the development of novel PAH-targeted drugs is desired. To this end, a detailed understanding of the mechanisms underlying excessive PASMC proliferation and the medial thickening that ensues is necessary. However, a lack of in vitro models that recapitulate medial thickening impedes our deeper understanding of the pathogenetic mechanisms involved. In the present study, we applied 3-dimensional (3D) cell culture technology to develop a novel in vitro model of the pulmonary artery medial layer using human PAH patient-derived PASMCs. The addition of platelet-derived growth factor (PDGF)-BB, a mitogen known to promote excessive PASMC proliferation in PAH, resulted in increased thickness of the 3D-PAH media tissues. Conversely, administration of the PDGF receptor inhibitor imatinib or other clinical PAH drugs inhibited this medial thickening-inducing effect of PDGF-BB. Altogether, by using 3D cell culture technology, we report the generation of an in vitro model of medial thickening in PAH, which had hitherto not been successfully modeled in vitro. This model is potentially useful for assessing the ability of candidate PAH drugs to suppress medial thickening.


The Toronto Postliver Transplantation Hepatocellular Carcinoma Recurrence Calculator: A Machine Learning Approach.
Liver transplantation (LT) listing criteria for hepatocellular carcinoma (HCC) remain controversial. To optimize the utility of limited donor organs, this study aims to leverage machine learning to develop an accurate posttransplantation HCC recurrence prediction calculator. Patients with HCC listed for LT from 2000 to 2016 were identified, with 739 patients who underwent LT used for modeling. Data included serial imaging, alpha-fetoprotein (AFP), locoregional therapies, treatment response, and posttransplantation outcomes. We compared the CoxNet (regularized Cox regression), survival random forest, survival support vector machine, and DeepSurv machine learning algorithms via the mean cross-validated concordance index. We validated the selected CoxNet model by comparing it with other currently available recurrence risk algorithms on a held-out test set (AFP, Model of Recurrence After Liver Transplant [MORAL], and Hazard Associated with liver Transplantation for Hepatocellular Carcinoma [HALT-HCC score]). The developed CoxNet-based recurrence prediction model showed a satisfying overall concordance score of 0.75 (95% confidence interval [CI], 0.64-0.84). In comparison, the recalibrated risk algorithms' concordance scores were as follows: AFP score 0.64 (outperformed by the CoxNet model, 1-sided 95% CI, >0.01; P = 0.04) and MORAL score 0.64 (outperformed by the CoxNet model 1-sided 95% CI, >0.02; P = 0.03). The recalibrated HALT-HCC score performed well with a concordance of 0.72 (95% CI, 0.63-0.81) and was not significantly outperformed (1-sided 95% CI, ≥0.05; P = 0.29). Developing a comprehensive posttransplantation HCC recurrence risk calculator using machine learning is feasible and can yield higher accuracy than other available risk scores. Further research is needed to confirm the utility of machine learning in this setting.


Experimentally testing the accuracy of an extinction estimator: Solow's optimal linear estimation model.
Mathematical methods for inferring time to extinction have been widely applied but poorly tested. Optimal linear estimation (also called the 'Weibull' or 'Weibull extreme value' model) infers time to extinction from a temporal distribution of species sightings. Previous studies have suggested optimal linear estimation provides accurate estimates of extinction time for some species; however, an in-depth test of the technique is lacking. The use of data from wild populations to gauge the error associated with estimations is often limited by very approximate estimates of the actual extinction date and poor sighting records. Microcosms provide a system in which the accuracy of estimations can be tested against known extinction dates, whilst incorporating a variety of extinction rates created by changing environmental conditions, species identity and species richness. We present the first use of experimental microcosm data to exhaustively test the accuracy of one sighting-based method of inferring time of extinction under a range of search efforts, search regimes, sighting frequencies and extinction rates. Our results show that the accuracy of optimal linear estimation can be affected by both observer-controlled parameters, such as change in search effort, and inherent features of the system, such as species identity. Whilst optimal linear estimation provides generally accurate and precise estimates, the technique is susceptible to both overestimation and underestimation of extinction date. Microcosm experiments provide a framework within which the accuracy of extinction predictors can be clearly gauged. Variables such as search effort, search regularity and species identity can significantly affect the accuracy of estimates and should be taken into account when testing extinction predictors in the future.


Residues critical for duck hepatitis B virus neutralization are involved in host cell interaction.
To date, no detailed analysis of the neutralization properties of duck hepatitis B virus (DHBV) has been reported, and it is not clear whether any of the known neutralization epitopes correspond to the viral receptor binding site or to sequences involved in the cell entry pathway. We demonstrate here that antibodies directed against two overlapping peptides (amino acids 83 to 97 and 93 to 107), covering the sequences of most DHBV pre-S neutralizing epitopes, both inhibit virus binding to primary duck hepatocytes and neutralize virus infectivity. An extensive mutagenesis of the motif 88WTP90, which is the shortest sequence of the epitope recognized by the virus-neutralizing monoclonal antibody (MAb) 900 was performed in order to define the amino acids involved in these interactions. Single point mutations within this epitope affected neither virus replication nor infectivity but abolished virus neutralization by MAb 900 completely. Interestingly, mutants with two and three consecutive residue replacements (SIP and SIH) within this epitope retained replication competence but were no longer infectious. The loss of infectivity of SIH and SIP mutant particles was associated with significantly reduced binding to primary duck hepatocytes and could be rescued by trans complementation with wild-type pre-S protein. Taken together, these results indicate that each amino acid of the DHBV pre-S sequence 88WTP90 is critical for recognition by the neutralizing MAb 900 and that replacement of the first two or all three residues strongly reduces virus interaction with hepatocytes and abrogates infectivity. These data imply that the motif 88WTP90 contains key residues which are critical for interaction with both the neutralizing MAb and the host cell.


Increased speed and accuracy of single nucleotide polymorphism (SNP) quantification by quencher extension (QEXT).
Extract: Single nucleotide polymorphisms (SNPs) often represent allelic variants of genes. The differences between individuals within a species are mainly due to SNPs. SNPs are commonly used as genetic markers for genetic diseases and other phenotypic traits. Currently, throughput and accuracy are limiting factors in the widespread use of SNPs in diagnostics. A large number of both individuals and SNPs often have to be screened when searching for correlation between specific alleles and phenotypic traits. SNP genotyping analysis of one sample at a time is extremely costly and time consuming. Pooling DNA samples prior to quantitative SNP allele frequency determination in affected and control populations is an attractive way to increase throughput and reduce costs. Individual genotyping is only done when there is a significant discrepancy in allele frequencies between the affected and control populations. Despite extensive efforts, the technology to accurately quantify SNPs in sample pools is still lacking.


NHS cadet schemes: do they widen access to professional healthcare education?
The aim of this paper is to report a study investigating the extent to which National Health Service cadet schemes widen access to professional health care education. Cadet schemes have been reintroduced in the United Kingdom to increase recruitment of nurses and other health care staff to the National Health Service and also to widen access and increase participation in professional health care education by groups poorly represented in such education, including minority ethnic groups. A questionnaire survey of all cadet schemes (n = 62) in England at the time of the study was carried out, and the respondents were cadet scheme leaders (n = 62) and cadet students (n = 411). The questionnaires to scheme leaders enquired about when the schemes were established, what the schemes were preparing cadets for, modes of delivery and entry qualifications. The questionnaires to cadets enquired about age, gender, family circumstances, prior experience and ethnic background. The majority of schemes had been established since the health service reforms of 1999 and most were preparing cadets to enter professional nurse education programmes. Very few provided opportunities for part-time study and some asked for entry qualifications. Cadets were younger on entry than a comparator group of student nurses, fewer were married, fewer had previous employment or health-related employment and a lower percentage of cadets were white. Cadet schemes have the potential to widen access to professional health care study, but there is only limited evidence that they are doing so. In particular there was a lack of mature entrants to health care professional education via the schemes. However, the majority of schemes offered a route into professional education for students who did not hold sufficient educational qualifications for direct entry to professional health care education. It is encouraging that cadet schemes appear to be attracting a significantly greater proportion of students from Black and minority ethnic groups than preregistration nursing programmes overall.