Towards the optimal design of numerical experiments.
This paper addresses the problem of the optimal design of numerical experiments for the construction of nonlinear surrogate models. We describe a new method, called learner disagreement from experiment resampling (LDR), which borrows ideas from active learning and from resampling methods: the analysis of the divergence of the predictions provided by a population of models, constructed by resampling, allows an iterative determination of the point of input space, where a numerical experiment should be performed in order to improve the accuracy of the predictor. The LDR method is illustrated on neural network models with bootstrap resampling, and on orthogonal polynomials with leave-one-out resampling. Other methods of experimental design such as random selection and D-optimal selection are investigated on the same benchmark problems.


Vestibular evoked myogenic potential responses in obstructive sleep apnea syndrome.
Obstructive sleep apnea syndrome (OSAS) provokes oxidative stress and ischemia, which affects the central nervous system. The degeneration of neurons in the brainstem due to periodic hypoxia can be evaluated by vestibular and audiologic tests. The objective of this study is to determine brainstem damage in severe OSAS patients with the help of vestibular evoked myogenic potential (VEMP) responses. Prospective, randomize, double-blind. Research-training hospital. We compared cervical vestibular evoked myogenic potential (cVEMP) responses between severe OSAS patients and a control group. 54 patients were included and divided into the OSAS group, with severe OSAS (apnea-hypopnea index, AHI >70), and a control group with snoring without OSAS (AHI <5). Both groups underwent cVEMP. Bilateral recordings with simultaneous binaural logon stimulations were used during VEMP recordings. The existing p1n1 and n2p2 responses, p1, n1, n2, and p2 latencies and amplitudes, and p1n1 and n2p2 intervals were measured. Statistically significant differences were revealed between patients and controls for the response rate of the p1n1, n2p2 and p1n1, n2p2 amplitudes. There were no significant differences between the two groups with respect to the latencies of p1, n1, n2 and p2, or the p1n1 and n2p2 intervals. The VEMP response rate was lower in severe OSAS patients, and all amplitudes were shorter than in healthy subjects. VEMP recordings in severe OSAS subjects demonstrates abnormalities in brainstem pathways. It appears that brainstem damage in severe OSAS can be detected by cVEMP recordings.


Structure and Characterization of Phosphoglucomutase 5 from Atlantic and Baltic Herring-An Inactive Enzyme with Intact Substrate Binding.
Phosphoglucomutase 5 (PGM5) in humans is known as a structural muscle protein without enzymatic activity, but detailed understanding of its function is lacking. PGM5 belongs to the alpha-D-phosphohexomutase family and is closely related to the enzymatically active metabolic enzyme PGM1. In the Atlantic herring, Clupea harengus, PGM5 is one of the genes strongly associated with ecological adaptation to the brackish Baltic Sea. We here present the first crystal structures of PGM5, from the Atlantic and Baltic herring, differing by a single substitution Ala330Val. The structure of PGM5 is overall highly similar to structures of PGM1. The structure of the Baltic herring PGM5 in complex with the substrate glucose-1-phosphate shows conserved substrate binding and active site compared to human PGM1, but both PGM5 variants lack phosphoglucomutase activity under the tested conditions. Structure comparison and sequence analysis of PGM5 and PGM1 from fish and mammals suggest that the lacking enzymatic activity of PGM5 is related to differences in active-site loops that are important for flipping of the reaction intermediate. The Ala330Val substitution does not alter structure or biophysical properties of PGM5 but, due to its surface-exposed location, could affect interactions with protein-binding partners.


Adenosine signalling in airways.
Current research endeavours indicate that adenosine elicits strong inflammatory responses in the lung and might be involved in the pathogenic mechanisms of chronic inflammatory disorders of the airways such as asthma and chronic obstructive pulmonary disease (COPD). The contribution of adenosine-associated effector mechanisms to the initiation, persistence and progression of the inflammatory response is highly heterogeneous and is dictated by the expression pattern of four different adenosine receptors. Selective activation or blockade of these sites can therefore be exploited in an attempt to generate novel therapies for asthma and COPD. In addition, an important development is the use of adenosine (or AMP) as a diagnostic test for discriminating asthma from COPD, and as an accurate biomarker to monitor corticosteroid requirements in asthma. It is likely that therapies interfering with adenosine signalling in the airways will offer a considerable advance in the management of asthma and COPD.


Brief Report: Public Awareness of Asperger Syndrome Following Greta Thunberg Appearances.
Thunberg's increased media attention coupled with her diagnosis-Asperger Syndrome (AS)-may foster help-seeking behaviors among those with similar psychiatric disorders. Using Google Trends data, we compared values of AS from the week of the UN Climate Summit through the end of the year compared to an ARIMA model predicting search interest had Thunberg not been in the media. The search trend for AS at peak was 254.07% higher than predicted and was on average 10.61 points above the projected model during this time. As the primary goal of AS intervention focuses on improving quality of life and preventing common comorbidities such as depression and anxiety, capitalizing on increased public interest in AS and help-seeking behaviors is imperative.


Local Perspectives on Environmental Insecurity and Its Influence on Illegal Biodiversity Exploitation.
Environmental insecurity is a source and outcome of biodiversity declines and social conflict. One challenge to scaling insecurity reduction policies is that empirical evidence about local attitudes is overwhelmingly missing. We set three objectives: determine how local people rank risk associated with different sources of environmental insecurity; assess perceptions of environmental insecurity, biodiversity exploitation, myths of nature and risk management preferences; and explore relationships between perceptions and biodiversity exploitation. We conducted interviews (N = 88) with residents of Madagascar's Torotorofotsy Protected Area, 2014. Risk perceptions had a moderate effect on perceptions of environmental insecurity. We found no effects of environmental insecurity on biodiversity exploitation. Results offer one if not the first exploration of local perceptions of illegal biodiversity exploitation and environmental security. Local people's perception of risk seriousness associated with illegal biodiversity exploitation such as lemur hunting (low overall) may not reflect perceptions of policy-makers (considered to be high). Discord is a key entry point for attention.


Calcium homeostasis in chronic streptozotocin-induced diabetes mellitus in the rat.
Calcium homeostasis was studied in freely fed control, streptozotocin diabetic, long-term and short-term insulin-treated diabetic rats 7 wk after the induction of diabetes. In contrast to the short-term (5-12 day) diabetic rat model, intestinal absorption of calcium was markedly enhanced in chronically insulin-deficient animals. Moreover, conventional balance studies showed that these animals were in positive calcium balance despite severe hypercalciuria. Intestinal hyperabsorption of calcium in long-standing diabetic rats occurred despite low levels of circulating 1,25-dihydroxyvitamin D and hypercorticosteronism and was attended by hypercalcemia and suppression of both plasma parathyroid hormone (PTH) and urinary cyclic 3',5'-AMP (cAMP). Long-term insulin replacement completely normalized the intestinal hyperabsorption of calcium, corrected the plasma calcium, and significantly increased circulating PTH and urinary cAMP excretion. Insulin therapy also corrected the decreased plasma 1,25-dihydroxyvitamin D observed in untreated diabetic animals. Intestinal hyperabsorption of calcium appeared to be only partially corrected by short-term insulin therapy. The accumulated results reveal decided differences in calcium homeostasis and hormonal response between the rats with long-standing diabetes and those with diabetes of short duration.


Attitudes of medical students to medical leadership and management: a systematic review to inform curriculum development.
There is a growing acknowledgement that doctors need to develop leadership and management competences to become more actively involved in the planning, delivery and transformation of patient services. We undertook a systematic review of what is known concerning the knowledge, skills and attitudes of medical students regarding leadership and management. Here we report the results pertaining to the attitudes of students to provide evidence to inform curriculum development in this developing field of medical education. We searched major electronic databases and citation indexes within the disciplines of medicine, education, social science and management. We undertook hand searching of major journals, and reference and citation tracking. We accessed websites of UK medical institutions and contacted individuals working within the field. 26 studies were included. Most were conducted in the USA, using mainly quantitative methods. We used inductive analysis of the topics addressed by each study to identity five main content areas: Quality Improvement; Managed Care, Use of Resources and Costs; General Leadership and Management; Role of the Doctor, and Patient Safety. Students have positive attitudes to clinical practice guidelines, quality improvement techniques and multidisciplinary teamwork, but mixed attitudes to managed care, cost containment and medical error. Education interventions had variable effects on students' attitudes. Medical students perceive a need for leadership and management education but identified lack of curriculum time and disinterest in some activities as potential barriers to implementation. The findings from our review may reflect the relatively little emphasis given to leadership and management in medical curricula. However, students recognise a need to develop leadership and management competences. Although further work needs to be undertaken, using rigorous methods, to identify the most effective and cost-effective curriculum innovations, this review offers the only currently available summary of work examining the attitudes of students to this important area of development for future doctors.


Economic analysis of continuous antibiotic prophylaxis for prevention of urinary tract infections in infants with high-grade hydronephrosis.
For infants with hydronephrosis, continuous antibiotic prophylaxis (CAP) may reduce urinary tract infections (UTIs); however, its value remains controversial. Recent studies have suggested that neonates with severe obstructive hydronephrosis are at an increased risk of UTIs, and support the use of CAP. Other studies have demonstrated the negligible risk for UTIs in the setting of suspected ureteropelvic junction obstruction and have highlighted the limited role of CAP in hydronephrosis. Furthermore, economic studies in this patient population have been sparse. This study aimed to evaluate whether the use of CAP is an efficient expenditure for preventing UTIs in children with high-grade hydronephrosis within the first 2 years of life. A decision model was used to estimate expected costs, clinical outcomes and quality-adjusted life years (QALYs) of CAP versus no CAP (Fig. 1). Cost data were collected from provincial databases and converted to 2013 Canadian dollars (CAD). Estimates of risks and health utility values were extracted from published literature. The analysis was performed over a time horizon of 2 years. One-way and probabilistic sensitivity analyses were carried out to assess uncertainty and robustness. Overall, CAP use was less costly and provided a minimal increase in health utility when compared to no CAP (Table). The mean cost over two years for CAP and no CAP was CAD$1571.19 and CAD$1956.44, respectively. The use of CAP reduced outpatient-managed UTIs by 0.21 infections and UTIs requiring hospitalization by 0.04 infections over 2 years. Cost-utility analysis revealed an increase of 0.0001 QALYs/year when using CAP. The CAP arm exhibited strong dominance over no CAP in all sensitivity analyses and across all willingness-to-pay thresholds. The use of CAP exhibited strong dominance in the economic evaluation, despite a small gain of 0.0001 QALYs/year. Whether this slight gain is clinically significant remains to be determined. However, small QALY gains have been reported in other pediatric economic evaluations. Strengths of this study included the use of data from a recent systematic review and meta-analysis, in addition to a comprehensive probabilistic sensitivity analysis. Limitations of this study included the use of estimates for UTI probabilities in the second year of life and health utility values, given that they were lacking in the literature. Spontaneous resolution of hydronephrosis and surgical management were also not implemented in this model. To prevent UTIs within the first 2 years of life in infants with high-grade hydronephrosis, this probabilistic model has shown that CAP use is a prudent expenditure of healthcare resources when compared to no CAP.


Transplantation immunology 1957-1975.
Knowledge of the transplantation immunity has increased rapidly in the past twenty years. The rejection of allograft is now known to involve the interaction of several subsets of lymphocytes, as well as humoral immunity. Efforts to suppress immunity to the allograft are effective but suppress other kinds of immunity also, thus rendering the recipient susceptible to opportunistic infections. Two approaches to modification of the immune response by impairing the ability of cells sensitized specifically against allograft antigen to kill such cells are described. These agents can and have been used therapeutically in humans for other reasons and have been shown in the laboratory to actually markedly prolong the life of renal allograft, without impairing the immune response to other antigens.


Taurine promotes muscle fiber type transformation through CaN/NFATc1 signaling in porcine myoblasts.
This study investigated the effect of taurine (TAU) on the muscle fiber type transformation in porcine myoblasts and its molecular mechanisms. The findings revealed that TAU augmented the protein expression of slow MyHC and the enzyme activities of oxidative metabolism markers like malate dehydrogenase and succinic dehydrogenase. Conversely, it curtailed the expression of fast MyHC and glycolytic metabolism enzyme activity of lactate dehydrogenase. Moreover, TAU elevated the expression of genes associated with oxidative fiber while diminishing the expression of those linked to glycolytic fibers, suggesting that TAU promoted the muscle fiber type transformation from glycolytic fiber to oxidative fiber. Additionally, TAU notably enhanced the expression of key molecules of calcineurin (CaN)/nuclear factor of activated T cells c1 (NFATc1) signaling and the CaN activity in porcine myoblasts. However, CaN inhibitor cyclosporine A abolished these effects induced by TAU. Our results indicated that TAU regulated the muscle fiber type transformation from glycolytic to oxidative fiber by activation of CaN/NFATc1 signaling.


Crystal Polymorphism Induced by Surface Tension.
We use classical density functional theory (cDFT) to calculate fluid-solid surface tensions for fcc and bcc crystals formed by hard spheres and Lennard-Jones (LJ) particles. For hard spheres, our results show that the recently introduced "explicitly stable" functionals perform as well as the state of the art, and for both interaction potentials, our results compare well to simulation. We use the resulting bulk and interfacial energies for LJ to parametrize a capillary model for the free energy of small solid clusters and thereby determine the relative stability of bcc and fcc LJ clusters. We show a crossover from bcc to fcc stability as cluster size increases, thus providing insight into long-standing tension between simulation results and theoretical expectations. We also confirm that the bcc phase in contact with a vapor is unstable, thus extending earlier zero-temperature results. Our Letter demonstrates the potential of cDFT as an important tool in understanding crystallization and polymorphism.


Pay-for-performance policy and data-driven decision making within nursing homes: a qualitative study.
Health systems globally and within the USA have introduced nursing home pay-for-performance (P4P) programmes in response to the need for improved nursing home quality. Central to the challenge of administering effective P4P is the availability of accurate, timely and clinically appropriate data for decision making. We aimed to explore ways in which data were collected, thought about and used as a result of participation in a P4P programme. Semistructured interviews were conducted with 232 nursing home employees from within 70 nursing homes that participated in P4P-sponsored quality improvement (QI) projects. Interview data were analysed to identify themes surrounding collecting, thinking about and using data for QI decision making. The term 'data' appeared 247 times in the interviews, and over 92% of these instances (228/247) were spontaneous references by nursing home staff. Overall, 34% of respondents (79/232) referred directly to 'data' in their interviews. Nursing home leadership more frequently discussed data use than direct care staff. Emergent themes included using data to identify a QI problem, gathering data in new ways at the local level, and measuring outcomes in response to P4P participation. Alterations in data use as a result of policy change were theoretically consistent with the revised version of the Promoting Action on Research Implementation in Health Services framework, which posits that successful implementation is a function of evidence, context and facilitation. Providing a reimbursement context that facilitates the collection and use of reliable local evidence may be an important consideration to others contemplating the adaptation of P4P policies.


Health Economists on Involving Patients in Modeling: Potential Benefits, Harms, and Variables of Interest.
Patient involvement in health economics modeling has been advocated on numerous grounds, including as a way to better manage social and ethical value judgments in the modeling process. However, some have pointed to potential risks and variables that could influence the overall benefit of involvement. To inform future research, there is a need to generate knowledge on potential benefits, harms, and variables relevant to patient involvement in health economics modeling. This analysis used data from a qualitative study in which 22 health economists were asked their views on the possibility of involving patients in the modeling process. Using qualitative methods, the authors organized participants' responses into theory-driven categories ("potential benefits", "potential harms", "variables of interest") and identified data-driven themes and subthemes within those categories. Findings point to potential benefits and harms to the model, modeler, patient, and modeling process. Variables of interest relevant to future research included patients' specific roles, modeler and patient characteristics, the goals of modeling, dynamics among participators, and features of high-level procedures. The findings raise a number of specific questions that may be fruitful to explore in future research on patient involvement in health economics modeling.


Electric acupuncture treatment of peripheral nerve injury.
54 cases of peripheral nerve injury were treated by electric acupuncture and compared with 54 control cases treated with supportive medication. The changes after treatment were observed chiefly by electromyography while sensory and motor improvement were also recorded as auxiliary indicators. The therapeutic results in the acupuncture group were 5 cases cured, 26 markedly effective, 19 improved, and 4 cases failed, a total effective rate of 92.6% in contrast to the 55.6% for the controls. Analysis of the therapeutic results showed that 1) those in the acupuncture group were significantly better than in the control group; 2) nerve injuries should be treated as early as possible; 3) the radial nerve and the common peroneal nerve recovered faster than others; 4) cases not surgically explored recovered faster than those that were, and 5) patients with prompt propagation of the needling sensation recovered significantly faster than those with slow propagation.


Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus.
Individuals with sleep apnea often exhibit changes in cognitive behaviors consistent with alterations in the hippocampus. It is hypothesized that adult neurogenesis in the dentate gyrus is an ongoing process that maintains normal hippocampal function in many mammalian species, including humans. However, the impact of chronic intermittent hypoxia (IH), a principal consequence of sleep apnea, on hippocampal adult neurogenesis remains unclear. Using a murine model, we examined the impact of 30 d of IH (IH30) on adult neurogenesis and synaptic plasticity in the dentate gyrus. Although IH30 did not affect paired-pulse facilitation, IH30 suppressed long-term potentiation (LTP). Immunohistochemical experiments also indicate that IH perturbs multiple aspects of adult neurogenesis. IH30 increased the number of proliferating Sox2+ neural progenitor cells in the subgranular zone yet reduced the number of doublecortin-positive neurons. Consistent with these findings, cell lineage tracing revealed that IH30 increased the proportion of radial glial cells in the subgranular zone, yet decreased the proportion of adult-born neurons in the dentate gyrus. While administration of a superoxide anion scavenger during IH did not prevent neural progenitor cell proliferation, it mitigated the IH-dependent suppression of LTP and prevented adult-born neuron loss. These data demonstrate that IH causes both reactive oxygen species-dependent and reactive oxygen species-independent effects on adult neurogenesis and synaptic plasticity in the dentate gyrus. Our findings identify cellular and neurophysiological changes in the hippocampus that may contribute to cognitive and behavioral deficits occurring in sleep apnea.SIGNIFICANCE STATEMENT Individuals with sleep apnea experience periods of intermittent hypoxia (IH) that can negatively impact many aspects of brain function. Neurons are continually generated throughout adulthood to support hippocampal physiology and behavior. This study demonstrates that IH exposure attenuates hippocampal long-term potentiation and reduces adult neurogenesis. Antioxidant treatment mitigates these effects indicating that oxidative signaling caused by IH is a significant factor that impairs synaptic plasticity and reduces adult neurogenesis in the hippocampus.


Elevation of plasma antidiuretic hormones (ADH) associated with chemotherapy-induced emesis in man.
Eleven randomly hydrated patients with metastatic malignancies received iv bolus chemotherapy. Serial observations of plasma antidiuretic hormone (ADH), serum osmolality, blood pressure, and presence of nausea or emesis were made over the next 3-4 hours. Group 1 (four patients) had no nausea or emesis and no change in ADH, osmolality, or mean blood pressure. Group 2 (seven patients) had nausea and emesis following chemotherapy, with an increase in mean ADH from a baseline level of 5.53 pg/ml to a peak after emesis of 33.83 pg/ml. Group 2 had no significant increase in osmolality or decrease in mean blood pressure before emesis. ADH levels increased 0-40 minutes before emesis and peaked 28-115 minutes (mean, 66) after emesis. Emesis caused by chemotherapy agents is associated with rapid, significant increases in plasma ADH levels, independent of changes in osmolality or blood pressure.


Calcinosis in scleroderma.
To provide an update on the available literature regarding the epidemiology, pathophysiology, diagnosis, and treatment of calcinosis cutis in patients with systemic sclerosis (SSc). We identified observational studies that describe the frequency of calcinosis in SSc and associated clinical features; molecular studies exploring potential pathogenic mechanisms; and case reports and case series describing new diagnostic approaches and treatments. Calcinosis cutis is the deposition of insoluble calcium in the skin and subcutaneous tissues. It represents a major clinical problem in patients with SSc affecting at least one quarter of patients. It is associated with longer disease duration, digital ulcers, acro-osteolysis, positive anticentromere antibody, and positive anti-PM/Scl antibody. Although pathogenesis is unknown, there is evidence supporting local trauma, chronic inflammation, vascular hypoxia, and dysregulation of bone matrix proteins as potential mechanisms. Diagnosis can be made clinically or with plain radiography. Several pharmacologic therapies have been tried for calcinosis with variable and modest results, but surgical excision of calcium deposits remains the mainstay of treatment.


Weight changes in postpartum women with remitted depression.
To compare weight loss after birth in women who took the antidepressants nortriptyline or sertraline or placebo in 2 clinical studies designed to prevent recurrent postpartum major depression. Data were collected from 1995 to 2001. All subjects had at least 1 prior episode of Research Diagnostic Criteria- or DSM-IV-defined major depressive disorder. Data on weight were available for 467 weeks from 60 women who were weighed 8 times from 2 to 17 weeks postpartum. The dependent measures were weight at weeks 11 and 17 and weight change from weeks 2 to 17 postpartum. At week 17, the women's weights ranged from 109 to 268 lb. Their weight change ranged from +14 to -19 lb over the 15-week postpartum period (mean = -1.8, SD = 5.1 lb). After controlling for week 2 weights, the mean weights at week 17 for the women treated with nortriptyline, sertraline, or placebo were not significantly different. Of 60 women with 3 or more weight assessments, those who were randomly assigned to nortriptyline lost weight more rapidly than the other 2 groups; however, the mean weight change across all groups was only -1.8 lb (SD = 5.1 lb). Weight loss was not compromised by antidepressant pharmacotherapy. Postpartum weight retention occurred in this group of nondepressed women with previous histories of major depression independent of drug treatment.


Peptide-based glioma-targeted drug delivery vector gHoPe2.
Gliomas are therapeutically challenging cancers with poor patient prognosis. New drug delivery strategies are needed to achieve a more efficient chemotherapy-based approach against brain tumors. The current paper demonstrates development of a tumor-targeted delivery vector that is based on a cell-penetrating peptide pVEC and a novel glioma-targeting peptide sequence gHo. The unique tumor-homing peptide gHo was identified using in vitro phage display technology. The novel delivery vector, which we designated as gHoPe2, was constructed by a covalent conjugation of pVEC, gHo, and a cargo; the latter could be either a labeling moiety (such as a fluorescent marker) or a cytostatic entity. Using a fluorescent marker, we demonstrate efficient uptake of the vector in glioma cells and selective labeling of glioma xenograft tumors in a mouse model. This is the first time that we know where in vitro phage display has yielded an efficient, in vivo working vector. We also demonstrate antitumor efficacy of the delivery vector gHoPe2 using a well-characterized chemotherapeutic drug doxorubicin. Vectorized doxorubicin proved to be more efficient than the free drug in a mouse glioma xenograft model after systemic administration of the drugs. In conclusion, we have characterized a novel glioma-homing peptide gHo, demonstrated development of a new and potential glioma-targeted drug delivery vector gHoPe2, and demonstrated the general feasibility of the current approach for constructing cell-penetrating peptide-based targeted delivery systems.


Quantitative evaluation of neutrophilic chemotaxis in beagles.
A quantitative evaluation of neutrophilic chemotaxis was performed, using neutrophils from 12 healthy Beagles. Dextran sedimentation, differential centrifugation, and hypotonic lysis allowed separation of a neutrophil-rich cell suspension. Chemotaxis was studied, using blind-well chambers with 3-micrometers (APD) polycarbonate filters. A frozen (-80 C) bank of pooled normal canine serum was used as the chemotactant, and the chemotactant properties of the serum were destroyed by heat inactivation at 56 C for 30 minutes. Based on membrane and lower blind-well chamber solution neutrophil counts, a method was devised to distinguish between normal neutrophilic chemotaxis, normal neutrophilic chemotaxis with decreased neutrophilic adherence, and defective neutrophilic chemotaxis.


Adhesion and migration, the diverse functions of the laminin alpha3 subunit.
The laminins are a secreted family of heterotrimeric molecules essential for basement membrane formation, structure, and function. It is now well established that the alpha3 subunit of laminins-332, -321, and -311 plays an important role in mediating epidermal-dermal integrity and is essential for the skin to withstand mechanical stresses. These laminins also regulate cell migration and mechanosignal transduction. This article provides an overview of the gene, transcripts, and protein structures of laminin alpha3. Also discussed are the proposed functions for the alpha3 subunit-containing laminins.


Of sound mind and body: depression, disease, and accelerated aging.
Major depressive disorder (MDD) is associated with a high rate of developing serious medical comorbidities such as cardiovascular disease, stroke, dementia, osteoporosis, diabetes, and the metabolic syndrome. These are conditions that typically occur late in life, and it has been suggested that MDD may be associated with "accelerated aging." We review several moderators and mediators that may accompany MDD and that may give rise to these comorbid medical conditions. We first review the moderating effects of psychological styles of coping, genetic predisposition, and epigenetic modifications (eg, secondary to childhood adversity). We then focus on several interlinked mediators occurring in MDD (or at least in subtypes of MDD) that may contribute to the medical comorbidity burden and to accelerated aging: limbic-hypothalamic-pituitary-adrenal axis alterations, diminution in glucocorticoid receptor function, altered glucose tolerance and insulin sensitivity, excitotoxicity, increases in intracellular calcium, oxidative stress, a proinflammatory milieu, lowered levels of "counter-regulatory" neurosteroids (such as allopregnanolone and dehydroepiandrosterone), diminished neurotrophic activity, and accelerated cell aging, manifest as alterations in telomerase activity and as shortening of telomeres, which can lead to apoptosis and cell death. In this model, MDD is characterized by a surfeit of potentially destructive mediators and an insufficiency of protective or restorative ones. These factors interact in increasing the likelihood of physical disease and of accelerated aging at the cellular level. We conclude with suggestions for novel mechanism-based therapeutics based on these mediators.


Association between number of wild birds sampled for identification of H5N1 avian influenza virus and incidence of the disease in the European Union.
Fourteen European Union (EU) countries have been affected by highly pathogenic avian influenza (HPAI) of the subtype H5N1 since 2005. Many of the H5N1 HPAI cases have been identified in wild bird populations from aquatic habitats. The objective of this contribution was to assess the association between the H5N1 HPAI incidence, estimated by a co-kriging approach, and the number of wild birds sampled for H5N1 HPAI surveillance in EU countries. The probability that a sample for H5N1 HPAI surveillance collected in the EU was obtained from a given country was associated (P<0.01) with the probability that a H5N1 HPAI case reported in the EU was located in the same country. The relation between probability of sampling and probability of infection in the Netherlands and in Spain was significantly higher (P<0.01) than that estimated in other EU countries, suggesting that political or social factors may have selectively influenced the number of samples for H5N1 HPAI surveillance collected in those two countries. The approach presented here will be useful for post hoc comparison of the relation between probability or risk for disease and the intensity of surveillance activities among administrative divisions of a region.


Influence of the dietary potassium intake on the natriuretic effect of hydrochlorothiazide in rats.
Hydrochlorothiazide (HCTZ)-induced Na requirement was examined in rats fed a standard diet containing 250 mg of HCTZ per kg of food and given a free choice between water and 0.46 M NaCl. HCTZ treatment led to a persistent 8-fold increase of NaCl intake. An increase of the K content of the food from 100 to 600 mmol/kg reduce the NaCl intake by 75%. Maintenance on a high K diet prevented the HCTZ-induced requirement for extra Na and diminished HCTZ-induced loss of body weight and urinary loss of Na. Determinations of lithium clearance (CLi) in unanesthetized rats by using nontoxic doses of lithium was used as a measure of Na clearance at the end of the proximal tubules (CNa prox). The urinary sodium clearance divided by the urinary lithium clearance (CNa/CLi) was used to express the fractional escape of Na from distal reabsorption. In HCTZ-treated rats, maintenance on a high K diet reduced CNa and CNa/CLi. A high potassium intake increased CNa prox, but this effect was least in HCTZ-treated rats. The results show that a high K intake reduced the natriuretic effect of HCTZ. The renal mechanism is presumably a potassium-induced compensatory increase of the reabsorption of Na delivered from the proximal tubules.


Perceptions about Research Participation among Individuals at Risk and Individuals with Premanifest Huntington's Disease: A Survey Conducted by the European Huntington Association.
There has been great progress in Huntington's disease (HD) research. Yet, effective treatments to halt disease before the onset of disabling symptoms are still unavailable. Scientific breakthroughs require an active and lasting commitment from families. However, they are traditionally less involved and heard in studies. Accordingly, the European Huntington Association (EHA) surveyed individuals at risk (HDRisk) and with premanifest HD (PreHD) to determine which factors affect their willingness to participate in research. Questions assessed research experience and knowledge, information sources, reasons for involvement and noninvolvement, and factors preventing and facilitating participation. The survey included 525 individuals, of which 68.8% never participated in studies and 38.6% reported limited research knowledge. Furthermore, 52% trusted patient organizations to get research information. Reasons for involvement were altruistic and more important than reasons for noninvolvement, which were related to negative emotions. Obstacles included time/financial constraints and invasive procedures, while professional support was seen as a facilitator. PreHD individuals reported less obstacles to research participation than HDRisk individuals. Overall, a high motivation to participate in research was noted, despite limited experience and literacy. This motivation is influenced by subjective and objective factors and, importantly, by HD status. Patient organizations have a key role in fostering motivation through education and support.


Anti-Inflammatory Targets for the Treatment of Reperfusion Injury in Stroke.
While the mainstay of acute stroke treatment includes revascularization via recombinant tissue plasminogen activator or mechanical thrombectomy, only a minority of stroke patients are eligible for treatment, as delayed treatment can lead to worsened outcome. This worsened outcome at the experimental level has been attributed to an entity known as reperfusion injury (R/I). R/I is occurred when revascularization is delayed after critical brain and vascular injury has occurred, so that when oxygenated blood is restored, ischemic damage is increased, rather than decreased. R/I can increase lesion size and also worsen blood barrier breakdown and lead to brain edema and hemorrhage. A major mechanism underlying R/I is that of poststroke inflammation. The poststroke immune response consists of the aberrant activation of glial cell, infiltration of peripheral leukocytes, and the release of damage-associated molecular pattern (DAMP) molecules elaborated by ischemic cells of the brain. Inflammatory mediators involved in this response include cytokines, chemokines, adhesion molecules, and several immune molecule effectors such as matrix metalloproteinases-9, inducible nitric oxide synthase, nitric oxide, and reactive oxygen species. Several experimental studies over the years have characterized these molecules and have shown that their inhibition improves neurological outcome. Yet, numerous clinical studies failed to demonstrate any positive outcomes in stroke patients. However, many of these clinical trials were carried out before the routine use of revascularization therapies. In this review, we cover mechanisms of inflammation involved in R/I, therapeutic targets, and relevant experimental and clinical studies, which might stimulate renewed interest in designing clinical trials to specifically target R/I. We propose that by targeting anti-inflammatory targets in R/I as a combined therapy, it may be possible to further improve outcomes from pharmacological thrombolysis or mechanical thrombectomy.


Relapse in anorexia nervosa: a systematic review and meta-analysis.
Relapse is common in patients with anorexia nervosa. The aim of this study is to systematically review the existing literature on relapse in anorexia nervosa. A systematic literature search was conducted in PubMed, PsychInfo and CINAHL published up to April 2018. Of the 1527 studies screened, 16 studies were included in the present review. This analysis shows that, of the patients included in this review, 31% relapsed after treatment. The highest risk of relapse is during the first year after discharge and this risk continues for up to 2 years. An overview was made of all factors significantly associated with a higher risk of relapse, resulting in the following four clusters: eating disorder variables, comorbidity symptoms, process treatment variables and demographic variables. Future research on relapse prevention is necessary to further unravel the mechanisms that might lead to relapse.


Clinical significance of serum anti-human papillomavirus 16 and 18 antibodies in cervical neoplasia.
To estimate the clinical significance of serum anti-human papillomavirus (HPV) antibodies and high-risk cervical HPV DNA in cervical neoplasia. The study population comprised patients who were histopathologically diagnosed with cervical intraepithelial neoplasia (CIN) 1 (n=64), CIN 2 and 3 (n=241), cervical cancer (n=170), and normal control participants (n=975). Cervical HPV DNA tests were performed through nucleic acid hybridization assay tests, and serum anti-HPV 16 and 18 antibodies were measured by competitive immunoassay. The associations of HPV DNA and anti-HPV antibodies were evaluated with demographic characteristics and compared according to the levels of disease severity. Anti-HPV antibodies were also investigated with clinicopathologic parameters, including survival data. Among various demographic characteristics, factors involving sexual behavior had a higher tendency of HPV DNA positivity and HPV seropositivity. Human papillomavirus DNA mean titer and positivity were both increased in patients with cervical neoplasia compared with those with normal control participants, but there was no statistical difference among types of cervical neoplasia. Serum anti-HPV 16 antibodies were also able to differentiate cervical neoplasia from a normal control participant and furthermore distinguished CIN 1 from CIN 2 and 3 (odd ratio 2.87 [1.43-5.78], P=.002). In cervical cancer, HPV 16 seropositivity was associated with prolonged disease-free survival according to the univariable analysis (hazard ratio=0.12 [0.01-0.94], P=.044). Serum anti-HPV 16 antibodies can distinguish cervical neoplasia from a normal control and has the advantage of identifying high-grade CIN. Moreover, in cervical cancer, HPV 16 seropositivity may be associated with a more favorable prognosis. II.


Characterization of a calf diarrheal coronavirus.
A coronavirus-like agent isolated from feces of a calf with diarrhea and attenuated by consecutive passage in a fetal bovine kidney cell line was characterized as a coronavirus. Negatively stained virions were approximately circular, had a mean diameter of 120 nm, and were covered with wide-spaced, petal-shaped projections about 20 nm long. Virions in ultrathin sections of infected cell monolayers had a mean diameter of 80 nm, lacked surface projections, and were found within cytoplasmic vesicles. Viral antigen was demonstrated by immunofluorescence microscopy to occur only in cytoplasm. Growth of the virus was not inhibited by 5-iodo-2'- deoxyuridine and actinomycin D. The virus was sensitive to ether, chloroform, deoxycholate, and heat treatment. However, thermosensitivity was stabilized in the presence of 1 M MgCl2; at pH 3, the virus was stable. Hemadsorption and hemagglutination were observed with erythrocytes of hamsters, mice, and rats but not with erythrocytes of cats, dogs, goats, sheep, cattle, horses, turkeys, chickens, guinea pigs, rabbits, geese, pigs, and man (type O). However, hemadsorption and hemagglutination were shown to be virus specific, since this could be inhibited by specific antiserum. Both infectivity and hemagglutinating activity were maximal at a particle density of 1.18 g/ml by sucrose density gradient centrifugation, indicating that hemagglutinin was part of the virion.


Transfection of v-rasH DNA into MCF-7 human breast cancer cells bypasses dependence on estrogen for tumorigenicity.
The natural history of estrogen-responsive breast cancers often involves a phenotypic change to an estrogen-unresponsive, more aggressive tumor. The human breast cancer cell line, MCF-7, which requires estradiol for tumor formation in vivo and shows growth stimulation in response to estradiol in vitro, is a model for hormone-responsive tumors. The v-rasH onc gene was transfected into MCF-7 cells. The cloned MCF-7ras transfectants, which expressed the v-rasH messenger RNA and v-rasH p21 protein (21,000 daltons), were characterized. In contrast to the parental cell line, MCF-7ras cells no longer responded to exogenous estrogen in culture and their growth was minimally inhibited by exogenous antiestrogens. When tested in the nude mouse, the MCF-7ras cells were fully tumorigenic in the absence of estrogen supplementation. Thus, cells acquiring an activated onc gene can bypass the hormonal regulatory signals that trigger the neoplastic growth of a human breast cancer cell line.


Differential proteomics analysis of liver failure in peripheral blood mononuclear cells using isobaric tags for relative and absolute quantitation.
The aim of the present study was to examine differentially expressed proteome profiles for candidate biomarkers in peripheral blood mononuclear cells (PBMCs) of liver failure (LF) patients. Ten patients were diagnosed as LF and 10 age- and gender-matched subjects were recruited as healthy controls. Isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic technology is efficiently applicable for identification and relative quantitation of the proteomes of PBMCs. Eight-plex iTRAQ coupled with strong cation exchange chromatography, and liquid chromatography coupled with tandem mass spectrometry were used to analyze total proteins in LF patients and healthy control subjects. Molecular variations were detected using the iTRAQ method, and western blotting was used to verify the results. LF is a complex type of medical emergency that evolves following a catastrophic insult to the liver, and its outcome remains the most ominous of all gastroenterologic diseases. Serious complications tend to occur during the course of the disease and further exacerbate the problems. Using the iTRAQ method, differentially expressed proteome profiles of LF patients were determined. In the present study, 627 proteins with different expression levels were identified in LF patients compared with the control subjects; with 409 proteins upregulated and 218 proteins downregulated. Among them, four proteins were significantly differentially expressed; acylaminoacyl-peptide hydrolase and WW domain binding protein 2 were upregulated, and resistin and tubulin β 2A class IIa were downregulated. These proteins demonstrated differences in their expression levels compared with other proteins with normal expression levels and the significant positive correlation with LF. The western blot results were consistent with the results from iTRAQ. Thus, investigation of the molecular mechanism of the proteins involved in LF may facilitate an improved understanding of the pathogenesis of LF and elucidation of novel biomarker candidates.


Awareness of Cognitive Decline in Patients With Alzheimer's Disease: A Systematic Review and Meta-Analysis.
Background: Identifying a poor degree of awareness of cognitive decline (ACD) could represent an early indicator of Alzheimer's disease (AD). Objectives: (1) to understand whether there is evidence of poor ACD in the pre-dementia stages of AD; (2) to summarize the main findings obtained investigating ACD in AD; (3) to propose a conceptual framework. Data Sources: We searched Scopus, Pubmed, and the reference lists for studies published up to August 2020. Original research articles must report a measure of ACD and included individuals with AD dementia, or prodromal AD (or MCI), or being at risk for AD. Data Synthesis: All studies covering preclinical, prodromal, and AD dementia were systematically reviewed. We intended to perform a meta-analysis of empirical studies on preclinical AD or prodromal AD (or MCI), to compare ACD between clinical groups. Due to the paucity of literature on preclinical AD, meta-analysis was only possible for prodromal AD (or MCI) studies. Results: We systematically reviewed 283 articles, and conducted a meta-analysis of 18 articles on prodromal AD (or MCI), showing that ACD was not significantly different between patients with amnestic and non-amnestic MCI (SMD = 0.09, p = 0.574); ACD was significantly poorer in amnestic MCI (SMD = -0.56, p = 0.001) and mild AD (SMD = -1.39, p < 0.001) than in controls; ACD was also significantly poorer in mild AD than in amnestic MCI (SMD = -0.75, p < 0.001), as well as poorer than in non-amnestic MCI (SMD = -1.00, p < 0.001). We also discuss key findings on ACD in AD, such as its neural and cognitive correlates. Conclusions and Implications: We propose that patients may be complaining of their initial subtle cognitive changes, but ACD would soon start to decrease. The individual would show mild anosognosia in the MCI stage, and severe anosognosia in dementia. The evaluation of ACD (comparing self-report to cognitive scores or to informant-report) could be useful to guide the clinician toward a timely diagnosis, and in trials targeting early-stage AD.


Improving Appropriate Neurologic Prognostication after Cardiac Arrest. A Stepped Wedge Cluster Randomized Controlled Trial.
Predictions about neurologic prognosis that are based on early clinical findings after out-of-hospital cardiac arrest (OHCA) are often inaccurate and may lead to premature decisions to withdraw life-sustaining treatments (LST) in patients who might otherwise survive with good neurologic outcomes. To improve adherence to recommendations for appropriate neurologic prognostication after OHCA and reduce deaths from premature decisions to withdraw LST. This was a pragmatic stepped wedge cluster randomized controlled trial evaluating a multifaceted quality intervention (education, pathways, local champions, audit-feedback). The primary outcome was appropriate neurologic prognostication, defined as (1a) no early withdrawal of LST (WLST) (within 72 h) based on estimates of poor neurologic prognosis and (1b) no WLST between 72 hours and 7 days in absence of clinical predictors of poor neurologic prognosis or (2) surviving beyond 7 days. Secondary outcomes were deaths from early WLST and survival with good neurologic outcome. Between June 1, 2011, and June 30, 2014, a total of 905 patients with OHCA were enrolled from ICUs of 18 Ontario hospitals. Rates of appropriate neurologic prognostication increased after the intervention (68% vs. 74% patients; odds ratio [OR], 1.79; 95% confidence interval [CI], 1.01-3.19; P = 0.05). However, rates of survival to hospital discharge (46% vs. 50%; OR, 1.71; 95% CI, 0.97-3.01; P = 0.06) and survival with good neurologic outcome remained similar (38% vs. 43%; OR, 1.43; 95% CI, 0.84-2.86; P = 0.19). A multicenter quality intervention improved rates of appropriate neurologic prognostication after OHCA but did not increase survival with good neurologic outcome. Clinical trial registered with www.clinicaltrials.gov (NCT 01472458).


Mending the broken valentine heart: a case report.
Mortality from myocardial infarction (MI) has been decreasing since the introduction of primary percutaneous intervention. Late complications still pose a dilemma, such as deterioration of left ventricle (LV) function, LV aneurysms, and LV thrombus formation. If not adequately managed in a timely manner, this can result in life-threatening consequences. Restoration of LV function by surgical resection of the infarcted LV wall is an option for a few complicated cases, with variable outcomes. A 66-year-old man presented with dyspnoea 2 years after his initial MI, which was treated with a drug-eluting stent to his left circumflex artery. His Warfarin had been stopped after 6 months of treatment of a small LV thrombus, which was noted at the time of his initial infarction. His echocardiogram on admission demonstrated severe LV systolic impairment of 23% (which had deteriorated from 40%) with a giant true aneurysm of the basal to mid-lateral wall, which resembled a Valentine heart. The presence of a large, organized thrombus filling the aneurysm complicated the case further. The patient underwent a resection of the LV aneurysm and thrombus. He remained asymptomatic and maintained a significant improvement of his LV function to 47% at his 5 months scan. The importance of imaging post-large MI and follow-up imaging once thrombus resolution has occurred is crucial. Patients with large LV aneurysm associated with severe refractory LV impairment and LV thrombus should be considered for LV aneurysmectomy for prognostic benefit and symptom relief.


Migration and fertility in Ticino.
Summary Migration in the Swiss canton of Ticino is one example of the wide variety of demographic systems that existed in pre-industrial Europe. The continuous movement of men was a consequence of economic, social and geographic conditions which restricted the demand for labour. Seasonal migration and overseas migration were both sex and age selective. They resulted in an imbalance of the sex ratio and a remarkably low female nuptiality. They also reduced fertility within marriage by separating husbands and wives during their childbearing years. The effect of long, medium and short-term migration on fertility can be isolated from census and vital registration sources.


[Treatment results following compound osteosyntheses. Pathological fractures and osteolyses in the extremities].
65 combined osteosyntheses were applied to 49 patients for existent or imminent pathological fractures. The most frequent reason was carcinoma of the breast in 2/3 of the cases. Surgical intervention was done palliatively non radical in 52 cases as a posttraumatic and in 13 cases as a prophylactic procedure. Surgery was well tolerated by all patients with a primary hospital mortality of 10,2%. On an average the survival time for 10 patients still living was 22 1/2 months, for 39 patients who had died 8 1/2 months. In all cases a substantial increase in quality of life was gained, both by enabling the patient to use the extremity concerned almost without pain and by greatly relieving bedside care. These results indicate that combined osteosyntheses should be applied on a broader basis.


Permanent depression of plasma cGMP during long-term space flight.
The purpose of this study was to investigate plasma concentrations of cyclic guanosine monophosphate (cGMP) and atrial natriuretic peptide (ANP) during and after real and simulated space flight. Venous blood was obtained 3 min after the beginning and 2 min after the lower body negative pressure maneuver in two cosmonauts preflight (supine), inflight, and postflight (supine) and in five other subjects before, at the end, and 4 days after a 5-day head-down tilt (-6 degrees) bed rest. In cosmonaut 1 (10 days in space), plasma cGMP fell from preflight 4.3 to 1.4 nM on flight day 6, and was 3.0 nM on the fourth day after landing. In cosmonaut 2 (438 days in space), it fell from preflight 4.9 to 0.5 nM on on flight day 3, and stayed <0.1 nM with 5, 9, and 14 months in space, as well as on the fourth day after landing. Three months after the flight his plasma cGMP was back to normal (6.3 nM). Cosmonaut 2 also displayed relatively low inflight ANP values but returned to preflight level immediately after landing. In a ground-based simulation on five other persons, supine plasma cGMP was reduced by an average of 30% within 5 days of 6 degrees head-down tilt bed rest. The data consistently demonstrate lowered plasma cGMP with real and simulated weightlessness, and a complete disappearance of cGMP from plasma during, and shortly after long-duration space flight.


Pilot study for compact microbeam radiation therapy using a carbon nanotube field emission micro-CT scanner.
Microbeam radiation therapy (MRT) is defined as the use of parallel, microplanar x-ray beams with an energy spectrum between 50 and 300 keV for cancer treatment and brain radiosurgery. Up until now, the possibilities of MRT have mainly been studied using synchrotron sources due to their high flux (100s Gy/s) and approximately parallel x-ray paths. The authors have proposed a compact x-ray based MRT system capable of delivering MRT dose distributions at a high dose rate. This system would employ carbon nanotube (CNT) field emission technology to create an x-ray source array that surrounds the target of irradiation. Using such a geometry, multiple collimators would shape the irradiation from this array into multiple microbeams that would then overlap or interlace in the target region. This pilot study demonstrates the feasibility of attaining a high dose rate and parallel microbeam beams using such a system. The microbeam dose distribution was generated by our CNT micro-CT scanner (100 μm focal spot) and a custom-made microbeam collimator. An alignment assembly was fabricated and attached to the scanner in order to collimate and superimpose beams coming from different gantry positions. The MRT dose distribution was measured using two orthogonal radiochromic films embedded inside a cylindrical phantom. This target was irradiated with microbeams incident from 44 different gantry angles to simulate an array of x-ray sources as in the proposed compact CNT-based MRT system. Finally, phantom translation in a direction perpendicular to the microplanar beams was used to simulate the use of multiple parallel microbeams. Microbeams delivered from 44 gantry angles were superimposed to form a single microbeam dose distribution in the phantom with a FWHM of 300 μm (calculated value was 290 μm). Also, during the multiple beam simulation, a peak to valley dose ratio of ~10 was found when the phantom translation distance was roughly 4x the beam width. The first prototype CNT-based x-ray tube dedicated to the development of compact MRT technology development was proposed and planned based on the preliminary experimental results presented here and the previous corresponding Monte Carlo simulations. The authors have demonstrated the feasibility of creating microbeam dose distributions at a high dose rate using a proposed compact MRT system. The flexibility of CNT field emission x-ray sources could possibly bring compact and low cost MRT devices to the larger research community and assist in the translational research of this promising new approach to radiation therapy.


Muc5b is required for airway defence.
Respiratory surfaces are exposed to billions of particulates and pathogens daily. A protective mucus barrier traps and eliminates them through mucociliary clearance (MCC). However, excessive mucus contributes to transient respiratory infections and to the pathogenesis of numerous respiratory diseases. MUC5AC and MUC5B are evolutionarily conserved genes that encode structurally related mucin glycoproteins, the principal macromolecules in airway mucus. Genetic variants are linked to diverse lung diseases, but specific roles for MUC5AC and MUC5B in MCC, and the lasting effects of their inhibition, are unknown. Here we show that mouse Muc5b (but not Muc5ac) is required for MCC, for controlling infections in the airways and middle ear, and for maintaining immune homeostasis in mouse lungs, whereas Muc5ac is dispensable. Muc5b deficiency caused materials to accumulate in upper and lower airways. This defect led to chronic infection by multiple bacterial species, including Staphylococcus aureus, and to inflammation that failed to resolve normally. Apoptotic macrophages accumulated, phagocytosis was impaired, and interleukin-23 (IL-23) production was reduced in Muc5b(-/-) mice. By contrast, in mice that transgenically overexpress Muc5b, macrophage functions improved. Existing dogma defines mucous phenotypes in asthma and chronic obstructive pulmonary disease (COPD) as driven by increased MUC5AC, with MUC5B levels either unaffected or increased in expectorated sputum. However, in many patients, MUC5B production at airway surfaces decreases by as much as 90%. By distinguishing a specific role for Muc5b in MCC, and by determining its impact on bacterial infections and inflammation in mice, our results provide a refined framework for designing targeted therapies to control mucin secretion and restore MCC.


Use of monoclonal antibodies to confirm vaccine-induced rabies in ten dogs, two cats, and one fox.
A panel of 8 monoclonal antibodies to rabies glycoprotein antigen was used to characterize the modified-live virus vaccines marketed in the United States during the last 10 years. Thirteen of 14 rabies virus isolates from 11 dogs, 2 cats, and 1 fox suspected of developing vaccine-induced rabies were shown to have reactivity patterns that were identical to the vaccine administered. Reactivity patterns for 20 rabies isolates from human beings, wild animals, or domestic animals with no history of recent vaccination with modified-live virus rabies vaccine were different from those obtained for vaccines.


NLRP12 autoinflammatory disease: a Chinese case series and literature review.
As one of the systemic autoinflammatory diseases (SAIDs), the nucleotide-binding oligomerization domain-like receptor protein (NLRP)12 autoinflammatory disease (NLRP12-AD) is an autosomal dominant disorder associated with NLRP12 mutation. SAIDs have been hardly reported in the Chinese population, and NLRP12-AD has been reported only in Caucasians. We report the first case series of NLRP12-AD in the Chinese population coupled with literature review. Three Han Chinese adult patients with clinical phenotype suggestive of NLRP12-AD carrying NLRP12 variants were treated by the authors in 2015. Their phenotype and genotype were carefully studied. A PubMed search for SAIDs was conducted between January, 1990 and January, 2016, and we focused on NLRP12-AD. All three adult patients developed periodic disease in adulthood. They presented with recurrent fever (n = 3), polyarthralgia (n = 3), myalgia (n = 3), urticaria (n = 2), lymphadenopathy (n = 2), and erythema nodosa (n = 1). All patients carry the NLRP12 mutation F402L. Based upon our analysis of a total of 26 patients with NLRP12-AD in the literature, both familial and sporadic cases were equally reported and late-onset cases accounted for 28 %. NLRP12-AD patients typically present with periodic fever, urticaria-like rash, arthralgia/arthritis, myalgia, and lymphadenopathy. Genotyping identifies the NLRP12 gene mutations, notably F402L (55 %). Relative to the literature reports, our patients had the similar phenotypic and genotypic features. Patients with NLRP12-AD usually respond to glucocorticoid therapy. Our report is the first to confirm the presence of NLRP12-AD in the Chinese population. It highlights the importance of screening NLRP12 in patients with unexplained periodic fever syndrome.


The impact of the COVID-19 pandemic experiences on college drinking via mental distress: Cross-sectional mediation moderated by race.
The COVID-19 pandemic has been linked to stress, anxiety, and depression among college students, with heightened distress tied to greater drinking for some individuals. Emerging research suggests that these associations may differ across race, but few studies use adequate samples to examine this, particularly among college students, an at-risk population for both heavy drinking and mental distress. Specifically, pandemic-related stressors and mental distress may be higher among Black students than White students. The current study examined: (1) whether mental distress cross-sectionally mediates the association between pandemic-specific stressors and drinking and (2) whether race (Black or White) moderates these associations. A cross-sectional online survey of 400 college drinkers (43% White, 28% Black) in fall 2020 assessed pandemic-related stressors (e.g., losing a job, contracting COVID-19, changed living situation), mental distress (stress, anxiety, depression), and drinking (past-month drinking, perceived changes since the start of the pandemic). Cross-sectional mediation models indicated that financial stressors and social distancing were linked to greater quantity and frequency of past-month drinking through greater mental distress. For perceived changes in drinking, only financial stressors were linked to drinking greater quantities and drinking more often (compared to pre-pandemic levels) via mental distress. Moderated mediation models among students identifying as White or Black revealed that changed living situation was a robust stressor across race. Financial stressors and social distancing were linked with greater distress only among White students, whereas essential worker status was a protective factor against distress only among Black students. Select stressors were linked to increased drinking through greater mental distress, with differential risks across Black versus White students. Findings suggest campus administrators should focus on connecting students with resources (e.g., counseling centers and health promotion offices) during times of distress.


Effects of gait pattern and arm swing on intergirdle coordination.
Mature locomotion in humans is characterized by an anti-phase coordination (moving in opposite directions) between the pelvic and the scapular girdles. This pattern involves a specific relationship between the arm and leg motion is deemed to be most flexible and dynamically efficient. Still, when the arms are involved in another task, like a field player running with a ball in the hands, locomotion is still possible. In order to probe the flexibility of the locomotor synergy, the present study aimed to determine the persistence and the strength of the coordination patterns between the pelvic and scapular girdles when no arm swing was allowed during walking and running. Relative phase, the time difference between the girdle rotations, measured the ongoing inter-girdle coordination of eight healthy participants asked to walk and run with or without arm swing. Results showed that an absence of arm swing led to a change from an anti-phase to in-phase pattern (girdles moving in the same direction) and that an increase in velocity strengthened the adopted pattern. Moreover, the frequency distribution of relative phase for all gait patterns with arm swing proved to be bimodal, indicating that the prevailing anti-phase pattern was always mixed with a noticeable proportion of in-phase coordination. The presence of the in-phase pattern in the easy, natural locomotion with arm swing manifests its persistence and its stability, perhaps pertaining to its prevalence in earlier times in ontogeny or evolution.


Influence of common polymorphisms in the SLC5A2 gene on metabolic traits in subjects at increased risk of diabetes and on response to empagliflozin treatment in patients with diabetes.
Inhibition of the renal sodium-glucose cotransporter 2 (SGLT2) is a novel concept in the therapy of diabetes mellitus. In this study, we first assessed whether common single nucleotide polymorphisms (SNPs) in the SGLT2-encoding gene SLC5A2 affect diabetes-related metabolic traits in subjects at risk for type 2 diabetes and, second, whether these have pharmacogenetic relevance by interfering with the response to empagliflozin treatment in patients with type 2 diabetes. Samples from a metabolically well-phenotyped cross-sectional study population (total N=2600) at increased risk for type 2 diabetes and pooled pharmacogenetic samples from patients from four phase III trials of empagliflozin (in total: 603 receiving empagliflozin, 305 receiving placebo) were genotyped for five common SNPs (minor allele frequencies ≥5%) present in the SLC5A2 gene locus. In the cross-sectional study, none of the SLC5A2 SNPs significantly influenced metabolic traits such as body fat, insulin sensitivity/resistance, insulin release, HbA1c, plasma glucose, or systolic blood pressure when multiple testing was taken into account (all P≥0.0083). Further, no relevant effect on response to treatment with empagliflozin on HbA1c, fasting glucose, weight, or systolic blood pressure was observed for the SNPs tested in the pharmacogenetic study. Common genetic variants in the SLC5A2 gene neither affects diabetes-related metabolic traits nor have a clinically relevant impact on response to treatment with the SGLT2 inhibitor empagliflozin.


Bariatric surgery and bone metabolism: a systematic review.
Few studies have demonstrated the risk of metabolic bone disease and a reduction in bone mineral density (BMD) after bariatric surgery. A systematic review was conducted of case-control and cohort studies with the aim of evaluating the relationship between bariatric surgery and bone metabolism. The search was undertaken in MedLine, covering the period from January 1997 to August 2009, using the keywords: "bariatric surgery" AND "osteoporosis", "fracture", "bone diseases", "metabolic". Six studies were included, comprising four cohort and two case-control studies. Three studies evaluated bone metabolism and BMD, and the other evaluated bone metabolism only. Based on this review, bariatric surgery is associated with alterations in bone metabolism, loss of bone mass and an increased risk of fracture. However, the maximum evaluation period covered by these studies was two years after surgery, hence the need to undertake further studies of longer duration in order to achieve a more thorough understanding of this association.


[Social segregation and the health care of female immigrants in Taiwan].
Technology has reduced the distance between people, and also blurred the boundaries between nations. In recent years the development of Taiwan society has been affected by cross-national marriages. In these cases, the foreigner--usually the female--living in a new country and adapting to the pressures of being in a new society very different from her own, is also confronted by a succession of social distinctions and differentiating selection processes, giving rise gradually to the phenomenon of social segregation in culture, language and marriage. Such segregation has in turn led gradually to inferior medical care for female immigrants. It is therefore worth investigating whether the current medical system can offer appropriate health care to the female immigrant. This article's approach is to discuss trans-national marriage and analyze the living situations of female immigrants, to investigate their social segregation, and hence their situation in relation to medical care. It also prompts more advanced reflection, on the part of clinical professional caregivers, of the needs of female immigrants, in the hope that those needs will become the subject of greater interest and attention.


GLYCERINATED SKELETAL AND SMOOTH MUSCLE: CALCIUM AND MAGNESIUM DEPENDENCE.
Contractions of glycerinated skeletal (striated) and vascular (smooth) muscles are similar in their calcium dependence but differ in their magnesium dependence. The threshold concentration of free Ca(++) for contraction of either muscle was 1.8 x 10(-7)M; maximum tension developed when the concentration of free Ca(++) was slightly greater than 10(-6)M. The Mg concentration required for contraction of smooth muscle was at least ten times as great as that for skeletal muscle.


Comparison of parental stress among mothers and fathers of children with autistic spectrum disorder in Iran.
Most of the studies about parenting stress among parents of children with autistic spectrum disorder (ASD) have been conducted in western societies. The objective of this research, conducted in Iran, is to evaluate the parenting stress among fathers and mothers of children with ASD and find the correlation between severity of the disorder in children and the level of parental stress. Participants included 42 couples having children aged between 2 and 12 diagnosed with ASD based on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria. The diagnosis was made by two child and adolescent psychiatrists. Demographic information of the participants was collected using a questionnaire. The severity of pervasive developmental disorder in children was determined based on Childhood Autism Rating Scale (CARS); stress of parents was measured using Parenting Stress Index (PSI). Collected information was analyzed by the SPSS (version 16) software. Evaluation of subscales in participants' data showed a positive correlation coefficient between the PSI-parent domain and Childhood Autism Rating Scale-Parent form CARS-P rating (r = 0.339, P =0 0.028) and also between the total stress index and CARS-P rating (r = 0.333, P = 0.031) for fathers. It is thus suggested that fathers of children with more severe developmental disorders experience more stress. The results showed significant differences between fathers and mothers in the three PSI subscales including PSI-child domain score (P < 0.005), PSI-parent domain score (P < 0.005), and the total stress index (P < 0.005). Mothers had significantly more stress than fathers. These findings show that parents with ASD children have many emotional needs which should be considered in planning the effective treatment strategies for their children.


Artificial rearing of pigs. 12. Effect of replacement of dried skim-milk by either a soya-protein isolate or concentrate on the performance of the pigs and digestion of protein.
1. Pigs (sixteen/diet) were weaned at 2 d of age and given liquid diets (200 g dry matter/l) during a 26 d experiment. The pigs were fed on a scale based on live weight. Dried skim-milk was the only source of protein in diet U and was partially or totally replaced by a soya-bean isolate (diet B) or a concentrate (diets C and D). Soya-bean protein provided 500, 700 or 350 g/kg total crude protein (nitrogen x 6.25) in diets B, C and D respectively. 2. Performance was similar for diets B and D, but poorer than that of pigs given diet U. The apparent digestibility and retention of N of these diets was similar. Pigs given diet C scoured severely and twelve died. 3. Protein digestion was studied in pigs given diets U, B and D, killed at 28 d of age, at the termination of the feeding experiment. The dry matter content and proportion of N in the digesta in the stomach were reduced in pigs given soya-bean protein. Pepsin concentrations in digesta and stomach tissue were unchanged. 4. The concentrations of trypsin and chymotrypsin in the pancreas were greater in pigs given the soya-bean protein concentrate compared with milk protein, but only the increase in trypsin was significant (P less than 0.01). Digesta from the small intestine of pigs given the soya-bean-protein isolate contained less chymotrypsin (P less than 0.05). There were no differences in the proportion of non-protein-N in the total N in the digesta, suggesting that proteolysis of the milk and soya-bean proteins were equally by 28 d of age.


Use of arterially perfused rabbit ventricular wedge in predicting arrhythmogenic potentials of drugs.
A growing number of drugs have reportedly been associated with delayed ventricular repolarization and a potentially fatal but rare arrhythmia, torsade de pointes (TdP). There is obviously a call for a validated proarrhythmia model that distinguishes proarrhythmic drugs from nonarrhythmogenic drugs. In this article, we validated the arterially perfused rabbit left ventricular wedge preparation model and examined its use in predicting proarrhythmic potentials of drugs. A fairly detailed methodological description about this technically challenging model was given, aiming to help others establish the assay successfully. Parameters commonly used in the action potential studies were verified and critical experimental conditions (e.g. stability and reproducibility of recordings) were examined. Six commercially available compounds with various proarrhythmic potentials were administered in the model to evaluate their correlations with individual clinical outcomes. Our study indicated that, in a successful experiment, the action potential duration (APD) can be stably maintained for several hours without intervention. Dofetilide, DL-sotalol, cisapride, risperidone and moxifloxacin increased endo- and epicardial APD(90), QT interval and T(P-E) (peak-to-end time of the T wave) in a reverse use-dependent manner within clinically relevant concentration ranges. Phase 2 early afterdepolarizations (EADs) were observed at 1.6, 2.3, 16.7, 37.5 and 7.9 fold, respectively, their corresponding unbound therapeutic concentrations. In contrast, fluoxetine at up to 3 microM (approximately 35 fold unbound therapeutic mean plasma concentration after 60 mg/day, p.o. for 5 weeks) had only a mild prolonging effect on APD(90) and QT with essentially no effect on T(P-E). Our results strongly support the usefulness of this model in predicting a compound's arrhythmogenic potential in humans within clinically relevant concentration ranges, and the experimental results with this model need to be interpreted in light of each drug's pharmacokinetic and pharmacodynamic behavior in clinic.


[Laparoscopic surgery in the COVID-19 era].
Coexistence with COVID-19 infection (coronavirus disease 2019) in all hospital and health care settings is a current challenge of adaptation, as well as the creation of new protocols and care models. At present, there are still many unknowns about this infection, and much more unknown is the impact into the surgical field. Although evidence regarding the effect of SARS-CoV-2 and laparoscopic surgery is scarce, laparoscopy has been considered the method of choice by different scientific societies for most indications in gynaecology during the COVID-19 pandemic. This is due to the advantages over the open route. There is less morbidity and hospital stay, and in addition, as it involves autonomous and contained surgical procedures with respect to smoke release. Moreover, the instruments and the setting in the operating room mean that there can be safe distance from the surgeon and other staff to the patient. Overall, the main recommendations in laparoscopic surgery during the COVID era include: the use of Personal Protective Equipment for operating room personnel, and the adoption of safety measures to reduce CO2 exposure and surgical smoke release.


Age-related changes in glucuronidation and deglucuronidation in liver, small intestine, lung, and kidney of male Fischer rats.
Uridine diphosphoglucuronyltransferase (UDPGT) and beta-glucuronidase (beta G) activities were measured in liver, small intestine, lung, and kidney of male Fischer rats between the ages of 2 and 30 months in order to evaluate the balance between glucuronidation and deglucuronidation reactions as a function of age. Both enzyme activities were determined colorimetrically. UDPGT was measured using both p-nitrophenol (PNP) and phenolphthalein (PT) as substrates, while p-nitrophenyl-beta-D-glucuronide was used to measure BG activity. No age-related change was detected in small intestine or lung with either enzyme. UDPGT-PT activity was only detected in liver where its activity increased about 2-fold at 96 weeks of age and remained elevated. UDPGT-PNP activity displayed a maturational decrease up to 15 weeks in liver and then remained constant with age. BG activity was measured in both the microsomal and S9 fractions of these tissues. In liver, the microsomal BG activity remained constant with age. However, in the S9 fraction, this activity displayed an increasing trend after 24 weeks. BG activity in kidney microsomes also showed this increase in both fractions. UDPGT-PNP activity in kidney extract exhibited a gradual decreasing trend with age. If these results represent the in vivo situation, the changes in the balance between glucuronidation and deglucuronidation with age not only depend on the substrate, but also on the tissue. An emphasis is placed on separating out changes due to maturation or disease from those due to senescence.


MassBank: a public repository for sharing mass spectral data for life sciences.
MassBank is the first public repository of mass spectra of small chemical compounds for life sciences (<3000 Da). The database contains 605 electron-ionization mass spectrometry (EI-MS), 137 fast atom bombardment MS and 9276 electrospray ionization (ESI)-MS(n) data of 2337 authentic compounds of metabolites, 11 545 EI-MS and 834 other-MS data of 10,286 volatile natural and synthetic compounds, and 3045 ESI-MS(2) data of 679 synthetic drugs contributed by 16 research groups (January 2010). ESI-MS(2) data were analyzed under nonstandardized, independent experimental conditions. MassBank is a distributed database. Each research group provides data from its own MassBank data servers distributed on the Internet. MassBank users can access either all of the MassBank data or a subset of the data by specifying one or more experimental conditions. In a spectral search to retrieve mass spectra similar to a query mass spectrum, the similarity score is calculated by a weighted cosine correlation in which weighting exponents on peak intensity and the mass-to-charge ratio are optimized to the ESI-MS(2) data. MassBank also provides a merged spectrum for each compound prepared by merging the analyzed ESI-MS(2) data on an identical compound under different collision-induced dissociation conditions. Data merging has significantly improved the precision of the identification of a chemical compound by 21-23% at a similarity score of 0.6. Thus, MassBank is useful for the identification of chemical compounds and the publication of experimental data.


Wide diversity of PAX5 alterations in B-ALL: a Groupe Francophone de Cytogenetique Hematologique study.
PAX5 is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). We analyzed 153 adult and child B-ALL harboring karyotypic abnormalities at chromosome 9p, to determine the frequency and the nature of PAX5 alterations. We found PAX5 internal rearrangements in 21% of the cases. To isolate fusion partners, we used classic and innovative techniques (rolling circle amplification-rapid amplification of cDNA ends) and single nucleotide polymorphism-comparative genomic hybridization arrays. Recurrent and novel fusion partners were identified, including NCoR1, DACH2, GOLGA6, and TAOK1 genes showing the high variability of the partners. We noted that half the fusion genes can give rise to truncated PAX5 proteins. Furthermore, malignant cells carrying PAX5 fusion genes displayed a simple karyotype. These data strongly suggest that PAX5 fusion genes are early players in leukemogenesis. In addition, PAX5 deletion was observed in 60% of B-ALL with 9p alterations. Contrary to cases with PAX5 fusions, deletions were associated with complex karyotypes and common recurrent translocations. This supports the hypothesis of the secondary nature of the deletion. Our data shed more light on the high variability of PAX5 alterations in B-ALL. Therefore, it is probable that gene fusions occur early, whereas deletions should be regarded as a late/secondary event.


Hypertensive retinal vessel wall signs in a general older population: the Blue Mountains Eye Study.
To describe cross-sectional relations between hypertension and retinal vessel wall signs in an older white population. These signs were defined from fundus photographs in 3654 Blue Mountains Eye Study participants > or =49 years of age. Focal arteriolar narrowing and arteriovenous nicking were graded through the use of standard protocol. Photographs were digitized to measure retinal vessel diameters. Average arteriolar diameter, summarized as central retinal arteriolar equivalent and arteriole-to-venule ratio, were used as indexes of generalized arteriolar narrowing. Blood pressure was measured with the use of a mercury sphygmomanometer. Hypertension was defined through the use of antihypertensive medications, systolic blood pressure > or =160 mm Hg, or diastolic blood pressure > or =95 mm Hg. Hypertension was categorized as controlled (using medication, normal blood pressure), uncontrolled (using medication, high blood pressure), or untreated (not using medication). Hypertensive subjects had higher prevalence of all retinal microvascular signs. After adjusting for age, gender, body mass index, and smoking, persons with controlled (18.2%), uncontrolled (13.8%), or untreated hypertension (13.8%) were significantly more likely than normotensive subjects (54.2%) to have (a) lower central retinal arteriolar equivalent: adjusted odds ratios 1.5, (95% CI, 1.1 to 1.9), 2.1 (1.6 to 2.7), and 2.1 (1.6 to 2.7), respectively, and lower arteriole-to-venule ratio: 1.3 (1.0 to 1.6), 1.4 (1.1 to 1.8), and 1.7 (1.3 to 2.2), respectively; (b) focal arteriolar narrowing: 1.3 (0.9 to 1.9), 2.2 (1.5 to 3.2), and 2.5 (1.8 to 3.6), respectively; and (c) arteriovenous nicking: 1.3 (0.9 to 1.8), 2.3 (1.6 to 3.2), and 1.9 (1.3 to 2.7), respectively. Our findings demonstrate a strong relation between presence and severity of hypertension and retinal microvascular structural changes.


Twenty-year cohort study of health gain from orthodontic treatment: temporomandibular disorders.
Temporomandibular disorder (TMD) is a common condition. Studies of TMD in relation to orthodontic treatment did not show an association, but longitudinal studies from adolescence to adulthood are lacking. The aim of this study was to investigate the relationship between orthodontic treatment and TMD with a longitudinal study design. This prospective cohort study was conducted in South Wales, United Kingdom. The baseline investigation was carried out in 1981 and involved children aged 11 to 12 years (n = 1018). Follow-up investigations were done in 1984 (n = 792), 1989 (n = 456), and 2000 (n = 337). Overall TMD prevalence increased from the baseline (3.2%) to age 19 to 20 (17.6%) and decreased by age 30 to 31 (9.9%). TMD prevalence was higher in females at all follow-up points, except the baseline. Overall, incidences of TMD were 11.9%, 11.5%, and 6.0% at the first, second, and last follow-ups, respectively. Females were more likely to develop TMD than males (hazard ratio [HR], 2.1; 95% CI, 1.3 and 3.3), and those with high self-esteem were less likely to develop TMD (HR, 0.6; 95% CI, 0.4 and 0.8). There was no association between orthodontic treatment and new TMD onset. The incidences of persistent TMD were 20.0%, 34.9%, and 28.0% at the first, second, and last follow-ups, respectively. Females were more likely to have persistent TMD than males (HR, 2.5; 95% CI, 1.0 and 6.1). There was no association between orthodontic treatment and persistent TMD. The only significant predictors of TMD in adults aged 30 to 31 were female sex (odd ratio, 3.0; 95% CI, 1.1 and 8.2) and TMD in adolescence (odds ratio, 4.5; 95% CI, 2.0 and 10.0). Orthodontic treatment neither causes nor prevents TMD. Female sex and TMD in adolescence were the only predictors of TMD in young adulthood.


DIMPLE: AN R PACKAGE TO QUANTIFY, VISUALIZE, AND MODEL SPATIAL CELLULAR INTERACTIONS FROM MULTIPLEX IMAGING WITH DISTANCE MATRICES.
The tumor microenvironment (TME) is a complex ecosystem containing tumor cells, other surrounding cells, blood vessels, and extracellular matrix. Recent advances in multiplexed imaging technologies allow researchers to map several cellular markers in the TME at the single cell level while preserving their spatial locations. Evidence is mounting that cellular interactions in the TME can promote or inhibit tumor development and contribute to drug resistance. Current statistical approaches to quantify cell-cell interactions do not readily scale to the outputs of new imaging technologies which can distinguish many unique cell phenotypes in one image. We propose a scalable analytical framework and accompanying R package, DIMPLE, to quantify, visualize, and model cell-cell interactions in the TME. In application of DIMPLE to publicly available MI data, we uncover statistically significant associations between image-level measures of cell-cell interactions and patient-level covariates.


Quality of Soybean Products in Terms of Essential Amino Acids Composition.
The content of protein, moisture content and essential amino acids in conventional and genetically modified soybean grain and selected soybean products (soybean pâté, soybean drink, soybean dessert, tofu) was analyzed in this paper. The following comparative analysis of these products has not yet been carried out. No differences were observed in the amino acid profiles of soybeans and soybean products. The presence of essential amino acids was confirmed except for tryptophan. Its absence, however, may be due not to its absence in the raw material, but to its decomposition as a result of the acid hydrolysis of the sample occurring during its preparation for amino acid determination. Regardless of the type of soybean grain, the content of protein, moisture content and essential amino acids was similar (statistically insignificant difference). Thus, the type of raw material did not determine these parameters. There was a significant imbalance in the quantitative composition of essential amino acids in individual soybean products. Only statistically significant variation was found in genetically modified and conventional soybean pâté. Moreover, in each soy product their amount was lower irrespective of the raw material from which they were manufactured. Therefore, the authors indicate the necessity of enriching soybean products with complete protein to increase their nutritional value.


Mitochondrial DNA reveals distinct evolutionary histories for Jewish populations in Yemen and Ethiopia.
Southern Arabia and the Horn of Africa are important geographic centers for the study of human population history because a great deal of migration has characterized these regions since the first emergence of humans out of Africa. Analysis of Jewish groups provides a unique opportunity to investigate more recent population histories in this area. Mitochondrial DNA is used to investigate the maternal evolutionary history and can be combined with historical and linguistic data to test various population histories. In this study, we assay mitochondrial control region DNA sequence and diagnostic coding variants in Yemenite (n = 45) and Ethiopian (n = 41) Jewish populations, as well as in neighboring non-Jewish Yemeni (n = 50) and Ethiopian (previously published Semitic speakers) populations. We investigate their population histories through a comparison of haplogroup distributions and phylogenetic networks. A high frequency of sub-Saharan African L haplogroups was found in both Jewish populations, indicating a significant African maternal contribution unlike other Jewish Diaspora populations. However, no identical haplotypes were shared between the Yemenite and Ethiopian Jewish populations, suggesting very little gene flow between the populations and potentially distinct maternal population histories. These new data are also used to investigate alternate population histories in the context of historical and linguistic data. Specifically, Yemenite Jewish mitochondrial diversity reflects potential descent from ancient Israeli exiles and shared African and Middle Eastern ancestry with little evidence for large-scale conversion of local Yemeni. In contrast, the Ethiopian Jewish population appears to be a subset of the larger Ethiopian population suggesting descent primarily through conversion of local women.


Using word embedding technique to efficiently represent protein sequences for identifying substrate specificities of transporters.
Membrane transport proteins and their substrate specificities play crucial roles in various cellular functions. Identifying the substrate specificities of membrane transport proteins is closely related to protein-target interaction prediction, drug design, membrane recruitment, and dysregulation analysis, thus being an important problem for bioinformatics researchers. In this study, we applied word embedding approach, the main cause for natural language processing breakout in recent years, to protein sequences of transporters. We defined each protein sequence based on the word embeddings and frequencies of its biological words. The protein features were then fed into machine learning models for prediction. We also varied the lengths of protein sequence's constituent biological words to find the optimal length which generated the most discriminative feature set. Compared to four other feature types created from protein sequences, our proposed features can help prediction models yield superior performance. Our best models reach an average area under the curve of 0.96 and 0.99, respectively on the 5-fold cross validation and the independent test. With this result, our study can help biologists identify transporters based on substrate specificities as well as provides a basis for further research that enriches a field of applying natural language processing techniques in bioinformatics.


Postanaesthetic effects of ketamine-midazolam and ketamine-medetomidine on gastrointestinal transit time in rabbits anaesthetised with isoflurane.
Gastrointestinal stasis is a common perianaesthetic complication in rabbits. The objective of this study was to assess the impact on gastrointestinal transit time of ketamine-midazolam (KMZ) versus ketamine-medetomidine (later antagonised by atipamezole) (KMT-A) in rabbits anaesthetised with isoflurane. This was a cross-over, randomised, single-blinded, controlled, experimental trial. Seven healthy adult New Zealand White rabbits were used. Gastrointestinal transit time was assessed by contrast radiography in awake rabbits. Presence of contrast medium in the small intestine (gastric transit time), in the caecum (small intestinal transit time) and in faeces in the colon was assessed. One week later, 55 minutes isoflurane anaesthesia was induced with ketamine (15 mg/kg) and either midazolam (3 mg/kg) or medetomidine (0.25 mg/kg) by intramuscular injection. Thirty minutes after discontinuation of isoflurane, atipamezole (0.5 mg/kg) was administered only to rabbits in KMT-A treatment. Gastrointestinal transit time was then assessed in both treatment groups, beginning 30 minutes after cessation of isoflurane administration. Two weeks later, the treatment groups were interchanged. Gastric and small intestinal transit times were significantly longer with KMT-A (92±109 minutes and 214±119 minutes, respectively) than with KMZ (1±0 minutes and 103±6 minutes, respectively) and in the awake state (7±7 minutes and 94±32 minutes, respectively). Clinicians should therefore be aware of the potential gastrointestinal side effects of KMT-A, particularly in rabbits at risk for gastrointestinal stasis.


Spectral caustics of high-order harmonics in one-dimensional periodic crystals.
We theoretically investigate the spectral caustics of high-order harmonics in solids. We analyze the one-dimensional model of high-order harmonic generation (HHG) in solids and find that apart from the caustics originating from the van Hove singularities in the energy band structure, another kind of catastrophe enhancement also emerges in solids when the different branches of electron-hole trajectories generating high-order harmonics coalesce into a single branch. We solve the time-dependent Schrödinger equation in terms of the periodic potential and demonstrate the control of this kind of singularity in HHG with the aid of two-color laser fields. The diffraction patterns of the harmonic spectrum near the caustics agree well with the interband electron-hole recombination trajectories predicted by the semiconductor semiclassical equation. This work is expected to improve our understanding of the HHG dynamics in solids and enable us to manipulate the harmonic spectrum by adjusting the driving field parameters.


The fate of cyclamate in man and other species.
1. (14)C-labelled cyclamate has been administered to guinea pigs, rabbits, rats and humans. When given orally to these species on a cyclamate-free diet, cyclamate is excreted unchanged. In guinea pigs some 65% of a single dose is excreted in the urine and 30% in the faeces, the corresponding values for rats being 40 and 50%, for man, 30-50% and 40-60%, and for rabbits, 90 and 5%, the excretion being over a period of 2-3 days. 2. Cyclamate appears to be readily absorbed by rabbits but less readily by guinea pigs, rats and humans. 3. If these animals, including man, are placed on a diet containing cyclamate they develop the ability to convert orally administered cyclamate into cyclohexylamine and consequently into the metabolites of the latter. The extent to which this ability develops is variable, the development occurring more readily in rats than in rabbits or guinea pigs. In three human subjects, one developed the ability quite markedly in 10 days whereas two others did not in 30 days. Removal of the cyclamate from the diet caused a diminution in the ability to convert cyclamate into the amine. 4. In rats that had developed the ability to metabolize orally administered cyclamate, intraperitoneally injected cyclamate was not metabolized and was excreted unchanged in the urine. The biliary excretion of injected cyclamate in rats was very small, i.e. about 0.3% of the dose. 5. The ability of animals to convert cyclamate into cyclohexylamine appears to depend upon a continuous intake of cyclamate and on some factor in the gastrointestinal tract, probably the gut flora.


Labetalol as monotherapy in hypertensive black patients.
The antihypertensive effect of labetalol was evaluated in 18 adult black patients with mild to moderate essential hypertension previously controlled with a combination of a diuretic and a beta blocker. After a 4-week washout period, standing blood pressure had increased from 138 +/- 2.2/85 +/- 1.5 mmHg, (mean +/- SEM) to 154 +/- 1.9/100 +/- 0.6 mmHg. Labetalol was then titrated to a maximum of 600 mg BID to obtain a standing diastolic blood pressure of less than or equal to 90 mmHg and/or a decrease of greater than or equal to 10 mmHg from baseline (end of washout period). By the end of the labetalol titration period, standing blood pressure had decreased to 140 +/- 2.0/84 +/- 1.5 (p less than 0.01). Following a 2-week maintenance period, standing blood pressure was 136 +/- 1.6/80 +/- 1.5 mmHg (NS vs. titration). Labetalol therapy was well tolerated and reduced diastolic blood pressure to less than or equal to 90 mmHg in 17 of 18 patients, 13 of whom required dosages less than or equal to 300 mg BID. The average reduction in standing heart rate while on labetalol was 4 bpm (p less than 0.01). Side effects were limited to skin rash in one patient and possible mild urinary retention in another. These data indicate that labetalol is an effective antihypertensive for black patients with mild to moderate essential hypertension.


Single dose of rasburicase for treatment of hyperuricemia in acute kidney injury: a report of 3 cases.
Severe hyperuricemia accompanied by the other comorbidities such as anuria, fluid overload, calcium-phosphate imbalance, and/or tumor lysis syndrome is one of the indications for dialysis in the setting of acute kidney injury. Rasburicase is used in different clinical conditions such as tumor lysis syndrome and uric acid nephropathy. Among referred patients to our center from 2008 to 2010, there were 3 patients who had an indication for dialysis because of hyperuricemia. Contributing factors to the acute kidney injury were multi-organ dysfunction, rapidly progressive glomerulonephritis, and spontaneous tumor lysis syndrome. None of the patients showed any response to treatment with bicarbonate and hydration. After rasburicase administration, serum uric acid level declined, and urine output increased. Treatment with a single low dose of rasburicase would be effective to decrease the serum uric acid level and reverse kidney injury secondary to uric acid nephropathy.