Kernel methods for predicting protein-protein interactions.
Despite advances in high-throughput methods for discovering protein-protein interactions, the interaction networks of even well-studied model organisms are sketchy at best, highlighting the continued need for computational methods to help direct experimentalists in the search for novel interactions. We present a kernel method for predicting protein-protein interactions using a combination of data sources, including protein sequences, Gene Ontology annotations, local properties of the network, and homologous interactions in other species. Whereas protein kernels proposed in the literature provide a similarity between single proteins, prediction of interactions requires a kernel between pairs of proteins. We propose a pairwise kernel that converts a kernel between single proteins into a kernel between pairs of proteins, and we illustrate the kernel's effectiveness in conjunction with a support vector machine classifier. Furthermore, we obtain improved performance by combining several sequence-based kernels based on k-mer frequency, motif and domain content and by further augmenting the pairwise sequence kernel with features that are based on other sources of data. We apply our method to predict physical interactions in yeast using data from the BIND database. At a false positive rate of 1% the classifier retrieves close to 80% of a set of trusted interactions. We thus demonstrate the ability of our method to make accurate predictions despite the sizeable fraction of false positives that are known to exist in interaction databases. The classification experiments were performed using PyML available at http://pyml.sourceforge.net. Data are available at: http://noble.gs.washington.edu/proj/sppi.


Work productivity and activity impairment in patients with hidradenitis suppurativa: a cross-sectional study.
The understanding of absenteeism, presenteeism, and impairments in daily activities among patients with hidradenitis suppurativa (HS) is limited. We examined the impact of disease-specific factors of HS on work and daily life among a cohort of outpatients in a tertiary hospital setting. Consecutive patients with HS were clinically evaluated and completed the Work Productivity and Activity Impairment (WPAI) questionnaire modified for HS. A total of 100 patients were included. Among 57 (57.0%) patients who were employed, 21.2% reported missing work, and 60.4% reported loss of work productivity during the preceding week as a result of HS. The overall work productivity was reduced by 26.6%. Seventy-two percent reported daily activity impairment, averaging 32.7% reduction in daily activities. Moderate to strong correlations were observed between reduction in quality of life and the WPAI outcomes; presenteeism, overall work impairment, and activity impairment (r = 0.50-0.77). There were moderate correlations between disease severity and the same outcomes (r = 0.35-0.46). The mean rank of activity impairment among patients with Hurley stage I was 34.8, 60.1 for Hurley stage II, and 64.0 for Hurley stage III, P < 0.0001. Unemployed patients had higher activity impairment compared with employed patients (mean rank: 61.0 vs. 42.6, P = 0.001). There are considerable rates of presenteeism, overall work impairment, and activity impairment in HS patients. Presenteeism, loss of overall work productivity, and activity impairment are positively correlated with greater disease severity and reduction in quality of life.


Review of self-awareness and its clinical application in stroke rehabilitation.
The objectives of this study were (i) to explore, following a literature review, the concepts of self-awareness, its assessment, and intervention for self-awareness deficits, as well as its clinical significance in stroke rehabilitation; and (ii) to apply the concepts of self-awareness in the context of a rehabilitation program. The search was conducted by the electronic databases Web of Science, Science Direct, MEDLINE, and PsychcInfo. A systematic literature search of publications written in English between 1980 and 2010 was conducted using the keywords, self-awareness or self-regulation. The search was limited to the following keywords: stroke, deficits, assessment, intervention, and rehabilitation. Two important conceptual models, namely, the Pyramid Model of Self-Awareness and the Dynamic Comprehensive Model of Awareness, were reviewed. Suggestions were made to the constraint-induced movement therapy for enhancement of both assessment and treatment of self-awareness deficits. In conclusion, self-awareness is essential for the success of rehabilitation. It is hoped that more studies can be conducted on the effectiveness of awareness enhancement programs incorporated in on-going therapies can be conducted, so that the evidence base can be further built up in this evolving area of practice.


Solid state and solution studies of lithium tris(n-butyl)magnesiates stabilised by Lewis donors.
Several Lewis base adducts of the synthetically important lithium tris(n-butyl)magnesiate LiMg((n)Bu)3 have been prepared and structurally characterised. The complexes were prepared by a co-complexation approach i.e., by combining the monometallic (n)BuLi and (n)Bu2Mg reagents in hydrocarbon solution before adding a molar equivalent of a donor molecule (a bidentate amine, tridentate amine or cyclic ether). The lithium magnesiates all adopt variants of the "Weiss motif" structure, i.e., contacted ion pair dimers with a linear arrangement and metals connected by butyl anions, where tetrahedral magnesium ions are in the central positions and the lithiums occupy the outer region, solvated by a neutral Lewis donor [(donor)Li(μ-(n)Bu)2Mg(μ-(n)Bu)2Mg(μ-(n)Bu)2Li(donor)]. When TMPDA, PMDETA or (R,R)-TMCDA [TMPDA = N,N,N'N'-tetramethylpropanediamine; PMDETA = N,N,N',N'',N''-pentamethyldiethylenetriamine; and (R,R)-TMCDA = (R,R)-N,N,N',N'-tetramethylcyclohexane-1,2-diamine], are employed, dimeric tetranuclear lithium magnesiates are produced. Due to the tridentate nature of the ligand, the PMDETA-containing structure (2) has an unusual 'open'-motif. When TMEDA (TMEDA = N,N,N',N'-tetramethylethylenediamine) is employed, a n-butoxide-containing complex [(TMEDA)Li(μ-(n)Bu)(μ-O(n)Bu)Mg2((n)Bu)2(μ-(n)Bu)(μ-O(n)Bu)Li(donor)] has been serendipitously prepared and adopts a ladder conformation which is commonly observed in lithium amide chemistry. This complex has also been prepared using a rational methodology. When 1,4-dioxane is employed, the donor stitches together a polymeric array of tetranuclear dimeric units (6). The hydrocarbon solution structures of the compounds have been characterised by (1)H, (7)Li, (13)C NMR spectroscopy; 2 has been studied by variable temperature and DOSY NMR.


Zataria multiflora and its main ingredient, carvacrol, affect on the renal function, histopathological, biochemical and antioxidant parameters in adriamycin-induced nephrotic rats.
Oxidative stress has a major role in the nephrosis. In the present study, the effects of hydroalcoholic extract of Zataria multiflora (ZM) and carvacrol (CAR) were evaluated on the renal damage induced by adriamycin (ADR). The animals accidentally divided into four groups including: Control, ADR, ZM + ADR and CAR + ADR. The renal tissue, urine, and blood samples subjected to biochemical markers and histopathological evaluation. ADR significantly decreased glomerular filtration rate (GFR) while escalated urine protein excretion as well as protein clearance (p < .01 to p < .001). Also, ADR significantly reduced the antioxidants and boosted the malondialdehyde (MDA) compared to the control (p < .05 to p < .01). In groups treated by ZM and CAR, GFR, and antioxidants significantly increased, whereas urine protein excretion and MDA decreased (p < .05 to p < .001). ZM and CAR induced an improvement in ADR-induced renal damage by improving renal function as well as antioxidant activity.


Friendly foes: The evolution of host protection by a parasite.
Hosts are often infected by multiple parasite species, yet the ecological and evolutionary implications of the interactions between hosts and coinfecting parasites are largely unknown. Most theoretical models of evolution among coinfecting parasites focus on the evolution of virulence, but parasites may also evolve to protect their hosts by reducing susceptibility (i.e., conferring resistance) to other parasites or reducing the virulence of coinfecting parasites (i.e., conferring tolerance). Here, we analyze the eco-evolutionary dynamics of parasite-conferred resistance and tolerance using coinfection models. We show that both parasite-conferred resistance and tolerance can evolve for a wide range of underlying trade-offs. The shape and strength of the trade-off qualitatively affects the outcome causing shifts between the minimisation or maximization of protection, intermediate stable strategies, evolutionary branching, and bistability. Furthermore, we find that a protected dimorphism can readily evolve for parasite-conferred resistance, but find no evidence of evolutionary branching for parasite-conferred tolerance, in general agreement with previous work on host evolution. These results provide novel insights into the evolution of parasite-conferred resistance and tolerance, and suggest clues to the underlying trade-offs in recent experimental work on microbe-mediated protection. More generally, our results highlight the context dependence of host-parasite relationships in complex communities.


The Effects of a Cluster Randomized Controlled Workplace Intervention on Sleep and Work-Family Conflict Outcomes in an Extended Care Setting.
To evaluate the effects of a workplace-based intervention on actigraphic and self-reported sleep outcomes in an extended care setting. Cluster randomized trial. Extended-care (nursing) facilities. US employees and managers at nursing homes. Nursing homes were randomly selected to intervention or control settings. The Work, Family and Health Study developed an intervention aimed at reducing work-family conflict within a 4-month work-family organizational change process. Employees participated in interactive sessions with facilitated discussions, role-playing, and games designed to increase control over work processes and work time. Managers completed training in family-supportive supervision. Primary actigraphic outcomes included: total sleep duration, wake after sleep onset, nighttime sleep, variation in nighttime sleep, nap duration, and number of naps. Secondary survey outcomes included work-to-family conflict, sleep insufficiency, insomnia symptoms and sleep quality. Measures were obtained at baseline, 6-months and 12-months post-intervention. A total of 1,522 employees and 184 managers provided survey data at baseline. Managers and employees in the intervention arm showed no significant difference in sleep outcomes over time compared to control participants. Sleep outcomes were not moderated by work-to-family conflict or presence of children in the household for managers or employees. Age significantly moderated an intervention effect on nighttime sleep among employees (p=0.040), where younger employees benefited more from the intervention. In the context of an extended-care nursing home workplace, the intervention did not significantly alter sleep outcomes in either managers or employees. Moderating effects of age were identified where younger employees' sleep outcomes benefited more from the intervention.


Approaches to antifungal therapies and their effectiveness among patients with cryptococcosis.
The goal of this study was to determine the degree to which the persistence of cryptococcosis, overall 1-year mortality, and 1-year mortality due to cryptococcosis were influenced by initial antifungal treatment regimen in a cohort of adults with cryptococcosis treated at a tertiary care medical center. Risk factors, underlying conditions, treatment, and mortality information were obtained for 204 adults with cryptococcosis from Duke University Medical Center (DUMC) from 1996 to 2009. Adjusted risk ratios (RR) for persistence and hazard ratios (HR) for mortality were estimated for each exposure. The all-cause mortality rate among patients with nonsevere disease (20%) was similar to that in the group with disease (26%). However, the rate of cryptococcosis-attributable mortality with nonsevere disease (5%) was much lower than with severe disease (20%). Flucytosine exposure was associated with a lower overall mortality rate (HR, 0.4; 95% confidence interval [CI], 0.2 to 0.9) and attributable mortality rate (HR, 0.5; 95% CI, 0.2 to 1.2). Receiving a nonrecommended antifungal regimen was associated with a higher relative risk of persistent infection at 4 weeks (RR, 1.9; 95% CI, 0.9 to 4.3), and the rate of attributable mortality among those not receiving the recommended dose of initial therapy was higher than that of those receiving recommended dosing (HR, 2.3; 95% CI, 1.0 to 5.0). Thus, the 2010 Infectious Diseases Society of America (IDSA) guidelines are supported by this retrospective review as a best-practice protocol for cryptococcal management. Future investigations should consider highlighting the distinction between all-cause mortality and attributable mortality so as not to overestimate the true effect of cryptococcosis on patient death.


Influence of chemically p-type doped active organic semiconductor on the film thickness versus performance trend in cyanine/C60 bilayer solar cells.
Simple bilayer organic solar cells rely on very thin coated films that allow for effective light absorption and charge carrier transport away from the heterojunction at the same time. However, thin films are difficult to coat on rough substrates or over large areas, resulting in adverse shorting and low device fabrication yield. Chemical p-type doping of organic semiconductors can reduce Ohmic losses in thicker transport layers through increased conductivity. By using a Co(III) complex as chemical dopant, we studied doped cyanine dye/C60 bilayer solar cell performance for increasing dye film thickness. For films thicker than 50 nm, doping increased the power conversion efficiency by more than 30%. At the same time, the yield of working cells increased to 80%. We addressed the fate of the doped cyanine dye, and found no influence of doping on solar cell long term stability.


Replay of large-scale spatio-temporal patterns from waking during subsequent NREM sleep in human cortex.
Animal studies support the hypothesis that in slow-wave sleep, replay of waking neocortical activity under hippocampal guidance leads to memory consolidation. However, no intracranial electrophysiological evidence for replay exists in humans. We identified consistent sequences of population firing peaks across widespread cortical regions during complete waking periods. The occurrence of these "Motifs" were compared between sleeps preceding the waking period ("Sleep-Pre") when the Motifs were identified, and those following ("Sleep-Post"). In all subjects, the majority of waking Motifs (most of which were novel) had more matches in Sleep-Post than in Sleep-Pre. In rodents, hippocampal replay occurs during local sharp-wave ripples, and the associated neocortical replay tends to occur during local sleep spindles and down-to-up transitions. These waves may facilitate consolidation by sequencing cell-firing and encouraging plasticity. Similarly, we found that Motifs were coupled to neocortical spindles, down-to-up transitions, theta bursts, and hippocampal sharp-wave ripples. While Motifs occurring during cognitive task performance were more likely to have more matches in subsequent sleep, our studies provide no direct demonstration that the replay of Motifs contributes to consolidation. Nonetheless, these results confirm a core prediction of the dominant neurobiological theory of human memory consolidation.


16S gut community of the Cameron County Hispanic Cohort.
Obesity and type 2 diabetes (T2D) are major public health concerns worldwide, and their prevalence has only increased in recent years. Mexican Americans are disproportionately afflicted by obesity and T2D, and rates are even higher in the United States-Mexico border region. To determine the factors associated with the increased risk of T2D, obesity, and other diseases in this population, the Cameron County Hispanic Cohort was established in 2004. In this study, we characterized the 16S gut community of a subset of 63 subjects from this unique cohort. We found that these communities, when compared to Human Microbiome Project subjects, exhibit community shifts often observed in obese and T2D individuals in published studies. We also examined microbial network relationships between operational taxonomic units (OTUs) in the Cameron County Hispanic Cohort (CCHC) and three additional datasets. We identified a group of seven genera that form a tightly interconnected network present in all four tested datasets, dominated by butyrate producers, which are often increased in obese individuals while being depleted in T2D patients. Through a combination of increased disease prevalence and relatively high gut microbial homogeneity in the subset of CCHC members we examined, we believe that the CCHC may represent an ideal community to dissect mechanisms underlying the role of the gut microbiome in human health and disease. The lack of CCHC subject gut community segregation based on all tested metadata suggests that the community structure we observe in the CCHC likely occurs early in life, and endures. This persistent 'disease'-related gut microbial community in CCHC subjects may enhance existing genetic or lifestyle predispositions to the prevalent diseases of the CCHC, leading to increased attack rates of obesity, T2D, non-alcoholic fatty liver disease, and others.


Increasing tendency of urine protein is a risk factor for rapid eGFR decline in patients with CKD: A machine learning-based prediction model by using a big database.
Artificial intelligence is increasingly being adopted in medical fields to predict various outcomes. In particular, chronic kidney disease (CKD) is problematic because it often progresses to end-stage kidney disease. However, the trajectories of kidney function depend on individual patients. In this study, we propose a machine learning-based model to predict the rapid decline in kidney function among CKD patients by using a big hospital database constructed from the information of 118,584 patients derived from the electronic medical records system. The database included the estimated glomerular filtration rate (eGFR) of each patient, recorded at least twice over a period of 90 days. The data of 19,894 patients (16.8%) were observed to satisfy the CKD criteria. We characterized the rapid decline of kidney function by a decline of 30% or more in the eGFR within a period of two years and classified the available patients into two groups-those exhibiting rapid eGFR decline and those exhibiting non-rapid eGFR decline. Following this, we constructed predictive models based on two machine learning algorithms. Longitudinal laboratory data including urine protein, blood pressure, and hemoglobin were used as covariates. We used longitudinal statistics with a baseline corresponding to 90-, 180-, and 360-day windows prior to the baseline point. The longitudinal statistics included the exponentially smoothed average (ESA), where the weight was defined to be 0.9*(t/b), where t denotes the number of days prior to the baseline point and b denotes the decay parameter. In this study, b was taken to be 7 (7-day ESA). We used logistic regression (LR) and random forest (RF) algorithms based on Python code with scikit-learn library (https://scikit-learn.org/) for model creation. The areas under the curve for LR and RF were 0.71 and 0.73, respectively. The 7-day ESA of urine protein ranked within the first two places in terms of importance according to both models. Further, other features related to urine protein were likely to rank higher than the rest. The LR and RF models revealed that the degree of urine protein, especially if it exhibited an increasing tendency, served as a prominent risk factor associated with rapid eGFR decline.


A Possible Case of Gabapentin-Induced Mild Hyperglycemia.
Objective: A possible case of gabapentin-induced mild hyperglycemia is reported. Case Summary: A 63-year-old Caucasian gentleman was treated in a pharmacist-run pharmacotherapy clinic for type 2 diabetes management. His comorbidities included type 2 diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, peripheral vascular disease, Barrett's esophagus, chronic back pain, and obesity. His medications for these comorbidities were continued throughout his care. The patient had no known drug allergies. After 3 months of pharmacist-managed diabetes management, the patient's glucose levels had improved and were within the desired range for a majority of the readings. The patient was consulted to the pain clinic for uncontrolled pain and initiated and titrated on gabapentin from 300 mg per day to 600 to 900 mg 3 times per day. Two weeks later, the patient's glucose levels increased to levels of 150 to 165 mg/dL. The patient's increasing blood glucose values were treated with NPH insulin, which was titrated for several months until he was switched to insulin glargine. Gabapentin was not discontinued since it provided adequate pain control. Discussion: An objective causality assessment revealed that the adverse effect was possible. No other new medications were introduced, current medications were not adjusted, and no alternate causes could be found for increased glucose values. Conclusion: A 63-year-old Caucasian gentleman with type 2 diabetes mellitus developed a possible case of gabapentin-induced mild hyperglycemia after receiving gabapentin for several months with a dose titration. Gabapentin could be considered as a cause for otherwise unexplained hyperglycemia in a patient.


Oxygen-enhanced MRI MOLLI T1 mapping during chemoradiotherapy in anal squamous cell carcinoma.
Oxygen-enhanced magnetic resonance imaging (MRI) and T1-mapping was used to explore its effectiveness as a prognostic imaging biomarker for chemoradiotherapy outcome in anal squamous cell carcinoma. T2-weighted, T1 mapping, and oxygen-enhanced T1 maps were acquired before and after 8-10 fractions of chemoradiotherapy and examined whether the oxygen-enhanced MRI response relates to clinical outcome. Patient response to treatment was assessed 3 months following completion of chemoradiotherapy. A mean T1 was extracted from manually segmented tumour regions of interest and a paired two-tailed t-test was used to compare changes across the patient population. Regions of subcutaneous fat and muscle tissue were examined as control ROIs. There was a significant increase in T1 of the tumour ROIs across patients following the 8-10 fractions of chemoradiotherapy (paired t-test, p < 0.001, n = 7). At baseline, prior to receiving chemoradiotherapy, there were no significant changes in T1 across patients from breathing oxygen (n = 9). In the post-chemoRT scans (8-10 fractions), there was a significant decrease in T1 of the tumour ROIs across patients when breathing 100% oxygen (paired t-test, p < 0.001, n = 8). Out of the 12 patients from which we successfully acquired a visit 1 T1-map, only 1 patient did not respond to treatment, therefore, we cannot correlate these results with clinical outcome. These clinical data demonstrate feasibility and potential for T1-mapping and oxygen enhanced T1-mapping to indicate perfusion or treatment response in tumours of this nature. These data show promise for future work with a larger cohort containing more non-responders, which would allow us to relate these measurements to clinical outcome.


Intensive care unit surveillance of influenza infection in France: the 2009/10 pandemic and the three subsequent seasons.
During the 2009/10 pandemic, a national surveillance system for severe influenza cases was set up in France. We present results from the system's first four years. All severe influenza cases admitted to intensive care units (ICU) were reported to the Institut de Veille Sanitaire using a standardised form: data on demographics, immunisation and virological status, risk factors, severity (e.g. acute respiratory distress syndrome (ARDS) onset, mechanical ventilation, extracorporeal life support) and outcome. Multivariate analysis was performed to identify factors associated with ARDS and death. The number of confirmed influenza cases varied from 1,210 in 2009/10 to 321 in 2011/12. Most ICU patients were infected with A(H1N1)pdm09, except during the 2011/12 winter season when A(H3N2)-related infections predominated. Patients' characteristics varied according to the predominant strain. Based on multivariate analysis, risk factors associated with death were age ≥ 65 years, patients with any of the usual recommended indications for vaccination and clinical severity. ARDS occurred more frequently in patients who were middle-aged (36-55 years), pregnant, obese, or infected with A(H1N1)pdm09. Female sex and influenza vaccination were protective. These data confirm the persistent virulence of A(H1N1)pdm09 after the pandemic and the heterogeneity of influenza seasons, and reinforce the need for surveillance of severe influenza cases.


Face image modeling by multilinear subspace analysis with missing values.
Multilinear subspace analysis (MSA) is a promising methodology for pattern-recognition problems due to its ability in decomposing the data formed from the interaction of multiple factors. The MSA requires a large training set, which is well organized in a single tensor, which consists of data samples with all possible combinations of the contributory factors. However, such a "complete" training set is difficult (or impossible) to obtain in many real applications. The missing-value problem is therefore crucial to the practicality of the MSA but has been hardly investigated up to present. To solve the problem, this paper proposes an algorithm named M(2)SA, which is advantageous in real applications due to the following: 1) it inherits the ability of the MSA to decompose the interlaced semantic factors; 2) it does not depend on any assumptions on the data distribution; and 3) it can deal with a high percentage of missing values. M(2)SA is evaluated by face image modeling on two typical multifactorial applications, i.e., face recognition and facial age estimation. Experimental results show the effectiveness of M(2) SA even when the majority of the values in the training tensor are missing.


Postoperative complications of posterior ankle and hindfoot arthroscopy.
Posterior ankle and hindfoot arthroscopy, performed with use of posteromedial and posterolateral portals with the patient in the prone position, has been utilized for the treatment of various disorders. However, there is limited literature addressing the postoperative complications of this procedure. In this study, the postoperative complications in patients treated with posterior ankle and hindfoot arthroscopy were analyzed to determine the type, rate, and severity of complications. The study included 189 ankles in 186 patients (eighty-two male and 104 female; mean age, 37.1 ± 16.4 years). The minimum duration of follow-up was six months, and the mean was 17 ± 13 months. The most common preoperative intra-articular diagnoses were subtalar osteoarthritis (forty-six ankles), an osteochondral lesion of the talus (forty-two), posterior ankle impingement (thirty-four), ankle osteoarthritis (twenty), and subtalar coalition (five). The most common extra-articular diagnoses were painful os trigonum (forty-six), flexor hallucis longus tendinitis (thirty-two), and insertional Achilles tendinitis (five). The most common intra-articular procedures were osteochondral lesion debridement (forty-four ankles), subtalar debridement (thirty-eight), subtalar fusion (thirty-three), ankle debridement (thirty), and partial talectomy (nine). The most common extra-articular procedures were os trigonum excision (forty-eight), tenolysis of the flexor hallucis longus tendon (thirty-eight), and endoscopic partial calcanectomy (five). Complications were noted following sixteen procedures (8.5%); four patients had plantar numbness, three had sural nerve dysesthesia, four had Achilles tendon tightness, two had complex regional pain syndrome, two had an infection, and one had a cyst at the posteromedial portal. One case of plantar numbness and one case of sural nerve dysesthesia failed to resolve. Our experience demonstrated that posterior ankle and hindfoot arthroscopy can be performed with a low rate of major postoperative complications.


Assessing the potential cost-effectiveness of a gene therapy for the treatment of hemophilia A.
Aim: Hemophilia A is a genetic, chronic disorder classified by deficient or defective coagulation factor VIII (FVIII) that puts those affected at risk for spontaneous bleeding episodes, which lead to joint damage and chronic pain over time. Currently, most severe hemophilia A patients are treated with prophylactic FVIII, which requires costly and frequent infusions and life-long adherence to medication. A gene therapy (valoctocogene roxaparvovec) is currently in development for the treatment of severe hemophilia A. This model assessed the potential cost-effectiveness of treating patients with valoctocogene roxaparvovec rather than prophylactic therapy.Materials and methods: We developed an individual-based, state-transition microsimulation model for assessing the likely cost-effectiveness of valoctocogene roxaparvovec compared to prophylactic FVIII. Men aged 30 with severe hemophilia A were modeled over a lifetime horizon, and costs were reported from the perspective of the United States health care system. Through microsimulation, patient-level heterogeneity was captured in starting weight, starting Pettersson score (PS), durability of valoctocogene roxaparvovec, and annual bleed rate (ABR).Results: The model projects that treatment with single-administration valoctocogene roxaparvovec would be cost-saving to people with hemophilia A at a price point comparable to other currently available gene therapy products due to its potential to reduce FVIII utilization, direct medical costs, lifetime bleeds, and accumulated joint damage.Limitations: The model relies upon evidence-based assumptions for clinical inputs due to limited data availability. Such uncertainty was mitigated by modeling heterogeneity across the population, specifically with regards to long-term gene therapy durability, lifetime bleed rates, and joint damage progression.Conclusion: Valoctocogene roxaparvovec was found to be cost-saving-on average by about $6.8 million per patient-and more effective than prophylactic therapy for treatment of hemophilia A. The comparative benefit of gene therapy was observed across a broad range of simulated patients that were representative of the real-world severe hemophilia A population.


The relationship between genetic variations of the cholesteryl ester transfer protein gene and coronary artery disease in Turkish subjects.
Although the relationship between cholesteryl ester transfer protein (CETP) and cholesterol metabolism has been characterized in recent years, the effect of CETP genetic variants associated with coronary artery disease (CAD) is still unclear. Therefore, we investigated the association between CETP gene polymorphism and levels of lipid in patients with CAD. We conducted a case-control study that included 194 unrelated subjects who underwent coronary angiography for suspected ischemic heart disease. This group was divided into 96 patients with angiographically documented CAD and 98 subjects (individuals matched for age and gender) without angiographically documented CAD (CAD-free subjects), all of whom were studied to examine the genotypic distribution of the CETP gene polymorphism in CAD. Genotyping was performed via polymerase chain reaction. Of the 96 patients with CAD, 38 (40%) were B1B1, 42 (44%) B1B2 and 16 (16%) B2B2, compared with the control subjects, of which 35 (36%) were B1B1, 44 (45%) B1B2 and 19 (19%) B2B2. There were no significant differences between patients with CAD and control subjects in the distribution of the CETP gene polymorphism. Patients with the B1B1 genotype had lower high-density lipoprotein-cholesterol (HDL-C) and higher triglyceride (TG) levels than patients with the B2B2 genotype (p<0.05). In addition, among control subjects HDL-C levels were significantly higher in subjects with the B2B2 genotype than in subjects with the B1B1 genotype (p<0.01). Our results suggest that genetic variations of the CTEP gene may be responsible for low HDL-C levels but may not be considered as a risk factor for CAD in the Turkish population.


Expression of the high molecular weight glutenin 1Ay gene from Triticum urartu in barley.
In this study, we successfully expressed the active 1Ay subunit of Triticum urartu in barley by Agrobacterium-mediated transformation with a transformation efficiency of 19.9%. The results of SDS-PAGE revealed that the expressed proteins of 1Ay subunit were present at some grains of each of 46 original T0 plants, showing identical mobility to those of positive standards of T. urartu grain protein and bacteria expressional proteins. In the T2 generation, three homozygous lines, 2-28, 3-11, and 5-6, were identified. The results of scanning electron microscopy showed an increased amount of protein bodies in these transgenic lines. The main effects in the expression of the 1Ay subunits was a considerable increase in the glutenin content, but a decrease in the contents of gliadins while there were no effects in the contents of albumin, globulin and the total protein. We found that the gluten could not be washed out from the flour obtained from transgenic barley lines when using a Gluten index analyzer and a Farinograph indicating that the transgenic barley lines could not form dough. The lack of x-type HMW-GS and the reduction in number of subunit were inferred as the possible reasons for the inability to form gluten polymer.


Synthetic physiology strategies for adapting tools from nature for genetically targeted control of fast biological processes.
The life and operation of cells involve many physiological processes that take place over fast timescales of milliseconds to minutes. Genetically encoded technologies for driving or suppressing specific fast physiological processes in intact cells, perhaps embedded within intact tissues in living organisms, are critical for the ability to understand how these physiological processes contribute to emergent cellular and organismal functions and behaviors. Such "synthetic physiology" tools are often incredibly complex molecular machines, in part because they must operate at high speeds, without causing side effects. We here explore how synthetic physiology molecules can be identified and deployed in cells, and how the physiology of these molecules in cellular contexts can be assessed and optimized. For concreteness, we discuss these methods in the context of the "optogenetic" light-gated ion channels and pumps that we have developed over the past few years as synthetic physiology tools and widely disseminated for use in neuroscience for probing the role of specific brain cell types in neural computations, behaviors, and pathologies. We anticipate that some of the insights revealed here may be of general value for the field of synthetic physiology, as they raise issues that will be of importance for the development and use of high-performance, high-speed, side-effect free physiological control tools in heterologous expression systems.


Genetics of human stature: Lessons from genome-wide association studies.
Over the past 2 to 3 years, linkage disequilibrium mapping methods, or genome-wide association studies (GWAS), have made a seminal turn in the molecular genetic studies of complex human traits such as height, i.e., stature. Human stature is a highly heritable trait across populations and the phenotype for stature is easily measured and related to many other traits; therefore, it is available in most studies evaluating any phenotype. For this reason, it has become a beacon for large consortium genetic studies, during both the pre-GWAS and GWAS eras. Tens of thousands of genome-scanned individuals have been analysed together against their genome. Several loci have been implicated in association with stature (54 of these have been published), and most chromosomes have a locus linked to the trait in family studies. However, the prediction power of loci indentified by molecular genetic methods still remains inferior to clinical assessment of offspring stature using midparental height as a guide. Although the genomic methods provide important insights into heritability of stature, it will be a major challenge for molecular genetic studies to provide information that surpasses that of midparental height.


Flip-invariant SIFT for copy and object detection.
Scale-invariant feature transform (SIFT) feature has been widely accepted as an effective local keypoint descriptor for its invariance to rotation, scale, and lighting changes in images. However, it is also well known that SIFT, which is derived from directionally sensitive gradient fields, is not flip invariant. In real-world applications, flip or flip-like transformations are commonly observed in images due to artificial flipping, opposite capturing viewpoint, or symmetric patterns of objects. This paper proposes a new descriptor, named flip-invariant SIFT (or F-SIFT), that preserves the original properties of SIFT while being tolerant to flips. F-SIFT starts by estimating the dominant curl of a local patch and then geometrically normalizes the patch by flipping before the computation of SIFT. We demonstrate the power of F-SIFT on three tasks: large-scale video copy detection, object recognition, and detection. In copy detection, a framework, which smartly indices the flip properties of F-SIFT for rapid filtering and weak geometric checking, is proposed. F-SIFT not only significantly improves the detection accuracy of SIFT, but also leads to a more than 50% savings in computational cost. In object recognition, we demonstrate the superiority of F-SIFT in dealing with flip transformation by comparing it to seven other descriptors. In object detection, we further show the ability of F-SIFT in describing symmetric objects. Consistent improvement across different kinds of keypoint detectors is observed for F-SIFT over the original SIFT.


Defining asthma in epidemiological studies.
It has been suggested that, in epidemiological studies, asthma should be defined as symptomatic bronchial hyperresponsiveness (BHR). This paper critically examines the validity of this and alternative methods of defining asthma by reviewing population-based studies validating BHR and symptom questionnaires against asthma defined on the basis of a clinical assessment. It is emphasized that a single definition of asthma will not be applicable to all studies. When the aim of a study is to compare differences in prevalence of asthma between populations, Youden's Index (sensitivity + specificity - 1) is the best single measure of validity. BHR has similar or better specificity, but much worse sensitivity, and therefore a worse Youden's Index, than symptom questionnaires. When the aim is to estimate relative risks, the validity of the definition of asthma depends more on its positive predictive value. Therefore, more specific methods of detecting asthmatics, such as severe symptoms, diagnoses of asthma, or symptomatic BHR may be most useful in cohort and case-control studies. In contrast, conversely, the method of choice for the first phase of prevalence comparisons is standardized written or video symptom questionnaires. In order to explore reasons for the differences in asthma prevalence, and to estimate possible differential symptom reporting, questionnaires can be supplemented with bronchial hyperresponsiveness and other testing in subsamples of the symptomatic and nonsymptomatic subjects. However, symptoms and bronchial hyperresponsiveness should usually be analysed separately rather than combined due to the poor agreement between bronchial hyperresponsiveness and clinical asthma.


Prediction of spontaneous onset of labor at term: the role of cervical length measurement and funneling of internal cervical os detected by transvaginal ultrasonography.
The objective of this study was to examine the values of the cervical length measurement and detection of internal cervical os funneling by transvaginal ultrasonography in the prediction of spontaneous labor within a 7-day period at term. Ninety-three pregnant women were enrolled into this study. All patients were evaluated by transvaginal ultrasonography first at the 37th completed week of gestation and weekly thereafter. Endocervical canal length was measured and the presence of funneling was recorded. The end points were the percentage of patients with a spontaneous onset of labor in the week after these data were recorded. The optimal cutoff values for predicting the onset of spontaneous labor within 7 days were 29.5 mm for cervical length at 37 weeks, 27.5 mm at 38 weeks, 25.5 mm at 39 weeks, and 24.5 mm at 40 weeks of gestation. There was also statistically significant agreement between the presence of the funneling and spontaneous labor within 7 days. Measurement of cervical length and detection of funneling at the internal cervical os by transvaginal ultrasonography might help us to predict the spontaneous onset of labor in a 7-day period, and help clinicians to decide about the time of labor induction in certain complicated pregnancies.


Reovirus M2 gene is associated with chromium release from mouse L cells.
In this study, we investigated the interaction of reovirus particles with cell membranes by using a 51Cr release assay. We confirmed prior observations (J. Borsa, B. D. Morash, M. D. Sargent, T. P. Copps, P. A. Lievaart, and J. G. Szekely, J. Gen. Virol. 45:161-170, 1979) that intermediate subviral particles (ISVPs) of reovirus type 3 strain Abney (T3A) induced the release of 51Cr from preloaded L cells and showed that the intact virion and core forms did not. Reovirus type 1 strain Lang (T1L) ISVPs were found to be less efficient at 51Cr release than T3A ISVPs. Reassortants between these strains indicated that the 51Cr release phenotype segregates with the M2 gene segment. Biochemical studies indicated that the ISVPs' acquisition of the capacity to induce 51Cr release followed the cleavage of the viral M2 gene product mu 1/mu 1C to fragments delta and phi during virion conversion to ISVP but did not directly correlate with this cleavage. These studies suggest that the reovirus M2 gene product (in its cleaved form) plays a role in interacting with cell membranes.


The MicroArray Quality Control (MAQC)-II study of common practices for the development and validation of microarray-based predictive models.
Gene expression data from microarrays are being applied to predict preclinical and clinical endpoints, but the reliability of these predictions has not been established. In the MAQC-II project, 36 independent teams analyzed six microarray data sets to generate predictive models for classifying a sample with respect to one of 13 endpoints indicative of lung or liver toxicity in rodents, or of breast cancer, multiple myeloma or neuroblastoma in humans. In total, >30,000 models were built using many combinations of analytical methods. The teams generated predictive models without knowing the biological meaning of some of the endpoints and, to mimic clinical reality, tested the models on data that had not been used for training. We found that model performance depended largely on the endpoint and team proficiency and that different approaches generated models of similar performance. The conclusions and recommendations from MAQC-II should be useful for regulatory agencies, study committees and independent investigators that evaluate methods for global gene expression analysis.


Invasive aspergillosis in patients with acute myeloid leukemia: a SEIFEM-2008 registry study.
The aim of this study was to evaluate prognostic factors, treatments and outcome of invasive aspergillosis in patients with acute myeloid leukemia based on data collected in a registry. The registry, which was activated in 2004 and closed in 2007, collected data on patients with acute myeloid leukemia, admitted to 21 hematologic divisions in tertiary care centers or university hospitals in Italy, who developed proven or probable invasive aspergillosis. One hundred and forty cases of invasive aspergillosis were collected, with most cases occurring during the period of post-induction aplasia, the highest risk phase in acute myeloid leukemia. The mortality rate attributable to invasive aspergillosis was 27%, confirming previous reports of a downward trend in this rate. Univariate and multivariate analyses revealed that the stage of acute myeloid leukemia and the duration of, and recovery from, neutropenia were independent prognostic factors. We analyzed outcomes after treatment with the three most frequently used drugs (liposomal amphotericin B, caspofungin, voriconazole). No differences emerged in survival at day 120 or in the overall response rate which was 71%, ranging from 61% with caspofungin to 84% with voriconazole. Our series confirms the downward trend in mortality rates reported in previous series, with all new drugs providing similar survival and response rates. Recovery from neutropenia and disease stage are crucial prognostic factors. Efficacious antifungal drugs bridge the period of maximum risk due to poor hematologic and immunological reconstitution.


The influence of subconjunctival depot corticosteroid on choroidal detachment following retinal detachment surgery.
This study indicates that primary retinal detachment surgery on patients aged 55 or over is complicated by uveitis and choroidal detachment at approximate rates of 24% and 44%, respectively. These complications did not influence the anatomic cure rate or recovery of visual acuity. Although only 89 patients were recruited, the technique of random selection equally distributed the parameters studied and provided results of high reliability. The internal controls of the protocol prevented the examiners from being aware of whether the drug or placebo had been administered. We were concerned that the corticosteroid injection might have been producing the apparent increase in infection rate of 7.7% and the study was temporarily discontinued. Because statistical analysis showed there was no significant difference in infection rate between the treatment and control groups, the project could have been continued again.


Lineage of origin in rhabdomyosarcoma informs pharmacological response.
Lineage or cell of origin of cancers is often unknown and thus is not a consideration in therapeutic approaches. Alveolar rhabdomyosarcoma (aRMS) is an aggressive childhood cancer for which the cell of origin remains debated. We used conditional genetic mouse models of aRMS to activate the pathognomonic Pax3:Foxo1 fusion oncogene and inactivate p53 in several stages of prenatal and postnatal muscle development. We reveal that lineage of origin significantly influences tumor histomorphology and sensitivity to targeted therapeutics. Furthermore, we uncovered differential transcriptional regulation of the Pax3:Foxo1 locus by tumor lineage of origin, which led us to identify the histone deacetylase inhibitor entinostat as a pharmacological agent for the potential conversion of Pax3:Foxo1-positive aRMS to a state akin to fusion-negative RMS through direct transcriptional suppression of Pax3:Foxo1.


What is the optimum number of CD34+ peripheral blood stem cells for an autologous transplant?
There is a wide variation in the number of CD34+ cells infused for an autologous transplantation. While the minimum number of hematopoietic stem cells for a successful transplantation has been established, there is no definite information on the optimum number or the maximum number of stem cells. It is generally agreed that a minimum dose of 2.5 x 10(6) CD34+ cells is necessary for successful engraftment. Although engraftment of neutrophils and platelets is achieved at that dose, it is delayed and is also negatively influenced by other factors. Reinfusion of 5.0 x 10(6) CD34+ cells results in prompt engraftment of all three cell lines and should be the preferred target. At least one study indicated that a very large number of cells (>15 x 10(6) CD34+ cells) resulted in further improvement in engraftment, decreased packed red blood cell and platelet transfusion, shorter hospitalization, and overall decreased costs. In contrast, a few studies showed that reinfusion of a large number of CD34+ cells causes fever and engraftment syndrome and may result in prolongation of the inpatient stay. Marrow culture assays performed post-transplant have shown decreased hematopoietic reserve as well as changes in the stromal cells. These changes persist for several years after the transplant. Generally, salvage chemotherapy is poorly tolerated post-transplant due to impaired marrow reserve. This hypothesis has not been validated by systematic clinical studies. It is undetermined if larger doses of stem cells improves the marrow reserve.


Developmental experiences of child sexual abusers and rapists.
The aim of this study is to identify the distinct developmental experiences associated with child sexual abuse and rape. For 269 sexual offenders (137 rapists and 132 child sexual abusers), developmental experiences were recorded from a behavioral checklist, a parental-bonding survey, and a sexual history questionnaire. Offender classification was obtained from official records and verified through polygraph examinations. Compared to rapists, child sexual abusers reported more frequent experiences of child sexual abuse (73%), early exposure to pornography (65% before age 10), an earlier onset of masturbation (60% before age 11), and sexual activities with animals (38%). In contrast to child sexual abusers, rapists reported more frequent experiences of physical abuse (68%), parental violence (78%), emotional abuse (70%), and cruelty to animals (68%). Both child sexual abusers and rapists (>93%) reported frequent exposure to violent media during their childhood. Most offenders (94%) described having insecure parental attachment bonds; 76% of rapists reported avoidant parental attachments and 62% of child sexual abusers reported anxious parental attachments. Findings from this study support the role of specific developmental experiences as etiological factors in differential sexual offending. Child sexual abusers' developmental histories were characterized by heightened sexuality; whereas rapists' childhood histories were more indicative of violence. These findings have implications for the treatment of sexual abusers and the prevention of sexual abuse. This study's findings suggest that sexual offenders have been socialized to satisfy human needs of intimacy and sexuality through maladaptive means, which implies that a risk management approach may not be sufficient treatment. Although risk models teach offenders skills to avoid high-risk situations, they fail to address the maladaptive strategies that they may have developed for satisfying needs. Instead, the focus of treatment should be to equip offenders with the knowledge, skills, and opportunities to achieve these needs in an acceptable manner. Thus, this model will provide these individuals with the opportunity to live a healthy life without sexual offending.


Identification of novel translational urinary biomarkers for acetaminophen-induced acute liver injury using proteomic profiling in mice.
Drug-induced liver injury (DILI) is the leading cause of acute liver failure. Currently, no adequate predictive biomarkers for DILI are available. This study describes a translational approach using proteomic profiling for the identification of urinary proteins related to acute liver injury induced by acetaminophen (APAP). Mice were given a single intraperitoneal dose of APAP (0-350 mg/kg bw) followed by 24 h urine collection. Doses of ≥275 mg/kg bw APAP resulted in hepatic centrilobular necrosis and significantly elevated plasma alanine aminotransferase (ALT) values (p<0.0001). Proteomic profiling resulted in the identification of 12 differentially excreted proteins in urine of mice with acute liver injury (p<0.001), including superoxide dismutase 1 (SOD1), carbonic anhydrase 3 (CA3) and calmodulin (CaM), as novel biomarkers for APAP-induced liver injury. Urinary levels of SOD1 and CA3 increased with rising plasma ALT levels, but urinary CaM was already present in mice treated with high dose of APAP without elevated plasma ALT levels. Importantly, we showed in human urine after APAP intoxication the presence of SOD1 and CA3, whereas both proteins were absent in control urine samples. Urinary concentrations of CaM were significantly increased and correlated well with plasma APAP concentrations (r = 0.97; p<0.0001) in human APAP intoxicants, who did not present with elevated plasma ALT levels. In conclusion, using this urinary proteomics approach we demonstrate CA3, SOD1 and, most importantly, CaM as potential human biomarkers for APAP-induced liver injury.


Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability.
The angiogenic sprout has been compared to the growing axon, and indeed, many proteins direct pathfinding by both structures. The Roundabout (Robo) proteins are guidance receptors with well-established functions in the nervous system; however, their role in the mammalian vasculature remains ill defined. Here we show that an endothelial-specific Robo, Robo4, maintains vascular integrity. Activation of Robo4 by Slit2 inhibits vascular endothelial growth factor (VEGF)-165-induced migration, tube formation and permeability in vitro and VEGF-165-stimulated vascular leak in vivo by blocking Src family kinase activation. In mouse models of retinal and choroidal vascular disease, Slit2 inhibited angiogenesis and vascular leak, whereas deletion of Robo4 enhanced these pathologic processes. Our results define a previously unknown function for Robo receptors in stabilizing the vasculature and suggest that activating Robo4 may have broad therapeutic application in diseases characterized by excessive angiogenesis and/or vascular leak.


Frequent Causal Pattern Mining: A Computationally Efficient Framework For Estimating Bias-Corrected Effects.
Our aging population increasingly suffers from multiple chronic diseases simultaneously, necessitating the comprehensive treatment of these conditions. Finding the optimal set of drugs for a combinatorial set of diseases is a combinatorial pattern exploration problem. Association rule mining is a popular tool for such problems, but the requirement of health care for finding causal, rather than associative, patterns renders association rule mining unsuitable. To address this issue, we propose a novel framework based on the Rubin-Neyman causal model for extracting causal rules from observational data, correcting for a number of common biases. Specifically, given a set of interventions and a set of items that define subpopulations (e.g., diseases), we wish to find all subpopulations in which effective intervention combinations exist and in each such subpopulation, we wish to find all intervention combinations such that dropping any intervention from this combination will reduce the efficacy of the treatment. A key aspect of our framework is the concept of closed intervention sets which extend the concept of quantifying the effect of a single intervention to a set of concurrent interventions. Closed intervention sets also allow for a pruning strategy that is strictly more efficient than the traditional pruning strategy used by the Apriori algorithm. To implement our ideas, we introduce and compare five methods of estimating causal effect from observational data and rigorously evaluate them on synthetic data to mathematically prove (when possible) why they work. We also evaluated our causal rule mining framework on the Electronic Health Records (EHR) data of a large cohort of 152000 patients from Mayo Clinic and showed that the patterns we extracted are sufficiently rich to explain the controversial findings in the medical literature regarding the effect of a class of cholesterol drugs on Type-II Diabetes Mellitus (T2DM).


Evaluation of Synergistic Antibacterial and Antioxidant Efficacy of Essential Oils of Spices and Herbs in Combination.
The present study was carried out to evaluate the possible synergistic interactions on antibacterial and antioxidant efficacy of essential oils of some selected spices and herbs [bay leaf, black pepper, coriander (seed and leaf), cumin, garlic, ginger, mustard, onion and turmeric] in combination. Antibacterial combination effect was evaluated against six important food-borne bacteria (Bacillus cereus, Listeria monocytogenes, Micrococcus luteus, Staphylococcus aureus, Escherichia coli and Salmonella typhimurium) using microbroth dilution, checkerboard titration and time-kill methods. Antioxidant combination effect was assessed by DPPH free radical scavenging method. Total phenolic content was measured by Folin-Ciocalteu method. Bioactivity -guided fractionation of active essential oils for isolation of bioactive compounds was done using TLC-bioautography assay and chemical characterization (qualitative and quantitative) of bioactive compounds was performed using DART-MS and HPLC analyses. Cytotoxic potential was evaluated by brine shrimp lethality assay as well as MTT assay using human normal colon cell line. Results showed that among the possible combinations tested only coriander/cumin seed oil combination showed synergistic interactions both in antibacterial (FICI : 0.25-0.50) and antioxidant (CI : 0.79) activities. A high positive correlation between total phenolic content and antibacterial activity against most of the studied bacteria (R2 = 0.688 - 0.917) as well as antioxidant capacity (R2 = 0.828) was also observed. TLC-bioautography-guided screening and subsequent combination studies revealed that two compounds corresponding to Rf values 0.35 from coriander seed oil and 0.53 from cumin seed oil exhibited both synergistic antibacterial and antioxidant activities. The bioactive compound corresponding to Rf 0.35 from coriander seed oil was identified as linalool (68.69%) and the bioactive compound corresponding to Rf 0.53 from cumin seed oil was identified as p-coumaric acid (7.14%) by DART-MS and HPLC analyses. The coriander/cumin seed oil combination did not show any cytotoxic effect both in brine shrimp lethality as well as human normal colon cell line assays. The LC50 in brine shrimp lethality assay was found to be 4945.30 μg/ml and IC50 in human normal colon cell line was > 1000 μg/ml. The results provide evidence that coriander/cumin seed oil combination might indeed be used as a potential source of safe and effective natural antimicrobial and antioxidant agents in pharmaceutical and food industries.


Petroleum in Pesticides: A Need to Change Regulatory Toxicology.
Toxicological investigations of pesticides largely focus on the declared active ingredient, which constitutes only between a few percent to around 50% of the total formulation. The complete formulations are unknown. For each declared active ingredient, there are dozens or hundreds of formulations. We demonstrate that petroleum has always been and is still always in pesticides. Gas chromatography and mass spectrometry (GC-MS) were applied for 24 pesticides. The measured compounds were the 16-priority polycyclic aromatic hydrocarbons (PAHs). The ratio of the PAHs to the threshold of toxicity was from 2.16 to 8288 times. The levels and distribution of PAHs per pesticide were different. Petroleum residues appear to be a waste product. The declared active component is taken alone for toxicity calculations, such as the acceptable daily intake (ADI). The PAHs with 2-3 cycles are more represented in pesticides than those with 4-6 cycles, which underlines that the petroleum residues appear to come mainly from crude unburned material. The ADI should be divided by 1000 if it is considered that petroleum residues amplify the toxicity by 1000. The admixture of PAHs in pesticides can be highly carcinogenic or toxic in the long term, even more than the declared active ingredient itself.


Effect of surface topography and wettability on the Leidenfrost effect.
When deposited on a superheated surface, a droplet can be levitated by its own vapour layer, a phenomenon that is referred to as the Leidenfrost effect. This dynamic effect has attracted interest for many potential applications, such as cooling, drag reduction and drop transport. A lot of effort has been paid to this mechanism over the past two and half centuries. Herein, we not only review the classical theories but also present the most recent theoretical advances in understanding the Leidenfrost effect. We first review the basic theories of the Leidenfrost effect, which mainly focuses on the relationship between the drop shape, vapour layer and lifetime. Then, the shift in the Leidenfrost point realized by fabricating special surface textures is introduced and the mechanisms behind this are analyzed. Furthermore, we present the reasons for the droplet transport in both classical Leidenfrost and pseudo-Leidenfrost regimes. Finally, the promising breakthroughs of the Leidenfrost effect are briefly addressed.


Sample concentration using optical chromatography.
Optical chromatography is a technique for the separation of particles that capitalizes on the balance between optic and fluidic forces. When microscopic particles in a fluid flow encounter a laser beam propagating in the opposite direction, they are trapped axially along the beam. They are then optically pushed upstream from the laser focal point to rest at a point where the optic and fluidic forces on the particle balance. Because optical and fluid forces are sensitive to differences in the physical and chemical properties of a particle, both coarse and fine separations are possible. We describe how an optical chromatography beam directed into a tailored flow environment, has been adapted to operate as an optical filter for the concentration / bioenrichment of colloidal and biological samples. In this work, the demonstrated ability to concentrate spores of the biowarfare agent, Bacillus anthracis, may have significant impact in the biodefense arena. Application of these techniques and further design of fluidic and optical environments will allow for more specific identification, concentration and separation of many more microscopic particle and biological suspensions.


So-eum type as an independent risk factor for irritable bowel syndrome: a population-based study in Korea.
It has been hypothesized that Sasang constitutional types (SCTs) have a specific hypoactive organ, which can account for vulnerability to related diseases or symptoms. This study examined the relationship between SCTs and irritable bowel syndrome (IBS). Cross-sectional study in a population-based cohort study in Korea. 1362 individuals (705 men and 657 women) who participated in the Korean Genome and Epidemiology Study. The participants were classified into SCTs by the integrated diagnostic model and asked about symptoms related to IBS using the Rome II criteria. The prevalence of IBS differed significantly among the SCTs, with 33 (18.3%) of the So-eum (SE) type, 74 (9.9%) of the Tae-eum (TE) type, and 57 (13.2%) of the So-yang (SY) type having IBS. Even after adjustment for possible confounders, the SE type for both sexes continued to show 1.82-fold (95% confidence interval [CI], 1.05-3.16) excess odds of having IBS. Men with SE type had a 2.97 times (95% CI, 1.34-6.58) and a 2.50 times (95% CI, 1.15-5.47) significantly higher odds of having IBS than the TE and SY types, respectively. In analysis for the joint effect of SCT and psychological stress, the multivariate odds ratio of IBS was 3.21 (95% CI, 1.33-7.75) for the SE type and Psychological Well-Being Index-Short Form (PWI-SF) score (<27), and 5.83 (95% CI, 1.80-18.88) for the SE type and PWI-SF (≥27) compared with the TE type and PWI-SF score (<27). The SE type of SCT is an independent risk factor for IBS. The findings support the hypothesis that persons with SE type are vulnerable to gastrointestinal diseases.


Optimising a person-centred approach to stopping medicines in older people with multimorbidity and polypharmacy using the DExTruS framework: a realist review.
Tackling problematic polypharmacy requires tailoring the use of medicines to individual circumstances and may involve the process of deprescribing. Deprescribing can cause anxiety and concern for clinicians and patients. Tailoring medication decisions often entails beyond protocol decision-making, a complex process involving emotional and cognitive work for healthcare professionals and patients. We undertook realist review to highlight and understand the interactions between different factors involved in deprescribing and to develop a final programme theory that identifies and explains components of good practice that support a person-centred approach to deprescribing in older patients with multimorbidity and polypharmacy. The realist approach involves identifying underlying causal mechanisms and exploring how, and under what conditions they work. We conducted a search of electronic databases which were supplemented by citation checking and consultation with stakeholders to identify other key documents. The review followed the key steps outlined by Pawson et al. and followed the RAMESES standards for realist syntheses. We included 119 included documents from which data were extracted to produce context-mechanism-outcome configurations (CMOCs) and a final programme theory. Our programme theory recognises that deprescribing is a complex intervention influenced by a multitude of factors. The components of our final programme theory include the following: a supportive infrastructure that provides clear guidance around professional responsibilities and that enables multidisciplinary working and continuity of care, consistent access to high-quality relevant patient contextual data, the need to support the creation of a shared explanation and understanding of the meaning and purpose of medicines and a trial and learn approach that provides space for monitoring and continuity. These components may support the development of trust which may be key to managing the uncertainty and in turn optimise outcomes. These components are summarised in the novel DExTruS framework. Our findings recognise the complex interpretive practice and decision-making involved in medication management and identify key components needed to support best practice. Our findings have implications for how we design medication review consultations, professional training and for patient records/data management. Our review also highlights the role that trust plays both as a central element of tailored prescribing and a potential outcome of good practice in this area.


Calculation of argon trimer rovibrational spectrum.
Rovibrational spectra of Ar3 are computed for total angular momenta up to J=6 using row-orthonormal hyperspherical coordinates and an expansion of the wave function on hyperspherical harmonics. The sensitivity of the spectra to the two-body potential and to the three-body corrections is analyzed. First, the best available semiempirical pair potential (HFDID1) is compared with our recent ab initio two-body potential. The ab initio vibrational energies are typically 1-2 cm-1 higher than the semiempirical ones, which is related to the slightly larger dissociation energy of the semiempirical potential. Then, the Axilrod-Teller asymptotic expansion of the three-body correction is compared with our newly developed ab initio three-body potential. The difference is found smaller than 0.3 cm-1. In addition, we define approximate quantum numbers to describe the vibration and rotation of the system. The vibration is represented by a hyper-radial mode and a two-degree-of-freedom hyperangular mode, including a vibrational angular momentum defined in an Eckart frame. The rotation is described by the total angular momentum quantum number, its projection on the axis perpendicular to the molecular plane, and a hyperangular internal momentum quantum number, related to the vibrational angular momentum by a transformation between Eckart and principal-axes-of-inertia frames. These quantum numbers provide a qualitative understanding of the spectra and, in particular, of the impact of the nuclear permutational symmetry of the system (bosonic with zero nuclear spin). Rotational constants are extracted from the spectra and are shown to be accurate only for the ground hyperangular mode.


Progress on stem cell research towards the treatment of Parkinson's disease.
Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive accumulation of Lewy body inclusions along with selective destruction of dopaminergic (DA) neurons in the nigrostriatal tract of the brain. Genetic studies have revealed much about the pathophysiology of PD, enabling the identification of both biomarkers for diagnosis and genetic targets for therapeutic treatment, which are evolved in tandem with the development of stem cell technologies. The discovery of induced pluripotent stem (iPS) cells facilitates the derivation of stem cells from adult somatic cells for personalized treatment and thus overcomes not only the limited availability of human embryonic stem cells but also ethical concerns surrounding their use. Non-viral, non-integration, or non-DNA-mediated reprogramming technologies are being developed. Protocols for generating midbrain DA neurons are undergoing constant refinement. The iPS cell-derived DA neurons provide cellular models for investigating disease progression in vitro and for screening molecules of novel therapeutic potential and have beneficial effects on improving the behavior of parkinsonian animals. Further progress in the development of safer non-viral/non-biased reprogramming strategies and the subsequent generation of homogenous midbrain DA neurons shall pave the way for clinical trials. A combined approach of drugs, cell replacement, and gene therapy to stop disease progression and to improve treatment may soon be within our reach.


Consequences of 'tiger' parenting: a cross-cultural study of maternal psychological control and children's cortisol stress response.
Parenting strategies involving psychological control are associated with increased adjustment problems in children. However, no research has examined the extent to which culture and psychological control predict children's stress physiology. We examine cultural differences in maternal psychological control and its associations with children's cortisol. Chinese (N = 59) and American (N = 45) mother-child dyads participated in the study. Mothers reported on psychological control. Children's cortisol was collected during a stressor and two indices of Area Under the Curve (AUC) were computed: AUCg which accounts for total output, and AUCi, which captures reactivity. Results indicate that Chinese mothers reported higher levels of psychological control and Chinese children had higher levels of AUCg than their American counterparts. Across both cultures, psychological control was significantly associated with increased cortisol levels as indexed by AUCg. There were no associations for AUCi. Finally, mediation analyses demonstrated that psychological control fully explained cultural differences in children's cortisol stress response as indexed by AUCg.


Scrambled and fried: cigarette smoke exposure causes antral follicle destruction and oocyte dysfunction through oxidative stress.
Cigarette smoke is a reproductive hazard associated with pre-mature reproductive senescence and reduced clinical pregnancy rates in female smokers. Despite an increased awareness of the adverse effects of cigarette smoke exposure on systemic health, many women remain unaware of the adverse effects of cigarette smoke on female fertility. This issue is compounded by our limited understanding of the molecular mechanisms behind cigarette smoke induced infertility. In this study we used a direct nasal exposure mouse model of cigarette smoke-induced chronic obstructive pulmonary disease to characterise mechanisms of cigarette-smoke induced ovotoxicity. Cigarette smoke exposure caused increased levels of primordial follicle depletion, antral follicle oocyte apoptosis and oxidative stress in exposed ovaries, resulting in fewer follicles available for ovulation. Evidence of oxidative stress also persisted in ovulated oocytes which escaped destruction, with increased levels of mitochondrial ROS and lipid peroxidation resulting in reduced fertilisation potential. Microarray analysis of ovarian tissue correlated these insults with a complex mechanism of ovotoxicity involving genes associated with detoxification, inflammation, follicular activation, immune cell mediated apoptosis and membrane organisation. In particular, the phase I detoxifying enzyme cyp2e1 was found to be significantly up-regulated in developing oocytes; an enzyme known to cause molecular bioactivation resulting in oxidative stress. Our results provide a preliminary model of cigarette smoke induced sub-fertility through cyp2e1 bioactivation and oxidative stress, resulting in developing follicle depletion and oocyte dysfunction.


Dating the end of the Greek Bronze Age: a robust radiocarbon-based chronology from Assiros Toumba.
Over 60 recent analyses of animal bones, plant remains, and building timbers from Assiros in northern Greece form an unique series from the 14th to the 10th century BC. With the exception of Thera, the number of 14C determinations from other Late Bronze Age sites in Greece has been small and their contribution to chronologies minimal. The absolute dates determined for Assiros through Bayesian modelling are both consistent and unexpected, since they are systematically earlier than the conventional chronologies of southern Greece by between 70 and 100 years. They have not been skewed by reference to assumed historical dates used as priors. They support high rather than low Iron Age chronologies from Spain to Israel where the merits of each are fiercely debated but remain unresolved.


Cognitive processes in anesthesiology decision making.
The quality and safety of health care are under increasing scrutiny. Recent studies suggest that medical errors, practice variability, and guideline noncompliance are common, and that cognitive error contributes significantly to delayed or incorrect diagnoses. These observations have increased interest in understanding decision-making psychology.Many nonrational (i.e., not purely based in statistics) cognitive factors influence medical decisions and may lead to error. The most well-studied include heuristics, preferences for certainty, overconfidence, affective (emotional) influences, memory distortions, bias, and social forces such as fairness or blame.Although the extent to which such cognitive processes play a role in anesthesia practice is unknown, anesthesia care frequently requires rapid, complex decisions that are most susceptible to decision errors. This review will examine current theories of human decision behavior, identify effects of nonrational cognitive processes on decision making, describe characteristic anesthesia decisions in this context, and suggest strategies to improve decision making.


Design of a Power Efficient Artificial Neuron Using Superconducting Nanowires.
With the rising societal demand for more information-processing capacity with lower power consumption, alternative architectures inspired by the parallelism and robustness of the human brain have recently emerged as possible solutions. In particular, spiking neural networks (SNNs) offer a bio-realistic approach, relying on pulses, analogous to action potentials, as units of information. While software encoded networks provide flexibility and precision, they are often computationally expensive. As a result, hardware SNNs based on the spiking dynamics of a device or circuit represent an increasingly appealing direction. Here, we propose to use superconducting nanowires as a platform for the development of an artificial neuron. Building on an architecture first proposed for Josephson junctions, we rely on the intrinsic non-linearity of two coupled nanowires to generate spiking behavior, and use electrothermal circuit simulations to demonstrate that the nanowire neuron reproduces multiple characteristics of biological neurons. Furthermore, by harnessing the non-linearity of the superconducting nanowire's inductance, we develop a design for a variable inductive synapse capable of both excitatory and inhibitory control. We demonstrate that this synapse design supports direct fan-out, a feature that has been difficult to achieve in other superconducting architectures, and that the nanowire neuron's nominal energy performance is competitive with that of current technologies.


Microfluidic droplet-based PCR instrumentation for high-throughput gene expression profiling and biomarker discovery.
PCR is a common and often indispensable technique used in medical and biological research labs for a variety of applications. Real-time quantitative PCR (RT-qPCR) has become a definitive technique for quantitating differences in gene expression levels between samples. Yet, in spite of this importance, reliable methods to quantitate nucleic acid amounts in a higher throughput remain elusive. In the following paper, a unique design to quantify gene expression levels at the nanoscale in a continuous flow system is presented. Fully automated, high-throughput, low volume amplification of deoxynucleotides (DNA) in a droplet based microfluidic system is described. Unlike some conventional qPCR instrumentation that use integrated fluidic circuits or plate arrays, the instrument performs qPCR in a continuous, micro-droplet flowing process with droplet generation, distinctive reagent mixing, thermal cycling and optical detection platforms all combined on one complete instrument. Detailed experimental profiling of reactions of less than 300 nl total volume is achieved using the platform demonstrating the dynamic range to be 4 order logs and consistent instrument sensitivity. Furthermore, reduced pipetting steps by as much as 90% and a unique degree of hands-free automation makes the analytical possibilities for this instrumentation far reaching. In conclusion, a discussion of the first demonstrations of this approach to perform novel, continuous high-throughput biological screens is presented. The results generated from the instrument, when compared with commercial instrumentation, demonstrate the instrument reliability and robustness to carry out further studies of clinical significance with added throughput and economic benefits.


Fast gate-tunable photodetection in the graphene sandwiched WSe2/GaSe heterojunctions.
We investigated electrical and photoelectrical properties of graphene sandwiched WSe2/GaSe van der Waals heterojunctions. The device showed a high rectification ratio up to 300 at Vds = 1.5/-1.5 V, which is attributed to the built-in electric field in the device. Due to the bipolar property of WSe2, gate-tunable rectification inversion was observed. Meanwhile, the graphene sandwiched heterojunction showed excellent performances on photodetection, where the photoresponsivity of (6.2 ± 0.2) A W-1 can be reached under Vds = -1.5 V and P = 0.2 μW. The device also showed great external quantum efficiency of (1490 ± 50)% and fast response time of ∼30 μs. Our study identified the graphene sandwiched heterojunctions based on 2D materials have great potential for gate-tunable electronic and optoelectronic applications.


Collection and use of exposure data from human milk biomonitoring in the United States.
Human milk is a unique biological matrix that can be used to estimate exposures in both the mother and the breastfed infant. In addition, the presence of environmental chemicals in human milk may act as a sentinel for exposures to a broader population. Several factors play a role in determining the quantity of chemicals transferred to milk and, subsequently, to the breastfeeding infant, including maternal, infant, and chemical characteristics. Exposure to certain environmental chemicals during critical periods can disrupt normal infant development, yet few data exist to quantify the hazards posed by environmental chemicals in human milk. Chemicals measured in human milk may also provide insights to agents suspect in altering breast development and breast-related disease risk. Carefully designed exposure assessment and toxicokinetic studies are needed to elucidate mechanisms and establish relationships between human milk and other biologic matrices. Data from human milk biomonitoring studies can be used to inform and validate models that integrate information about chemical properties, human metabolism, and biomarker concentrations. Additional research is needed to determine the degree to which environmental chemicals enter, are present in, and are excreted from human milk, their impact on the host (mother), and the extent of their bioavailability to breastfeeding infants. This article describes how the collection and use of exposure data from human milk biomonitoring in the United States can be designed to inform future research and policy.


Deuterium oxide prevents hypertension and elevated cytosolic calcium in hypertensive rats.
Increased calcium uptake in vascular tissue, leading to elevated cytosolic free calcium, has been implicated in the pathophysiology of hypertension. This study examined the dose-dependent effect of deuterium oxide (5%, 10%, or 20% in drinking water) on systolic blood pressure, aortic calcium uptake, and platelet cytosolic free calcium in spontaneously hypertensive rats. Starting at age 8 weeks, spontaneously hypertensive rats were divided into four groups of six animals each. The drinking water of groups 1, 2, 3, and 4 was replaced by 100% water and 5%, 10%, and 20% deuterium oxide in water, respectively, for another 7 weeks. Ten Wistar-Kyoto rats, age 8 weeks, were given 100% water for the next 7 weeks. The usual increase in systolic blood pressure and the associated increase in aortic calcium uptake and platelet cytosolic free calcium in spontaneously hypertensive rats at age 15 weeks was lowered in a dose-dependent manner by deuterium oxide. Deuterium oxide also prevented renal vascular changes in spontaneously hypertensive rats. A minimum dose of 10% deuterium oxide was needed to completely prevent the development of hypertension, elevated aortic calcium uptake, platelet cytosolic free calcium, and renal vascular changes in spontaneously hypertensive rats.


Frequency Domain Channel-wise Attack to CNN Classifiers in Motor Imagery Brain-Computer Interfaces.
Convolutional neural network (CNN), a classical structure in deep learning, has been commonly deployed in the motor imagery brain-computer interface (MIBCI). Many methods have been proposed to evaluate the vulnerability of such CNN models, primarily by attacking them using direct temporal perturbations. In this work, we propose a novel attacking approach based on perturbations in the frequency domain instead. For a given natural MI trial in the frequency domain, the proposed approach, called frequency domain channel-wise attack (FDCA), generates perturbations at each channel one after another to fool the CNN classifiers. The advances of this strategy are two-fold. First, instead of focusing on the temporal domain, perturbations are generated in the frequency domain where discriminative patterns can be extracted for motor imagery (MI) classification tasks. Second, the perturbing optimization is performed based on differential evolution algorithm in a black-box scenario where detailed model knowledge is not required. Experimental results demonstrate the effectiveness of the proposed FDCA which achieves a significantly higher success rate than the baselines and existing methods in attacking three major CNN classifiers on four public MI benchmarks. Perturbations generated in the frequency domain yield highly competitive results in attacking MIBCI deployed by CNN models even in a black-box setting, where the model information is well-protected. To our best knowledge, existing MIBCI attack approaches are all gradient-based methods and require details about the victim model, e.g., the parameters and objective function. We provide a more flexible strategy that does not require model details but still produces an effective attack outcome.


ALG-2 interacting protein AIP1: a novel link between D1 and D3 signalling.
Dopamine signalling is a critically important process in the human brain that controls mood, cognition and motor activity. In order to gain detailed insight into this signalling pathway at the molecular level, we carried out yeast two-hybrid screens with D1-like (D1, D5) and D2-like (D2, D3, D4) dopamine receptors and identified 11 dopamine receptor interacting proteins (DRIPs). Using the C-terminal domain of D1 receptor as bait, we identified AIP1 (ALG-2 interacting protein 1), a known modulator of caspase-dependent and caspase-independent cell death, including neuronal cell death, that is also part of the endosomal transport system. In a separate yeast two-hybrid screen, using the third intracellular cytoplasmic loop of D3 as bait, we again identified AIP1. The interaction of AIP1 with both D1 and D3 was confirmed in vitro and in vivo using a variety of methods, including glutathione S-transferase (GST) pull-down, blot overlay and coimmunoprecipitation from mouse brain lysates. We have also observed colocalization of D1 and D3 with AIP1 in mouse brain tissue. In addition, coexpression of AIP1 with D1 resulted in > 50% reduction in binding capacity of D1 to its antagonist. Finally, AIP1 up-regulates D1 and D3 expression and appears to be important for their stability and trafficking.


Synaptic and Neuronal Autoantibody-Associated Psychiatric Syndromes: Controversies and Hypotheses.
Autoimmune encephalitis (AE) mediated by antibodies against synaptic and neuronal surface targets frequently presents with a psychiatric syndrome. In these patients, removal of autoantibodies treats the disease and outcomes are closely linked to early intervention. The discovery of these autoantibodies in isolated psychiatric syndromes has raised the possibility that these patients may derive similar benefits from immunotherapy, a potentially transformational approach to the treatment of mental illness. Although open-label case series suggest impressive therapeutic outcomes, the pathological relevance of these autoantibodies outside of canonical presentations is debated. The advent of diagnostic criteria for AE attempts to facilitate its prompt identification but risks prematurely neglecting the potential scientific and clinical significance of isolated syndromes that do not satisfy these criteria. Here, we propose using a syndrome-level taxonomy that has occasional, but not necessary, overlap with AE: synaptic and neuronal autoantibody-associated psychiatric syndromes or "SNAps". This will prevent confusion with AE and act heuristically to promote active investigation into this rare example of psychopathology defined on a molecular level. We suggest that this concept would have application in other autoantibody-associated syndromes including seizure, cognitive, and movement disorders, in which similar issues arise. We review putative direct and indirect mechanisms and outline experimentally testable hypotheses that would help to determine prospectively in whom autoantibody detection is relevant, and as important, in whom it is not. We summarize a pragmatic approach to autoantibody testing and management in severe mental illness in order to promptly diagnose AE and advocate a research-orientated experimental medicine paradigm for SNAps, where there is greater equipoise. We conclude that SNAps remains a nascent area of clinical neuroscience with great potential and in ongoing need of psychiatry-led basic and clinical research.


Coexisting incarcerated femoral and obturator hernia: a case report.
Obturator hernia is a rare condition associated with a high morbidity and mortality. It is an uncommon cause of bowel obstruction most commonly described in elderly females with comorbidity. Surgical intervention is often delayed as a result of subtle presenting signs. Coexisting ipsilateral femoral hernia is an even rarer condition represented by non-exhaustive series in the literature. We report a case of a healthy 36 years old lady, nulliparous, with abdominal pain and swelling in the right groin. Preoperative CT showed only a right groin hernia, that was found to be femoral at operative intervention. She recovered and was discharged from hospital but represented with further symptoms of obstruction 9 days later. Diagnostic laparoscopy demonstrated a ipsilateral obturator hernia with associated bowel infarct. The bowel was resected and the defect was repaired. Obturator hernia presents subtly with medial thigh pain and no lump. They are notorious for difficulty to diagnosis. We describe the first case of coexisting ipsilateral femoral and obturator hernias in a young nulliparous woman with bowel obstruction. Appropriate intraoperative exploration should always be considered.


PATHBIO: an international training program for precision mouse phenotyping.
Design and production of genetically engineered mouse strains by individual research laboratories, research teams, large-scale consortia, and the biopharmaceutical industry have magnified the need for qualified personnel to identify, annotate, and validate (phenotype) these potentially new mouse models of human disease. The PATHBIO project has been recently established and funded by the European Union's ERASMUS+ Knowledge Alliance program to address the current shortfall in formally trained personnel. A series of teaching workshops will be given by experts on anatomy, histology, embryology, imaging, and comparative pathology to increase the availability of individuals with formal training to contribute to this important niche of Europe's biomedical research enterprise. These didactic and hands-on workshops are organized into three modules: (1) embryology, anatomy, histology, and the anatomical basis of imaging, (2) image-based phenotyping, and (3) pathology. The workshops are open to all levels of participants from recent graduates to Ph.D., M.D., and veterinary scientists. Participation is available on a competitive basis at no cost for attending. The first series of Workshop Modules was held in 2019 and these will continue for the next 2 years.


Treatment of symptomatic diabetic peripheral neuropathy with the protein kinase C beta-inhibitor ruboxistaurin mesylate during a 1-year, randomized, placebo-controlled, double-blind clinical trial.
The aim of this study was to assess the effects of ruboxistaurin (RBX) mesylate on nerve function and sensory symptoms in patients with diabetes mellitus (DM) and diabetic peripheral neuropathy (DPN). Patients were enrolled in a multinational, randomized, Phase II, double-blind, placebo-controlled parallel-group trial comparing 32 mg/d or 64 mg/d RBX with placebo for 1 year. DPN was identified by abnormal measurable vibration detection threshold (VDT) and verified by abnormal neurologic examination and nerve electrophysiology measures. Baseline patient characteristics (eg, sex, type of DM, age, body mass index, glycosylated hemoglobin, and duration of DM and DPN) were measured. The primary end point was the change in VDT. Secondary end point measures included effects of RBX versus placebo on Neuropathy Total Symptom Score-6 (NTSS-6), neurologic examination, electrophysiologic nerve conduction studies, Neuropathy Impairment Score, Clinical Global Impressions, and safety. A post-hoc analysis was performed on patients with less severe DPN (sural sensory nerve action potential > or =0.5 microV and NTSS-6 total score >6). Two hundred five patients were assessed: 66 were assigned to the RBX 32 mg/d group, 71 to the RBX 64 mg/d group, and 68 to the placebo group. The demographic and baseline characteristics of the treatment groups were well matched between the RBX 32 mg/d, RBX 64 mg/d, and placebo groups: mean (SD) age, 45.6 (8.41) years; 122 (60%) men, 83 (40%) women; 110 (54%) with type 1 DM, 95 (46%) with type 2 DM; mean (SD) duration of DPN, 3.4 (4.21) years. The RBX 32 mg/d group had slightly more patients with type 1 DM (P = 0.05). Eighty-three patients had clinically significant symptoms at baseline (defined as NTSS-6 total score >6: RBX 32 mg/d, n = 22; RBX 64 mg/d, n = 26; placebo, n = 35); 122 patients had NTSS-6 total scores < or =6. No treatment differences were observed for change in VDT. Among the 83 patients with significant symptoms at baseline, there was a reduction from baseline at 12 months in the NTSS-6 total score in the RBX 32 mg/d (P = NS) and RBX 64 mg/d (P = 0.015) groups compared with placebo. In a subgroup of patients with clinically significant symptoms and less severe DPN (n = 50), there was a significantly greater reduction in the NTSS-6 total score with RBX 64 mg/d (P = 0.006 vs placebo). Furthermore, in these patients, there was a statistically significant improvement in VDT for both RBX 32 mg/d (P = 0.012) and RBX 64 mg/d (P = 0.026) compared with placebo. RBX appeared to be well tolerated in the patients with DPN who participated in this study. Overall, changes in VDT and NTSS-6 total scores did not differ among treatment groups at end point. However, RBX treatment appeared to be of benefit for the subgroup of patients with less severe symptomatic DPN by relieving sensory symptoms and improving nerve fiber function, as indicated by reductions in VDT and NTSS-6 total score.


Perspective: Accurate treatment of the quantum dynamics of light molecules inside fullerene cages: Translation-rotation states, spectroscopy, and symmetry breaking.
In this perspective, I review the current status of the theoretical investigations of the quantum translation-rotation (TR) dynamics and spectroscopy of light molecules encapsulated inside fullerenes, mostly C60 and C70. The methodologies developed in the past decade allow accurate quantum calculations of the TR eigenstates of one and two nanoconfined molecules and have led to deep insights into the nature of the underlying dynamics. Combining these bound-state methodologies with the formalism of inelastic neutron scattering (INS) has resulted in the novel and powerful approach for the quantum calculation of the INS spectra of a diatomic molecule in a nanocavity with an arbitrary geometry. These simulations have not only become indispensable for the interpretation and assignment of the experimental spectra but are also behind the surprising discovery of the INS selection rule for diatomics in near-spherical nanocavities. Promising directions for future research are discussed.


Regressive modifications of climbing fibres following Purkinje cell degeneration in the cerebellar cortex of the adult rat.
The role of postsynaptic neurons in the maintenance of adult terminal axon arbours was investigated in the rat olivocerebellar system. The degeneration of Purkinje cells, the main target of olivary axons in the cerebellar cortex, was obtained by intraparenchymal application of kainate. The structural features of target-deprived climbing fibres, visualized by Phaseolus vulgaris leucoagglutinin tracing, were examined from two days to six months after the lesion. Following the degeneration of its Purkinje cell, the climbing fibre underwent remarkable regressive modifications involving the disappearance of most of the terminal arborization. Never the less, atrophic arbours still spanned through the molecular layer six months after the lesion. Morphometric evaluations showed that, one week after kainate application, total arbour length was already reduced to 52% of control, whereas the number of branches and of varicosities had both dropped around 40%. This retraction process progressed in the following stages to reach its maximum at about one month after the lesion, when total length was 30% of control and only 10% of branches and varicosities were still present. Only a slight tendency to a further decrease of the values could be detected at longer survival times. Branching pattern analysis revealed that such regressive phenomena mainly involved the distal compartment of the climbing fibres, the one made of fine varicose branchlets, while sparing the proximal thick branches. In addition, the whole process appeared to follow some rather strict guiding principles leading to an ordered branch retraction, from the periphery of the arbour inwards. Finally, in order to rule out the possibility that the observed changes could be due to a direct action of kainate on climbing fibres, we designed an alternative method of killing Purkinje cells by intraparenchymal injection of propidium iodide. The structural features of climbing fibres deprived of their target by such a procedure were very similar to those shown by arbours from time-matched kainate-lesioned animals at both qualitative and quantitative levels. Our results show that target deprivation induces remarkable structural modifications in the climbing fibre, leading to the retraction of most of the arbour. Never the less, the integrity of the Purkinje cell is not necessary for the maintenance of the whole arborization since its proximal compartment is maintained in the molecular layer for several months after target degeneration. It is proposed that the Purkinje cell, most likely by acting through a contact factor, directly controls the formation and the maintenance of the distal climbing fibre branches with their varicosities, which represent the presynaptic compartment of the axonal arbour.