Biocatalytic Feedback-Driven Temporal Programming of Self-Regulating Peptide Hydrogels.
Switchable self-assemblies respond to external stimuli with a transition between near-equilibrium states. Although being a key to present-day advanced materials, these systems respond rather passively, and do not display autonomous dynamics. For autonomous behavior, approaches must be found to orchestrate the time domain of self-assemblies, which would lead to new generations of dynamic and self-regulating materials. Herein, we demonstrate catalytic control of the time domain of pH-responsive peptide hydrogelators in a closed system. We program transient acidic pH states by combining a fast acidic activator with the slow, enzymatic, feedback-driven generation of a base (dormant deactivator). This transient state can be programmed over orders of magnitude in time. It is coupled to dipeptides to create autonomously self-regulating, dynamic gels with programmed lifetimes, which are used for fluidic guidance, burst release, and self-erasing rapid prototyping.


Sloppy bypass of an abasic lesion catalyzed by a Y-family DNA polymerase.
DNA damage that eludes cellular repair pathways can arrest the replication machinery and stall the cell cycle. However, this damage can be bypassed by the Y-family DNA polymerases. Here, Dpo4, an archetypal Y-family member from the thermophilic Sulfolobus solfataricus, was used to extend our kinetic studies of the bypass of an abasic site, one of the most mutagenic and ubiquitous cellular lesions. A short oligonucleotide sequencing assay is developed to directly sequence DNA bypass products synthesized by Dpo4. Our results show that incorporation upstream of the abasic lesion is replicated error-free; yet dramatically, once Dpo4 encounters the lesion, synthesis became sloppy, with bypass products containing a myriad of mutagenic events. Incorporation of dAMP (29%) and dCMP (53%) opposite the abasic lesion at 37 degrees C correlates exceptionally well with our kinetic results and demonstrates two dominant bypass pathways via the A-rule and the lesion loop-out mechanism. Interestingly, the percentage of overall frameshift mutations increased from 71 (37 degrees C) to 87% (75 degrees C). Further analysis indicates that lesion bypass via the A-rule is strongly preferred over the lesion loop-out mechanism at higher temperatures and concomitantly reduces the occurrence of "-1 deletion" mutations observed opposite the lesion at lower temperatures. The bypass percentage via the latter pathway is confirmed by an enzymatic digestion assay, verifying the reliability of our sequencing assay. Our results demonstrate that an abasic lesion causes Dpo4 and possibly all Y-family members to switch from a normal to a very mutagenic mode of replication.


A survey of members of the American Academy of Pediatric Dentistry on their use of behavior management techniques.
The objective of this study was to survey members of the American Academy of Pediatric Dentistry (AAPD) regarding their use of behavior management techniques. Surveys were mailed to 4,180 members, with a follow-up mailing to nonrespondents 2 months later. The survey contained items on demographic variables and use (current, past, and future) of communicative and pharmacologic techniques. Information was also obtained on informed consent, parental presence in the operatory, and parenting styles. Survey response was 66%. Communicative techniques are widely used, with the exception of the hand-over-mouth exercise (HOME). Immobilization for sedated and nonsedated children and pharmacologic techniques are used by a majority or near majority of respondents. Little change was reported in technique use over time, except that 50% of respondents indicated they use HOME less now than 5 years ago, and 24% plan to use it less over the next 2 to 3 years. Parental presence in the operatory appeared to be a common practice for some procedures and for children with special health care needs. The majority of respondents believed that parenting styles had changed in ways that adversely impacted children's behavior in the dental setting. Most practitioners have not changed their use of behavior management techniques in recent years, nor do they plan to change their use of them in the near future. HOME was the exception to these trends.


Effect of butylated hydroxytoluene and other antioxidants on mouse lung metabolism.
Toxic doses of butylated hydroxytoluene (BHT), a phenolic antioxidant commonly used as a food additive, are known to produce lung damage. In this study, 3 days after a single ip injection of 62.5, 215, or 500 mg/kg BHT in mice there was a dose-dependent increase in lung weight. This concentration dependence with injected BHT was accompanied by increases in lung DNA and nonprotein sulfhydryl levels and in whole lung tissue enzyme activities of glutathione (GSH) peroxidase, GSH reductase, glucose-6-phosphate dehydrogenase, and superoxide dismutase. The increased enzyme activities are considered to correspond to inflammatory and proliferative pulmonary changes resulting from acute lung cell injury and necrosis, which have been described previously, and cannot be construed as evidence for a primary oxidant-induced pulmonary lesion. The mechanism of BHT-induced lung changes may not be related to the antioxidant property of BHT, since vitamin E, n-propyl gallate, ethoxyquin, N,N'-p-phenylenediamine, and the structurally similar compound, butylated hydroxyanisole did not appear to produce the gross anatomical or biochemical lung changes observed with BHT.


Radial head fractures: MRI evaluation of associated injuries.
The purpose of this study was to evaluate the incidence of combined osteochondral and ligamentous injuries by magnetic resonance imaging (MRI) in 24 patients with an acute radial head fracture (Mason type II and III) without documented dislocation or tenderness at the distal radioulnar joint. Elbow radiographs (anteroposterior and lateral views) were obtained on all patients as well as magnetic resonance images in the sagittal, coronal, axial, axial oblique, and coronal oblique planes with the injured elbow in a splint. The incidence of associated injuries revealed by MRI was medial collateral ligament not intact in 13 of 24 (54.16%), lateral ulnar collateral ligament not intact in 18 of 24 (80.1%), both collateral ligaments not intact in 12 of 24 (50%), capitellar osteochondral defects in 7 of 24 (29.1%), capitellar bone bruises in 23 of 24 (95.83%), and loose bodies in 22 of 24 (91.67%). A high level of suspicion should be used when one is treating displaced or comminuted radial head fractures, because concurrent osteochondral injuries and/or ligamentous injuries may be present.


First all-in-one diagnostic tool for DNA intelligence: genome-wide inference of biogeographic ancestry, appearance, relatedness, and sex with the Identitas v1 Forensic Chip.
When a forensic DNA sample cannot be associated directly with a previously genotyped reference sample by standard short tandem repeat profiling, the investigation required for identifying perpetrators, victims, or missing persons can be both costly and time consuming. Here, we describe the outcome of a collaborative study using the Identitas Version 1 (v1) Forensic Chip, the first commercially available all-in-one tool dedicated to the concept of developing intelligence leads based on DNA. The chip allows parallel interrogation of 201,173 genome-wide autosomal, X-chromosomal, Y-chromosomal, and mitochondrial single nucleotide polymorphisms for inference of biogeographic ancestry, appearance, relatedness, and sex. The first assessment of the chip's performance was carried out on 3,196 blinded DNA samples of varying quantities and qualities, covering a wide range of biogeographic origin and eye/hair coloration as well as variation in relatedness and sex. Overall, 95 % of the samples (N = 3,034) passed quality checks with an overall genotype call rate >90 % on variable numbers of available recorded trait information. Predictions of sex, direct match, and first to third degree relatedness were highly accurate. Chip-based predictions of biparental continental ancestry were on average ~94 % correct (further support provided by separately inferred patrilineal and matrilineal ancestry). Predictions of eye color were 85 % correct for brown and 70 % correct for blue eyes, and predictions of hair color were 72 % for brown, 63 % for blond, 58 % for black, and 48 % for red hair. From the 5 % of samples (N = 162) with <90 % call rate, 56 % yielded correct continental ancestry predictions while 7 % yielded sufficient genotypes to allow hair and eye color prediction. Our results demonstrate that the Identitas v1 Forensic Chip holds great promise for a wide range of applications including criminal investigations, missing person investigations, and for national security purposes.


A jasmonate ZIM-domain protein NaJAZd regulates floral jasmonic acid levels and counteracts flower abscission in Nicotiana attenuata plants.
Jasmonic acid is an important regulator of plant growth, development and defense. The jasmonate-ZIM domain (JAZ) proteins are key regulators in jasmonate signaling ubiquitously present in flowering plants but their functional annotation remains largely incomplete. Recently, we identified 12 putative JAZ proteins in native tobacco, Nicotiana attenuata, and initiated systematic functional characterization of these proteins by reverse genetic approaches. In this report, Nicotiana attenuata plants silenced in the expression of NaJAZd (irJAZd) by RNA interference were used to characterize NaJAZd function. Although NaJAZd transcripts were strongly and transiently up-regulated in the rosette leaves by simulated herbivory treatment, we did not observe strong defense-related phenotypes, such as altered herbivore performance or the constitutive accumulation of defense-related secondary metabolites in irJAZd plants compared to wild type plants, both in the glasshouse and the native habitat of Nicotiana attenuata in the Great Basin Desert, Utah, USA. Interestingly, irJAZd plants produced fewer seed capsules than did wild type plants as a result of increased flower abscission in later stages of flower development. The early- and mid-developmental stages of irJAZd flowers had reduced levels of jasmonic acid and jasmonoyl-L-isoleucine, while fully open flowers had normal levels, but these were impaired in NaMYB305 transcript accumulations. Previously, NaMYB305-silenced plants were shown to have strong flower abscission phenotypes and contained lower NECTARIN 1 transcript levels, phenotypes which are copied in irJAZd plants. We propose that the NaJAZd protein is required to counteract flower abscission, possibly by regulating jasmonic acid and jasmonoyl-L-isoleucine levels and/or expression of NaMYB305 gene in Nicotiana attenuata flowers. This novel insight into the function of JAZ proteins in flower and seed development highlights the diversity of functions played by jasmonates and JAZ proteins.


Comparison between intensity correlation and Fourier transform of the time interval probability techniques applied to laser Doppler velocimetry.
In this paper we study the improvement in a laser Doppler velocimetry experiment when the Fourier transform of the time interval probability is measured instead of the intensity correlation function. The errors involved in determination of the velocity are found to be greatly improved for low scattered intensities.


Total Sitting Time and Sitting Pattern in Postmenopausal Women Differ by Hispanic Ethnicity and are Associated With Cardiometabolic Risk Biomarkers.
Background Sedentary behavior is pervasive, especially in older adults, and is associated with cardiometabolic disease and mortality. Relationships between cardiometabolic biomarkers and sitting time are unexplored in older women, as are possible ethnic differences. Methods and Results Ethnic differences in sitting behavior and associations with cardiometabolic risk were explored in overweight/obese postmenopausal women (n=518; mean±SD age 63±6 years; mean body mass index 31.4±4.8 kg/m2). Accelerometer data were processed using validated machine-learned algorithms to measure total daily sitting time and mean sitting bout duration (an indicator of sitting behavior pattern). Multivariable linear regression was used to compare sitting among Hispanic women (n=102) and non-Hispanic women (n=416) and tested associations with cardiometabolic risk biomarkers. Hispanic women sat, on average, 50.3 minutes less/day than non-Hispanic women (P<0.001) and had shorter (3.6 minutes less, P=0.02) mean sitting bout duration. Among all women, longer total sitting time was deleteriously associated with fasting insulin and triglyceride concentrations, insulin resistance, body mass index and waist circumference; longer mean sitting bout duration was deleteriously associated with fasting glucose and insulin concentrations, insulin resistance, body mass index and waist circumference. Exploratory interaction analysis showed that the association between mean sitting bout duration and fasting glucose concentration was significantly stronger among Hispanic women than non-Hispanic women (P-interaction=0.03). Conclusions Ethnic differences in 2 objectively measured parameters of sitting behavior, as well as detrimental associations between parameters and cardiometabolic biomarkers were observed in overweight/obese older women. The detrimental association between mean sitting bout duration and fasting glucose may be greater in Hispanic women than in non-Hispanic women. Corroboration in larger studies is warranted.


Focal organizing pneumonia on surgical lung biopsy: causes, clinicoradiologic features, and outcomes.
Organizing pneumonia (OP) is a histologic pattern that is morphologically distinctive but nonspecific and can be seen in diverse clinical settings. Focal OP has been described as a discrete form of OP, but relatively little is known regarding this clinicopathologic entity. We sought to clarify the clinicoradiologic presentation, underlying causes, and outcomes associated with focal OP by retrospectively reviewing 26 consecutive cases diagnosed by surgical lung biopsy over an 8-year period from January 1, 1997, to December 31, 2004. All patients presented with an unifocal opacity detected on chest radiography (20 patients) or CT scans (6 patients). At the time of presentation, 10 patients (38%) had symptoms, including cough, shortness of breath, or chest pain; 16 patients were asymptomatic. Contrast-enhancement CT scanning or positron emission tomography (PET) scan was performed in 11 patients, and the results were positive in all. Surgical procedures included wedge resection in 21 patients (81%), segmentectomy in 3 patients (11%), and lobectomy in 2 patients (8%). Three case of focal OP (12%) were related to infections, but the remaining cases were cryptogenic. Follow-up over a median interval of 11 months (range, 1 to 71 months) yielded no recurrence of OP. The radiologic features of focal OP are often indistinguishable from those of lung cancer, and include positivity on contrast-enhancement CT scan and PET scan. Most cases of focal OP are cryptogenic, and infection is identified in a minority of cases. Surgical resection alone appears to suffice in the management of cryptogenic focal OP.


Management of frailty under COVID-19 pandemic in Japan.
Frailty prevention is a cornerstone for the extension of healthy life expectancy. It is a multi-dimensional construct that includes physical, mental, and social aspects. Frailty is reversible and can be attenuated by intervention; therefore, its early detection is important in primary and community care. The mainstream of disability prevention in Japan, which comprises the Japanese and local governments as well as healthcare workers, was a high-risk approach until 2014. Given the revision on Japan's long-term care insurance law, current ageing health policies have shifted to more population centric approach. Implements group activities called "Kayoi-no-ba" has been valued in Japan as disability prevention initiative. The Kihon Checklist - a 25-item questionnaire - has been broadly used by health experts and researchers to assess frailty in Japan. However, a new 15-item questionnaire has been newly developed to identify frailty and other health-related problems in older people of 75 years and above. This will enable providing the necessary support to frail individuals at any healthcare facility in local communities. The increase in frailty prevalence in older people has been concern during the COVID-19 pandemic. Home-based physical exercise programs are expected to be effective for frailty prevention. Utilization of information and communication technologies, social network services, and video calls has attracted attention for being effective tools to facilitate communication for older people during the pandemic. Further, life course approaches are needed to clarify the midlife risk of frailty development in later life.


The Role of Intuition in the Generation and Evaluation Stages of Creativity.
Both intuition and creativity are associated with knowledge creation, yet a clear link between them has not been adequately established. First, the available empirical evidence for an underlying relationship between intuition and creativity is sparse in nature. Further, this evidence is arguable as the concepts are diversely operationalized and the measures adopted are often not validated sufficiently. Combined, these issues make the findings from various studies examining the link between intuition and creativity difficult to replicate. Nevertheless, the role of intuition in creativity should not be neglected as it is often reported to be a core component of the idea generation process, which in conjunction with idea evaluation are crucial phases of creative cognition. We review the prior research findings in respect of idea generation and idea evaluation from the view that intuition can be construed as the gradual accumulation of cues to coherence. Thus, we summarize the literature on what role intuitive processes play in the main stages of the creative problem-solving process and outline a conceptual framework of the interaction between intuition and creativity. Finally, we discuss the main challenges of measuring intuition as well as possible directions for future research.


Reversible positioning of single molecules inside zero-mode waveguides.
We have developed a hybrid nanopore/zero-mode waveguide device for single-molecule fluorescence and DNA sequencing applications. The device is a freestanding solid-state membrane with sub-5 nm nanopores that reversibly delivers individual biomolecules to the base of 70 nm diameter waveguides for interrogation. Rapid and reversible molecular loading is achieved by controlling the voltage across the device. Using this device we demonstrate protein and DNA loading with efficiency that is orders of magnitude higher than diffusion-based molecular loading.


MuSK antibody-positive, seronegative myasthenia gravis in Korea.
Several reports from Western countries suggest differences in the clinical features of patients with muscle specific kinase (MuSK) antibody-positive and -negative seronegative myasthenia gravis (MG). We performed the first survey in Korea of MuSK antibodies, studying 23 patients with acetylcholine receptor (AChR)-antibody seronegative MG. MuSK antibodies were present in 4 (26.7%) of 15 generalized seronegative MG patients and none of 8 ocular seronegative MG patients. All four MuSK positive patients were females, with pharyngeal and respiratory muscle weakness, and required immunosuppressive treatment. However, overall disease severity and age at onset was similar to that of MuSK-negative MG and treatment responses were equally good.


Metabolic syndrome: identifying the risk factors.
To discuss the metabolic syndrome and identify its risk factors, including in the pediatric age group. Indexed review articles. The metabolic syndrome is characterized by insulin resistance and the presence of risk factors for cardiovascular diseases and diabetes mellitus type 2. Consensus has not yet been reached on its diagnostic criteria. This review presents diagnostic criteria defined by the American Heart Association (US National Cholesterol Education Program), the American Association of Clinical Endocrinologists, the World Health Organization and the International Diabetes Federation and discusses the possibilities of applying them to children. Pathophysiologic features of the syndrome are also covered, principally those related to the perinatal period and childhood. The metabolic syndrome is being diagnosed with ever greater frequency, principally during adolescence. Lifestyle changes, such as to diet and level of physical activity are fundamental to prevention. Treatment with medication and, in extreme cases, with surgery should also be considered, depending on severity and age.


Differential DNA methylation of potassium channel KCa3.1 and immune signalling pathways is associated with infant immune responses following BCG vaccination.
Bacillus Calmette-Guérin (BCG) is the only licensed vaccine for tuberculosis (TB) and induces highly variable protection against pulmonary disease in different countries. We hypothesised that DNA methylation is one of the molecular mechanisms driving variability in BCG-induced immune responses. DNA methylation in peripheral blood mononuclear cells (PBMC) from BCG vaccinated infants was measured and comparisons made between low and high BCG-specific cytokine responders. We found 318 genes and 67 pathways with distinct patterns of DNA methylation, including immune pathways, e.g. for T cell activation, that are known to directly affect immune responses. We also highlight signalling pathways that could indirectly affect the BCG-induced immune response: potassium and calcium channel, muscarinic acetylcholine receptor, G Protein coupled receptor (GPCR), glutamate signalling and WNT pathways. This study suggests that in addition to immune pathways, cellular processes drive vaccine-induced immune responses. Our results highlight mechanisms that require consideration when designing new TB vaccines.


Treatment Guidance for Patients With Lung Cancer During the Coronavirus 2019 Pandemic.
The global coronavirus disease 2019 pandemic continues to escalate at a rapid pace inundating medical facilities and creating substantial challenges globally. The risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with cancer seems to be higher, especially as they are more likely to present with an immunocompromised condition, either from cancer itself or from the treatments they receive. A major consideration in the delivery of cancer care during the pandemic is to balance the risk of patient exposure and infection with the need to provide effective cancer treatment. Many aspects of the SARS-CoV-2 infection currently remain poorly characterized and even less is known about the course of infection in the context of a patient with cancer. As SARS-CoV-2 is highly contagious, the risk of infection directly affects the cancer patient being treated, other cancer patients in close proximity, and health care providers. Infection at any level for patients or providers can cause considerable disruption to even the most effective treatment plans. Lung cancer patients, especially those with reduced lung function and cardiopulmonary comorbidities are more likely to have increased risk and mortality from coronavirus disease 2019 as one of its common manifestations is as an acute respiratory illness. The purpose of this manuscript is to present a practical multidisciplinary and international overview to assist in treatment for lung cancer patients during this pandemic, with the caveat that evidence is lacking in many areas. It is expected that firmer recommendations can be developed as more evidence becomes available.


Gray Wolf Exposure to Emerging Vector-Borne Diseases in Wisconsin with Comparison to Domestic Dogs and Humans.
World-wide concern over emerging vector-borne diseases has increased in recent years for both animal and human health. In the United Sates, concern about vector-borne diseases in canines has focused on Lyme disease, anaplasmosis, ehrlichiosis, and heartworm which infect domestic and wild canids. Of these diseases, Lyme and anaplasmosis are also frequently diagnosed in humans. Gray wolves (Canis lupus) recolonized Wisconsin in the 1970s, and we evaluated their temporal and geographic patterns of exposure to these four vector-borne diseases in Wisconsin as the population expanded between 1985 and 2011. A high proportion of the Wisconsin wolves were exposed to the agents that cause Lyme (65.6%) and anaplasma (47.7%), and a smaller proportion to ehrlichiosis (5.7%) and infected with heartworm (9.2%). Wolf exposure to tick borne diseases was consistently higher in older animals. Wolf exposure was markedly higher than domestic dog (Canis familiaris) exposure for all 4 disease agents during 2001-2013. We found a cluster of wolf exposure to Borrelia burgdorferi in northwestern Wisconsin, which overlaps human and domestic dog clusters for the same pathogen. In addition, wolf exposure to Lyme disease in Wisconsin has increased, corresponding with the increasing human incidence of Lyme disease in a similar time period. Despite generally high prevalence of exposure none of these diseases appear to have slowed the growth of the Wisconsin wolf population.


Ethnic differences in anthropometric characteristics of young children and their parents.
The distribution of body fat, or fat patterning, is an important risk factor for cardiovascular disease and diabetes, independent of obesity. Furthermore, the incidence of cardiovascular disease and diabetes varies by ethnicity. We documented ethnic differences in anthropometric characteristics and body fat distribution between Anglo, Black, and Mexican American men (n = 101), women (n = 245), boys (n = 111), and girls (n = 111). We used aggregates of skinfold measures to examine ethnic differences in the deposition of fat in body compartments (body, trunk, leg, and arm) and analyzed trunk-extremity skinfold ratios to determine which best reflected ethnic differences in fat distribution. The results show that Mexican American mothers have larger skinfold ratios and more body fat (as determined by skinfold aggregates) than either Anglo or Black American mothers, whereas Black American mothers have larger ratios than Anglo American mothers. Mexican American fathers also have larger skinfold ratios but not more body fat (skinfold aggregates) than Anglo American fathers. Mexican American fathers have more body fat than Black American fathers, but we found no differences between skinfold ratios. The ethnic differences among children in skinfold ratios and aggregates are similar to those found among fathers, with more differences among girls than boys. Fat patterning differences do exist among the three ethnicities, with greater trunk fat among Mexican and Black Americans. Those ethnicities are known to be at higher risk for cardiovascular disease and diabetes.


Are phytosomes a superior nanodelivery system for the antioxidant rutin?
Rutin, a strong antioxidant, has been implicated in the prevention of liver inflammation. However, low solubility and permeability through the gut wall limit development of rutin as a therapeutic agent for oral administration. Phytosomes are described as lipid nanocarriers with a complexation between the phospholipid headgroups and entrapped phytochemicals. The aim of this research was to compare the structure of rutin liposomes to rutin phytosomes. FT-IR, DSC and NMR were employed to investigate the presence of any molecular interactions between the formulation components. The FT-IR spectra showed that a new -OH bond had formed in the rutin phytosomes, suggesting the formation of a molecular complex. 31P NMR experiments revealed that the DPPC molecule is altered when formulated as liposomes but that these changes were greater for samples from the phytosome formulation. DSC data revealed that when rutin was added to DPPC there was a significant shift in the transition temperature of DPPC. Further, the shift was greater in the THF solvent used to produce phytosomes compared to CHCl3 used to produce liposomes. 1H NMR spectra of the phytosome samples indicated three additional peaks that were greater than in the liposome formulation. ROESY NMR spectra provided evidence supporting the interaction between rutin and DPPC in both liposomes and phytosomes. The apparent differences in molecular interaction between liposomes and phytosomes did not however impact rutin release in biorelevant media or during in vitro small intestinal lipolysis.


Pairwise statistical significance of local sequence alignment using sequence-specific and position-specific substitution matrices.
Pairwise sequence alignment is a central problem in bioinformatics, which forms the basis of various other applications. Two related sequences are expected to have a high alignment score, but relatedness is usually judged by statistical significance rather than by alignment score. Recently, it was shown that pairwise statistical significance gives promising results as an alternative to database statistical significance for getting individual significance estimates of pairwise alignment scores. The improvement was mainly attributed to making the statistical significance estimation process more sequence-specific and database-independent. In this paper, we use sequence-specific and position-specific substitution matrices to derive the estimates of pairwise statistical significance, which is expected to use more sequence-specific information in estimating pairwise statistical significance. Experiments on a benchmark database with sequence-specific substitution matrices at different levels of sequence-specific contribution were conducted, and results confirm that using sequence-specific substitution matrices for estimating pairwise statistical significance is significantly better than using a standard matrix like BLOSUM62, and than database statistical significance estimates reported by popular database search programs like BLAST, PSI-BLAST (without pretrained PSSMs), and SSEARCH on a benchmark database, but with pretrained PSSMs, PSI-BLAST results are significantly better. Further, using position-specific substitution matrices for estimating pairwise statistical significance gives significantly better results even than PSI-BLAST using pretrained PSSMs.


Geographic concentration of poverty and arteriovenous fistula use among ESRD patients.
There is substantial geographic variability in both incident and prevalent arteriovenous fistula (AVF) use among patients with ESRD. This study examined the degree to which these variations associate with poverty in the county of a patient's treatment center. We performed a cross-sectional study including 28,135 patients treated by 1127 hemodialysis centers in five ESRD networks (16 states) between June 1, 2005 and May 31, 2006. We used the 2000 U.S. Census to categorize county-level poverty and ascertained incident AVF use from the Medicare CMS 2728 form. We calculated the 30-month slope of change in AVF prevalence from monthly facility reports collected between 2003 and 2005. More than 33% of treatment centers were located in high-poverty counties. County poverty inversely associated with incident AVF use (P for trend = 0.001). In contrast, substantial increases in prevalent AVF rates from 30.9 to 38.6% (P < 0.001) among treatment centers did not associate with county poverty (P = 0.9519). In conclusion, the concentration of poverty in the county where a treatment is located associates with incident AVF use by patients with ESRD but not with subsequent improvement in AVF use among prevalent patients. These results suggest that the Medicare ESRD program may mitigate poverty effects on AVF use.


Topological isomorphisms of human brain and financial market networks.
Although metaphorical and conceptual connections between the human brain and the financial markets have often been drawn, rigorous physical or mathematical underpinnings of this analogy remain largely unexplored. Here, we apply a statistical and graph theoretic approach to the study of two datasets - the time series of 90 stocks from the New York stock exchange over a 3-year period, and the fMRI-derived time series acquired from 90 brain regions over the course of a 10-min-long functional MRI scan of resting brain function in healthy volunteers. Despite the many obvious substantive differences between these two datasets, graphical analysis demonstrated striking commonalities in terms of global network topological properties. Both the human brain and the market networks were non-random, small-world, modular, hierarchical systems with fat-tailed degree distributions indicating the presence of highly connected hubs. These properties could not be trivially explained by the univariate time series statistics of stock price returns. This degree of topological isomorphism suggests that brains and markets can be regarded broadly as members of the same family of networks. The two systems, however, were not topologically identical. The financial market was more efficient and more modular - more highly optimized for information processing - than the brain networks; but also less robust to systemic disintegration as a result of hub deletion. We conclude that the conceptual connections between brains and markets are not merely metaphorical; rather these two information processing systems can be rigorously compared in the same mathematical language and turn out often to share important topological properties in common to some degree. There will be interesting scientific arbitrage opportunities in further work at the graph-theoretically mediated interface between systems neuroscience and the statistical physics of financial markets.


Economic Circumstances in Childhood and Subsequent Substance Use in Adolescence - A Latent Class Analysis: The youth@hordaland Study.
The aim of the present study was to investigate the association between longitudinal registry-based data on family income during childhood and self-reported substance use in adolescence, including potential alcohol- or drug problems. Data from the Norwegian population-based youth@hordaland-survey was employed, and the analyzed included n = 8,983 adolescents aged 16-19 years. This information was linked to registry-based information about childhood family income for seven consecutive years prior to adolescents' participation in the youth@hordaland-survey. Latent class analyses (LCA) were used to examine associations between patterns of family economic circumstances in childhood and subsequent substance use in adolescence. Based on the LCA, we identified four distinct patterns of family economic circumstances: a 'never poor' (89.3%) group, followed by two groups characterized by moving in (3.0%) or out (4.6%) of poverty, and a final 'chronically poor' (3.1%) group. Several findings were of interest: the chronically poor reported less daily snus use, fewer had tried alcohol, were less likely to report frequent intoxication, and less prone to have potential alcohol- or drug-related problems compared to all other groups. They were also less likely to have tried any illicit drug compared to those moving in or out of poverty. Finally, the chronically poor reported more daily smoking than the never poor group, but less daily smoking than the moving out of poverty group. The never poor group was less likely to have tried any illicit drugs compared to the groups moving into or out of poverty, and less likely to smoke daily compared to the moving out of poverty group. In other words, the present study somewhat surprisingly suggested lower substance use among the chronically poor adolescents compared to other adolescents on several of the measures of substance use.


Osteopathic manipulative treatment for postural orthostatic tachycardia syndrome.
Postural orthostatic tachycardia syndrome (POTS) is associated with many symptoms including orthostatic intolerance, fatigue, palpitations, and cognitive dysfunction. Treatment, which typically consists of exercise, increased dietary sodium and fluids, compression garments, and medications for orthostatic intolerance, frequently produces unsatisfactory results. The authors report the case of a 26-year-old woman who presented with a 6-year history of severe fatigue, orthostatic intolerance, heat intolerance, cognitive dysfunction, and diffuse pain. She had previously injured her jaw on an obstacle course. Results of a standing test were consistent with POTS. After standard medical therapy was unsuccessful, the patient was referred for osteopathic manipulative treatment. At her 18-month follow-up, the patient's symptoms had improved dramatically. Physicians should consider osteopathic evaluation and manipulative treatment when caring for patients with POTS.


Comparison of axillounifemoral and axillobifemoral bypass operations.
Routine use of axillobifemoral (ABF) bypass has been advocated because this operation is thought to achieve better patency than the axillounifemoral (AUF) procedure. In 5 years we performed 34 AUF and 22 ABF bypass operations for limb salvage in high-risk patients using 6 mm polytetrafluoroethylene grafts. Five-year cumulative life table patency rates for AUF bypasses were 71% with reoperation (secondary patency) and 44% without reoperation (primary patency). These values were not significantly different (p greater than 0.5) from those for ABF bypasses (77% and 50%, respectively). Five-year limb salvage results (AUF 73%; ABF 89%) were also not significantly different (p greater than 0.1). Correlation of arterial outflow characteristics with graft patency revealed that 78% of the patients who never had graft occlusion had occluded superficial femoral arteries (SFA) demonstrated at the first operation, while 79% of the patients who experienced graft closure had comparable SFA occlusions. Our aggressive approach to graft thrombosis included angiographic study of the inflow arterial system. This revealed that 16% of the failed grafts were associated with hemodynamically significant stenosis of the donor subclavian artery. Our results indicate that AUF bypass is the procedure of choice for unilateral limb ischemia in high-risk patients who require an axillary source and that patency of the SFA does not affect outcome. These results also emphasize the need to obtain angiographic evaluation of the inflow system.


Disease burden and related medical costs of rotavirus infections in Taiwan.
The disease burden and associated medical costs of rotavirus infections in inpatient and outpatient sectors in Taiwan were examined in anticipation of the availability of new rotavirus vaccines. The yearly national case number and medical costs for all for inpatients and outpatients with acute gastroenteritis (AGE) were extracted from the Bureau of National Health Insurance database in Taiwan according to ICD-9-CM codes. A retrospective study was also performed using records of children with AGE seen at three hospitals in Taiwan in 2001 to identify laboratory confirmed rotavirus infection cases. The annual incidence and related medical costs of AGE due to rotavirus infection were then estimated. Children <5 years old comprised 83.6% of inpatient and 62.0% of outpatient pediatric AGE cases in Taiwan in 2001. Rotavirus was the most common agent detected among AGE patients in this age group in the three hospitals, and was detected in 32.9% (221/672) of inpatient and 24% (23/96) of outpatient stool specimens tested for microbial etiologies. An estimated 277,400 to 624,892 cases of rotavirus infections sought medical care in Taiwan in 2001, equaling one in 2 to 5 children <5 years old required medical care due to rotavirus infection. The incidence of hospitalization due to rotavirus infections was 1,528-1,997/100,000 for children <5 years old. The total associated medical costs due to rotavirus infection were estimated at US $10-16 millions in Taiwan in 2001. Although the per-capita medical cost of rotavirus infection was lower in Taiwan than in the United States or Hong Kong, the personal economic burden was similar among the three places when normalized for gross national incomes per capita. Infections caused by rotavirus constitute an important human and economic burden among young children in Taiwan. A safe and effective vaccine is urgently needed.


Electrochemical deposition of amorphous aluminum oxides on lead pipes to prevent lead leaching into the drinking water.
Over 5000 public drinking water systems in the US are out of compliance with the Lead and Copper Rule. Lead leaching from lead pipes is limited by the solubility of a naturally occurring scale. Changes in water quality may cause this scale to become more soluble, releasing lead into the drinking water. We propose a novel electrochemical method to prevent lead leaching from lead pipes. In this method, an aluminum wire and an alkaline phosphate electrolyte are inserted into the pipes. The pipes are then anodized for 2 h by using an external power supply, resulting in the electrodeposition of an insoluble aluminum oxide layer on top of the preexisting scale. This technology was tested on lead pipes from the EBMUD water distribution systems located in Berkeley, CA, using recirculating synthetic and actual tap water for 120 days. The untreated pipes leached an average of 23 ppb and 38 ppb of lead respectively, when using free chlorine and monochloramine as disinfection residuals. In contrast, the treated pipes leached 3 ppb and 5 ppb respectively. These results suggest that the proposed treatment has the potential to prevent lead leaching regardless of the disinfection residual and thus should be further explored in a field trial.


Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention.
Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre-MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0-22.0% (10.7-22.0% in clinical-based settings and 1.0-4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders.


Evolving the theory and praxis of knowledge translation through social interaction: a social phenomenological study.
As an inherently human process fraught with subjectivity, dynamic interaction, and change, social interaction knowledge translation (KT) invites implementation scientists to explore what might be learned from adopting the academic tradition of social constructivism and an interpretive research approach. This paper presents phenomenological investigation of the second cycle of a participatory action KT intervention in the home care sector to answer the question: What is the nature of the process of implementing KT through social interaction? Social phenomenology was selected to capture how the social processes of the KT intervention were experienced, with the aim of representing these as typical socially-constituted patterns. Participants (n = 203), including service providers, case managers, administrators, and researchers organized into nine geographically-determined multi-disciplinary action groups, purposefully selected and audiotaped three meetings per group to capture their enactment of the KT process at early, middle, and end-of-cycle timeframes. Data, comprised of 36 hours of transcribed audiotapes augmented by researchers' field notes, were analyzed using social phenomenology strategies and authenticated through member checking and peer review. Four patterns of social interaction representing organization, team, and individual interests were identified: overcoming barriers and optimizing facilitators; integrating 'science push' and 'demand pull' approaches within the social interaction process; synthesizing the research evidence with tacit professional craft and experiential knowledge; and integrating knowledge creation, transfer, and uptake throughout everyday work. Achieved through relational transformative leadership constituted simultaneously by both structure and agency, in keeping with social phenomenology analysis approaches, these four patterns are represented holistically in a typical construction, specifically, a participatory action KT (PAKT) model. Study findings suggest the relevance of principles and foci from the field of process evaluation related to intervention implementation, further illuminating KT as a structuration process facilitated by evolving transformative leadership in an active and integrated context. The model provides guidance for proactively constructing a 'fit' between content, context, and facilitation in the translation of evidence informing professional craft knowledge.


ECHO Autism STAT: Accelerating Early Access to Autism Diagnosis.
Although early diagnosis of autism is critical for promoting access to early intervention, many children experience significant diagnostic delays. Shortages of healthcare providers, limited capacity at autism centers, and geographic and socioeconomic challenges contribute to these delays. The current pilot study examined the feasibility of a new model for training community-based primary care providers (PCPs) in underserved areas in screening and diagnosis of young children at highest risk for autism. By combining hands-on training in standardized techniques with ongoing virtual mentorship and practice, the program emphasized both timely diagnosis and appropriate referral for more comprehensive assessment when necessary. Results indicated improvements in PCP practice and self-efficacy, and feasibility of the model for enhancing local access to care.


Centralization: prevalence and effect on treatment outcomes using a standardized operational definition and measurement method.
Retrospective, observational cohort design. Purpose 1 was to determine the association between age, symptom chronicity, and prevalence of centralization in a sample of patients with nonserious cervical or lumbar spinal syndromes referred to a hospital-based outpatient rehabilitation clinic. Purpose 2 was to examine if classifying these patients at intake to centralization or noncentralization predicts functional status, pain intensity, and number of treatment visits at discharge from rehabilitation. Purpose 3 was to compare clinically meaningful changes in functional status and pain intensity between patients subgrouped by centralization and noncentralization. Variations in operational definitions and measurements used to identify centralization affect patient classification, contribute to variation in reported prevalence rates, and influence treatment strategy and outcome interpretation. Investigating a standardized operational definition and measurement method for centralization may reduce practice and outcomes variation. Adults (n=418) with cervical or low back syndromes (mean +/- SD age, 58 +/- 17 years; range, 19-91 years; 33% male; 76% lumbar symptoms; 53% chronic symptoms) were assessed. Therapists classified patients using a standardized operational definition and method for centralization during initial evaluation. Prevalence rates were calculated for centralization by age and acuity. Multivariate models were used to assess discharge functional status, pain intensity, and visits while controlling important variables. Percentage of patients subgrouped by centralization and noncentralization achieving minimal clinically important differences (MCID) in functional status and pain intensity was assessed. Overall prevalence rate for centralization was 17%, but increased for patients who were younger and reported acute symptoms regardless of body part. For patients with lumbar syndromes, noncentralization was associated with lower discharge functional status and more pain, but not associated with number of visits compared to patients classified as centralization. For patients with cervical syndromes, noncentralization was associated with more pain but not associated with functional status or number of visits compared to patients classified as centralization. Pain pattern classification affected percentage of patients with lumbar and cervical impairment achieving MCID. Results supported the clinical use of a standardized definition of centralization to facilitate patient classification and management and interpretation of outcomes.


Immunolocalization of integrins in the human retina.
Integrins are cell surface proteins that participate in interactions between cells and with extracellular matrix. Binding of integrins to their ligands influences cell activities including proliferation, migration, and differentiation. Expression of integrin subunits from three different subfamilies were examined in human retina. Integrins were detected in frozen sections of two human retinas with an avidin-biotin-complex immunohistochemical technique, using nine different monoclonal antibodies specific for alpha 2, alpha 3, alpha 4, alpha 5, alpha 6, alpha v, beta 1, beta 2, and beta 3. One retina was from a patient who had conjunctival squamous cell carcinoma, and the other was from uninvolved regions of an eye with a choroidal melanoma. All integrins tested were detectable in consistent patterns in two retinas. All except alpha 2 and alpha 4 were stained vibrantly in retinal and choroidal vessels. All alpha subunit staining of vessels showed overlap or close proximity to beta 1 staining. In addition to vessels, beta 1 was also present in the internal limiting membrane; alpha 2, alpha 3, alpha 4, alpha 5, and beta 2 were all found throughout much of the neural retina, albeit with distinctive staining patterns. Other than in association with vessels, alpha 6 and alpha v were not detected in neural retina, and beta 3 was only weakly detected in the nerve fiber layer; alpha 4 and beta 2 were expressed in the retinal pigment epithelium; beta 1 and beta 2 were strongly expressed in drusen present in one of the eyes. Nine integrin subunits have been found to have unique distributions in adult human retina. An understanding of the distribution in normal retina can serve as a useful contrast to patterns of staining associated with retinal diseases.


Recent Incidence Trend of Surgically Resected Esophagogastric Junction Adenocarcinoma and Microsatellite Instability Status in Japanese Patients.
The incidence trend of esophagogastric junction (EGJ) adenocarcinoma in Japan has not been sufficiently investigated. Little is known about the microsatellite instability (MSI) status of this tumor. Previously published studies analyzing the trend of EGJ adenocarcinoma in Japan were reviewed. And a trend of surgically resected cases (Siewert type I-III) utilizing a retrospective multicenter cohort of 379 patients from 4 academic institutions in Japan investigated. Although an increasing trend in the last 2 reports was considered controversial, our cohort demonstrated a growing number of EGJ adenocarcinoma cases between 2006 and 2013. This trend was evident, especially in Siewert type I cases. In the previous 16 studies that performed MSI testing, MSI-high tumors ranged 0-8.3%, though there were no fixed microsatellite markers on EGJ adenocarcinoma. In a recent comprehensive genetic analysis by The Cancer Genome Atlas, MSI testing using the following 7 markers, BAT25, BAT26, BAT40, D2S123, D5S346, D17S250 and TGFR-II showed a favorable correlation with hypermutated tumors. We performed MSI testing using 6 of those markers, except TGFR-II, on 206 cases from one institution, and detected 15 cases (7.3%) with MSI-high. The prevalence of MSI-high was 0% in Siewert type I, 7.6% in type II, and 16.7% in type III. Key message: The number of surgically resected EGJ adenocarcinoma cases gradually increased, and MSI-high was infrequent in Siewert type I-II tumors in our Japanese cohort. Considering MSI-high as a predictive biomarker for emerging immune checkpoint inhibitors, MSI status is becoming more beneficial in EGJ adenocarcinoma.


Origin of HTLV-1 in hunters of nonhuman primates in Central Africa.
Of 78 Gabonese individuals who had received bites from nonhuman primates (NHPs) while hunting, 7 were infected with human T lymphotropic virus (HTLV-1). Five had been bitten by gorillas and were infected with subtype B strains; however, a 12-year-old girl who was severely bitten by a Cercopithecus nictitans was infected with a subtype D strain that was closely related to the simian T lymphotropic virus (STLV-1) that infects this monkey species. Her mother was infected with a subtype B strain. These data confirm that hunters in Africa can be infected by HTLV-1 that is closely related to the strains circulating among local NHP game. Our findings strongly suggest that a severe bite represent a risk factor for STLV-1 acquisition.


Gs alpha-dependent and -independent desensitisation of prostanoid IP receptor-activated adenylyl cyclase in NG108-15 cells.
NG108-15 mouse neuroblastoma x rat glioma cells were treated with the prostanoid IP receptor agonist iloprost (1 microM) and the time course of changes in the levels of prostanoid IP receptors, adenylyl cyclase activity, and the alpha-subunit of the stimulatory guanine nucleotide binding regulatory protein, Gs, were measured. Incubation of cells with iloprost produced a biphasic time course of desensitisation of prostanoid IP receptor-activated adenylyl cyclase. Parallel analysis of iloprost-induced loss of membrane Gs alpha, NaF-stimulated adenylyl cyclase and [3H]iloprost binding suggested only monophasic curves, with t0.5 values similar to the initial phase of desensitisation of iloprost-stimulated adenylyl cyclase activity. This suggests that the loss of receptor and Gs alpha occur at the same time and account for the initial period of desensitisation due to iloprost pretreatment. Pretreatment of NG108-15 cells with cholera toxin produced a near complete loss of membrane-associated Gs alpha, but the loss of [3H]iloprost binding due to iloprost treatment was not affected by pretreatment with cholera toxin, suggesting that prostanoid IP receptors can be down-regulated in the absence of any coupling to Gs. The second phase of desensitisation of iloprost-stimulated adenylyl cyclase activity, during which there was no further change in NaF-stimulated adenylyl cyclase or in the membrane levels of Gs alpha, was not due to protein kinase A activation, since elevating intracellular cyclic AMP levels with forskolin did not subsequently decrease iloprost-stimulated adenylyl cyclase activity or [3H]iloprost binding. These results demonstrate that iloprost pretreatment of NG108-15 cells induces two distinct phases of desensitisation; an initial desensitisation due to concurrent loss of prostanoid IP receptors and Gs alpha, and then a further desensitisation by an as yet uncharacterized mechanism during which there is no further loss of Gs alpha.


Intravascular pressure and diameter profile of the utero-ovarian resistance artery network: estrous cycle-dependent modulation of resistance artery tone.
Blood flow to the ovary varies dramatically in both magnitude and distribution throughout the estrous cycle to meet the hormonal and metabolic demands of the ovarian parenchyma as it cyclically develops and regresses. Several vascular components appear to be critical to vascular regulation of the ovary. As a first step in resolving the role of the resistance arteries and their paired veins in regulating ovarian blood flow and transvascular exchange, we characterized the architecture and intravascular pressure profile of the utero-ovarian resistance artery network in an in vivo preparation of the ovary of the anesthetized Golden hamster. We also investigated estrous cycle-dependent changes in resistance artery tone. The right ovary and the cranial aspect of the uterus in 26 female hamsters were exposed for microcirculatory observations. Estrous-cycle phase was determined in each animal before experimentation. The utero-ovarian vascular architecture was determined and resistance artery diameters were measured in each animal by video microscopy. Servo-null intravascular pressure measurements were made throughout the uteroovarian arterial network in 11 of the animals. Architectural data showed a complex anastomotic network jointly supplying the uterus and ovary. Resistance arteries showed a high degree of coiling and close apposition to veins, maximizing countercurrent-exchange capabilities. Arterial pressure dropped below 60% of systemic arterial pressure before the arteries entered the ovary. Both the ovarian artery and the uterine artery, which jointly feed the ovary, showed cycle day-dependent changes in diameter. Arterial diameters were smallest on the day following ovulation, during the brief luteal phase of the hamster. The data show that resistance arteries comprise a critical part of a complex network designed for intimate local communication and control and suggest that these arteries may play an important role in regulating ovarian blood flow in an estrous cycle-specific manner.


Plant metabolomics: from holistic data to relevant biomarkers.
Metabolomics is playing an increasingly important role in plant science. It aims at the comprehensive analysis of the plant metabolome which consists both of primary and secondary metabolites. The goal of metabolomics is ultimately to identify and quantify this wide array of small molecules in biological samples. This new science is included in several systems biology approaches and is based primarily on the unbiased acquisition of mass spectrometric (MS) or nuclear magnetic resonance (NMR) data from carefully selected samples. This approach provides the most ''functional'' information of the 'omics' technologies of a given organism since metabolites are the end products of the cellular regulatory processes. The application of state-of-the-art data mining, that includes various untargeted and targeted multivariate data analysis methods, to the vast amount of data generated by this data-driven approach leads to sample classification and the identification of relevant biomarkers. The biological areas that have been successfully studied by this holistic approach include global metabolite composition assessment, mutant and phenotype characterisation, taxonomy, developmental processes, stress response, interaction with the environment, quality control assessment, lead finding and mode of action of botanicals. This review summarises the main MS- and NMR-based approaches that are used to perform these studies and discusses the potential and current limitations of the various methods. The intent is not to provide an exhaustive overview of the field, which has grown considerably over the past decade, but to summarise the main strategies that are used and to discuss the potential and limitations of the different approaches as well as future trends.


The genomes of polyextremophilic cyanidiales contain 1% horizontally transferred genes with diverse adaptive functions.
The role and extent of horizontal gene transfer (HGT) in eukaryotes are hotly disputed topics that impact our understanding of the origin of metabolic processes and the role of organelles in cellular evolution. We addressed this issue by analyzing 10 novel Cyanidiales genomes and determined that 1% of their gene inventory is HGT-derived. Numerous HGT candidates share a close phylogenetic relationship with prokaryotes that live in similar habitats as the Cyanidiales and encode functions related to polyextremophily. HGT candidates differ from native genes in GC-content, number of splice sites, and gene expression. HGT candidates are more prone to loss, which may explain the absence of a eukaryotic pan-genome. Therefore, the lack of a pan-genome and cumulative effects fail to provide substantive arguments against our hypothesis of recurring HGT followed by differential loss in eukaryotes. The maintenance of 1% HGTs, even under selection for genome reduction, underlines the importance of non-endosymbiosis related foreign gene acquisition.


[3H]ketanserin (serotonin type 2) binding increases in rat cortex following basal forebrain lesions with ibotenic acid.
The response of the serotonergic system following injury to the basal forebrain cholinergic system was investigated in rats. The density of 5-hydroxytryptamine (serotonin) type 2 (S2) receptor sites in the frontal cortex and hippocampus was determined 1 week and 4 months after production of lesions by injections of ibotenic acid into the medial septum and nucleus basalis magnocellularis. One week later, the number of S2 receptor sites in the frontal neocortex, as defined by [3H]ketanserin binding, was unchanged. Four months later, the number of [3H]ketanserin binding sites (and Bmax) was increased and high-affinity [3H]serotonin uptake was decreased in the frontal neocortex, but not in the hippocampus, relative to unlesioned controls. Choline acetyltransferase (acetyl-CoA:choline O-acetyltransferase; EC 188.8.131.52) activity was decreased significantly in the frontal neocortex and hippocampus 1 week and 4 months after surgery. The change in frontal neocortical S2 receptor site density was inversely related to the level of choline acetyltransferase activity, was specific for cholinergic denervation associated with the cortex but not the hippocampus, and may represent a localized denervation supersensitivity due to degeneration of median raphe cortical afferents.


Molecular phylogenetics and comparative modeling of HEN1, a methyltransferase involved in plant microRNA biogenesis.
Recently, HEN1 protein from Arabidopsis thaliana was discovered as an essential enzyme in plant microRNA (miRNA) biogenesis. HEN1 transfers a methyl group from S-adenosylmethionine to the 2'-OH or 3'-OH group of the last nucleotide of miRNA/miRNA* duplexes produced by the nuclease Dicer. Previously it was found that HEN1 possesses a Rossmann-fold methyltransferase (RFM) domain and a long N-terminal extension including a putative double-stranded RNA-binding motif (DSRM). However, little is known about the details of the structure and the mechanism of action of this enzyme, and about its phylogenetic origin. Extensive database searches were carried out to identify orthologs and close paralogs of HEN1. Based on the multiple sequence alignment a phylogenetic tree of the HEN1 family was constructed. The fold-recognition approach was used to identify related methyltransferases with experimentally solved structures and to guide the homology modeling of the HEN1 catalytic domain. Additionally, we identified a La-like predicted RNA binding domain located C-terminally to the DSRM domain and a domain with a peptide prolyl cis/trans isomerase (PPIase) fold, but without the conserved PPIase active site, located N-terminally to the catalytic domain. The bioinformatics analysis revealed that the catalytic domain of HEN1 is not closely related to any known RNA:2'-OH methyltransferases (e.g. to the RrmJ/fibrillarin superfamily), but rather to small-molecule methyltransferases. The structural model was used as a platform to identify the putative active site and substrate-binding residues of HEN and to propose its mechanism of action.


Further delineation of the KBG syndrome phenotype caused by ANKRD11 aberrations.
Loss-of-function variants in ANKRD11 were identified as the cause of KBG syndrome, an autosomal dominant syndrome with specific dental, neurobehavioural, craniofacial and skeletal anomalies. We present the largest cohort of KBG syndrome cases confirmed by ANKRD11 variants reported so far, consisting of 20 patients from 13 families. Sixteen patients were molecularly diagnosed by Sanger sequencing of ANKRD11, one familial case and three sporadic patients were diagnosed through whole-exome sequencing and one patient was identified through genomewide array analysis. All patients were evaluated by a clinical geneticist. Detailed orofacial phenotyping, including orthodontic evaluation, intra-oral photographs and orthopantomograms, was performed in 10 patients and revealed besides the hallmark feature of macrodontia of central upper incisors, several additional dental anomalies as oligodontia, talon cusps and macrodontia of other teeth. Three-dimensional (3D) stereophotogrammetry was performed in 14 patients and 3D analysis of patients compared with controls showed consistent facial dysmorphisms comprising a bulbous nasal tip, upturned nose with a broad base and a round or triangular face. Many patients exhibited neurobehavioural problems, such as autism spectrum disorder or hyperactivity. One-third of patients presented with (conductive) hearing loss. Congenital heart defects, velopharyngeal insufficiency and hip anomalies were less frequent. On the basis of our observations, we recommend cardiac assessment in children and regular hearing tests in all individuals with a molecular diagnosis of KBG syndrome. As ANKRD11 is a relatively common gene in which sequence variants have been identified in individuals with neurodevelopmental disorders, it seems an important contributor to the aetiology of both sporadic and familial cases.


Intracranial squamous cell carcinoma arising in a cerebellopontine angle epidermoid cyst: A case report and literature review.
Most of the intracranial epidermoid cysts are benign, but malignant lesions are occasionally reported. These lesions appear as squamous cell carcinoma and carry a dismal prognosis. Here, we report a case of a primary intracranial squamous cell carcinoma arising in a cerebellopontine epidermoid cyst. The relevant literatures were also reviewed. A 53-year-old woman presented with dizziness and diplopia 9 months in duration. Magnetic resonance imaging revealed an epidermoid cyst in the left cerebellopontine angle and prepontine region with a focal enhancing lesion on T1-weighted gadolinium-enhanced images. Histopathologic diagnosis revealed squamous cell carcinoma on a background of epidermoid cyst. Imaging studies excluded metastases. The tumor was removed subtotally through a lateral suboccipital approach. The patient received intensity modulated radiation therapy (6720 cGy total) postoperatively. The patient was free from recurrence of the tumor until 3 years after surgery, at which point she was lost to follow-up. The patient died 4 years after the surgery. The epidermoid cyst may occasionally become malignant. Finding an area of enhancement through preoperative magnetic resonance imaging can help to make a correct diagnosis. Based on the review of previous reports, surgical removal followed by radiotherapy shows the best result to treat malignant epidermoid cysts.


The impact of medical errors on ninety-day costs and outcomes: an examination of surgical patients.
To estimate the effect of medical errors on medical expenditures, death, readmissions, and outpatient care within 90 days after surgery. 2001-2002 MarketScan insurance claims for 5.6 million enrollees. The Agency for Healthcare Research and Quality Patient Safety Indicators (PSIs) were used to identify 14 PSIs among 161,004 surgeries. We used propensity score matching and multivariate regression analyses to predict expenditures and outcomes attributable to the 14 PSIs. Excess 90-day expenditures likely attributable to PSIs ranged from $646 for technical problems (accidental laceration, pneumothorax, etc.) to $28,218 for acute respiratory failure, with up to 20 percent of these costs incurred postdischarge. With a third of all 90-day deaths occurring postdischarge, the excess death rate associated with PSIs ranged from 0 to 7 percent. The excess 90-day readmission rate associated with PSIs ranged from 0 to 8 percent. Overall, 11 percent of all deaths, 2 percent of readmissions, and 2 percent of expenditures were likely due to these 14 PSIs. The effects of medical errors continue long after the patient leaves the hospital. Medical error studies that focus only on the inpatient stay can underestimate the impact of patient safety events by up to 20-30 percent.


Neutropenic enterocolitis: is there a right timing for surgery? Assessment of a clinical case.
Neutropenic enterocolitis is a severe and potentially life-threatening complication that may affect patients undergoing chemotherapy for acute leukemia or lymphoma. These patients may develop systemic sepsis through bacterial or fungal translocation across the intestinal wall. In many cases neutropenic enterocolitis is confined to the cecum, but the entire colon is sometimes involved. Most patients are treated conservatively because an improvement occurs when the absolute neutrophil count rises. However, a surgical approach consisting of resection of the colon may sometimes be necessary, even in patients with complete aplasia and a high risk of complications. The right time to perform surgery is hard to define. Intestinal wall thickness, evaluated by ultrasound, is an important prognostic factor which could act as a guide to surgical indication. We analyze a case of neutropenic enterocolitis which occurred in a patient with acute myeloid leukemia during chemotherapy and we suggest that, as well as intestinal wall thickness, hemodynamic worsening should be considered an indication for surgery.


African experiences of humanitarian cardiovascular medicine: a Kenyan perspective.
The burden of cardiovascular diseases (CVD) is on the rise in Kenya; this is in tandem with that of other non-communicable diseases. Most cardiovascular services are available in the main cities (Nairobi and Mombasa), but almost non-existent in rural and other urban centers. In an attempt to bridge this gap on service delivery, humanitarian activities have been developed over the years by various interested parties. Three models of humanitarian activities are described. The first model (hereby referred to as Model 1) is a school-based rheumatic fever and rheumatic heart disease (RF/RHD) prevention outreach program which offers diagnostic, preventive, educational and curative services to primary and secondary school children in various parts of the country. The second model (hereby referred to as Model 2) is a hospital-based cardiovascular outreach program located in Kericho, a highland tea growing region that has long been perceived as a "hot spot" for CVD. The third model (hereby referred to as Model 3) is a fixed clinic-based cardiovascular outreach in Kisumu, the lake shore town, about 400 kilometers west of Nairobi. prevention services, early detection and prophylaxis, facilitation for further treatment, follow-up, early disease management, staff motivation, training in basic cardiology skills and increased local awareness of CVD to clinicians in there far-flung centers. Data from these programs is also presented, with two of the programs reporting Kericho County as a 'hot spot' in RF/RHD. Despite various challenges, the future is still bright with sustainable initiatives.


Two-dimensional charge order stabilized in clean polytype heterostructures.
Compelling evidence suggests distinct correlated electron behavior may exist only in clean 2D materials such as 1T-TaS2. Unfortunately, experiment and theory suggest that extrinsic disorder in free standing 2D layers disrupts correlation-driven quantum behavior. Here we demonstrate a route to realizing fragile 2D quantum states through endotaxial polytype engineering of van der Waals materials. The true isolation of 2D charge density waves (CDWs) between metallic layers stabilizes commensurate long-range order and lifts the coupling between neighboring CDW layers to restore mirror symmetries via interlayer CDW twinning. The twinned-commensurate charge density wave (tC-CDW) reported herein has a single metal-insulator phase transition at ~350 K as measured structurally and electronically. Fast in-situ transmission electron microscopy and scanned nanobeam diffraction map the formation of tC-CDWs. This work introduces endotaxial polytype engineering of van der Waals materials to access latent 2D ground states distinct from conventional 2D fabrication.


Development of the Rural Active Living Perceived Environmental Support Scale (RALPESS).
Evidence supports the role of physical and social environments in active living, including perception of environment. However, measurement of perceived environments in rural settings is lacking. This study describes the development of the Rural Active Living Perceived Environmental Support Scale (RALPESS). Premised on social ecological and cognitive perspectives, 85 initial items were generated through a literature review and a mixed-methods investigation of "activity-friendly" environments. Items were organized by resource areas--town center, indoor and outdoor physical activity areas, schools, churches, and areas around the home/neighborhood--and submitted for expert panel review. In 2009, a revised questionnaire was disseminated to adolescents, parents, public school staff, and older adults in 2 rural southeastern United States counties. Principal component analysis with varimax rotation was used to explore factor structure (n = 542). The final analysis yielded 33 items with 7 factors: 1) church facilities, 2) town center connectivity, 3) indoor areas, 4) around the home/neighborhood, 5) town center physical activity resources, 6) school grounds, and 7) outdoor areas. The RALPESS is a valid, internally consistent, and practically useful instrument to measure perceptions of rural environments in the context of physical activity across the lifespan. Confirmatory factor analysis is recommended to validate factor structure.


Community-based interventions for diarrhoeal diseases and acute respiratory infections in Nepal.
Acute diarrhoeal diseases and acute respiratory infections (ARIs) are the most common causes of child mortality worldwide. Safe, effective and inexpensive solutions are available for prevention and control, but they do not reach needy communities. Interventions based on research were designed to train and engage community health volunteers (CHVs) to implement a community-based control programme in Nepal. With the advent of the Integrated Management of Childhood Illnesses (IMCI) strategy, this programme subsequently emerged as a community-based IMCI but retained its mainstream activities. We reviewed and analysed policy decisions and programme development, implementation and expansion. Severe resource constraints and difficult terrain limit access to health-care facilities in many parts of Nepal. In districts with interventions, more cases of acute diarrhoea and of ARIs (including pneumonia) were reported. The proportion of diarrhoea cases with dehydration and the proportion of ARI cases with pneumonia were significantly lower in districts with interventions. Case fatality rates due to acute diarrhoea and the proportion of severe pneumonia among ARI cases across the country showed a significant trend towards a decrease from 2004 to 2007. Nepal has succeeded in training many CHVs and is on course to meet the Millennium Development Goal for child mortality. The burden of acute diarrhoea and ARIs can be reduced by training and engaging CHVs to implement community-based case management and prevention strategies. Monitoring, supervision and logistical support are essential. Policy decisions based on evidence from national research contributed to the success of the programme.


The perceptual preferences in learning among dental students in clinical subjects.
VARK is a questionnaire which was developed by Neil Fleming (www.vark.learn.com), who was a teacher and an educator in New Zealand, with respect to the perceptual preferences in learning. V stands for Visual- the students learn best from pictures, graphs and diagrams. A stand for Aural - the students learn best from spoken words, lectures and discussions. R stands for Reading - the students learn best from reading and writing texts. K stands for Kinesthetic - the students learn best when they move their bodies and manipulate things with their own hands. The aim of the recent study was to investigate the learning styles among the dental students in our clinical set up. The VARK-questionnaire contains 13 multiple-choice- questions with four possibilities to select an answer. Each possibility represents one of the four modes of perception. But, one can select more than one answer for each question, which is necessary for the identification of the poly modal modes of perception and learning. This is also a psychometric problem when an attempt is being made to state a measure of the reliability of the questionnaire. The VARK-questionnaire was distributed among 100 students and we received filled forms from only 70 students. This sample size represented a 70% response rate from the students in the class and it was markedly above the level which was required to make conclusions about the student preferences for receiving and processing information. The students spent about 10 minutes in an ordinary lesson to fill in the questionnaire. The students' register numbers and names were used in the study and no blinding was practised. We analyzed their learning styles with their performances in the university exams. This was a questionnaire based clinical study. The responses from the students in our University where classified into the multi-modal (VARK), tri-modal (VRK, VAK, VAR, ARK), bi-modal (VR, VA, VK, RK) and the uni-modal (V, A, R.K) categories. The results showed that the subjects had a higher preference for multimodal learning. With our preliminary data, we conclude that the students in our clinical set up preferred a multimodal and a more of kinesthetic method of learning. To meet their needs, variations in the teaching, learning and the examination must be implemented. If not, the students with a high kinesthetic preference for perception and learning may be at the losing end.


Reactive Oxygen Species/Hypoxia-Inducible Factor-1α/Platelet-Derived Growth Factor-BB Autocrine Loop Contributes to Cocaine-Mediated Alveolar Epithelial Barrier Damage.
Abuse of psychostimulants, such as cocaine, has been shown to be closely associated with complications of the lung, such as pulmonary hypertension, edema, increased inflammation, and infection. However, the mechanism by which cocaine mediates impairment of alveolar epithelial barrier integrity that underlies various pulmonary complications has not been well determined. Herein, we investigate the role of cocaine in disrupting the alveolar epithelial barrier function and the associated signaling cascade. Using the combinatorial electric cell-substrate impedance sensing and FITC-dextran permeability assays, we demonstrated cocaine-mediated disruption of the alveolar epithelial barrier, as evidenced by increased epithelial monolayer permeability with a concomitant loss of the tight junction protein zonula occludens-1 (Zo-1) in both mouse primary alveolar epithelial cells and the alveolar epithelial cell line, L2 cells. To dissect the signaling pathways involved in this process, we demonstrated that cocaine-mediated induction of permeability factors, platelet-derived growth factor (PDGF-BB) and vascular endothelial growth factor, involved reactive oxygen species (ROS)-dependent induction of hypoxia-inducible factor (HIF)-1α. Interestingly, we demonstrated that ROS-dependent induction of another transcription factor, nuclear factor erythroid-2-related factor-2, that did not play a role in cocaine-mediated barrier dysfunction. Importantly, this study identifies, for the first time, that ROS/HIF-1α/PDGF-BB autocrine loop contributes to cocaine-mediated barrier disruption via amplification of oxidative stress and downstream signaling. Corroboration of these cell culture findings in vivo demonstrated increased permeability of the alveolar epithelial barrier, loss of expression of Zo-1, and a concomitantly increased expression of both HIF-1α and PDGF-BB. Pharmacological blocking of HIF-1α significantly abrogated cocaine-mediated loss of Zo-1. Understanding the mechanism(s) by which cocaine mediates barrier dysfunction could provide insights into the development of potential therapeutic targets for cocaine-mediated pulmonary hypertension.


Contraceptive use among HIV-infected women and men receiving antiretroviral therapy in Lusaka, Zambia: a cross-sectional survey.
Family planning (FP) is an essential health service and an important part of comprehensive HIV care. However, there is limited information about the contraceptive needs of people living with HIV in sub-Saharan Africa, which in turn has hampered efforts to expand and integrate FP services into existing HIV programs. We performed a cross-sectional survey to determine FP prevalence and predictors among HIV-positive women and men attending 18 public antiretroviral therapy (ART) clinics in Lusaka, Zambia. Trained peer counselors administered the 10-question survey to those seeking care for five days at each of the target sites. From February to April 2014, we surveyed 7,046 HIV-infected patients receiving routine HIV services. Use of modern contraception was reported by 69 % of female ART patients and 79 % of male ART patients. However, highly effective contraceptive use and dual method use were low among women (38 and 25 %, respectively) and men (19 and 14 %, respectively). HIV disclosure status (adjusted odds ratio (AOR) = 4.91, 95 % confidence interval (CI) = 3.32-7.24 for women, AOR = 3.58, 95 % CI = 2.39-5.38 for men) and sexual activity in the last 6 months (AOR = 5.80, 95 % CI = 4.51-7.47 for women, AOR = 6.24, 95 % CI = 3.51-11.08 for men) were associated with modern contraceptive use in multivariable regression. Most respondents said they would access FP services if made available within ART clinic. While FP-ART integration may be a promising strategy for increasing FP service uptake, such services must focus on assessing sexual activity and advocating for dual method use to increase effective contraceptive use and prevent unintended pregnancies.


The potential role of vildagliptin in the management and prevention of type 2 diabetes mellitus.
Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of 'incretins,' particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4.


Rapid molecular differentiation and genotypic heterogeneity among Candida parapsilosis and Candida orthopsilosis strains isolated from clinical specimens in Kuwait.
Recent molecular studies have led to the recognition of three distinct species within the Candida parapsilosis complex, namely Candida parapsilosis, Candida orthopsilosis and Candida metapsilosis. As currently available yeast identification systems fail to differentiate these species, there is a paucity of information on their occurrence in different geographical regions. This study describes a simple PCR-based protocol for rapid discrimination among C. parapsilosis, C. orthopsilosis and C. metapsilosis strains by using primers derived from unique sequences within the internally transcribed spacer 1 (ITS1)-5.8 rRNA-ITS2 region. Retrospective analysis of 114 C. parapsilosis-complex isolates recovered from clinical specimens in Kuwait identified 109 as C. parapsilosis, five as C. orthopsilosis and none as C. metapsilosis. The results were further validated by PCR-RFLP patterns of the secondary alcohol dehydrogenase gene fragment. DNA sequencing of the ITS region and the D1/D2 regions of the 28S rRNA gene confirmed the species-specific identification of all five C. orthopsilosis strains. The amplicon length of the intergenic spacer between the 28S and 5S rRNA genes (IGS1) was also species-specific, and PCR-RFLP analyses of the IGS1 region identified two distinct genotypes among the five C. orthopsilosis strains, which corresponded with the ITS region sequence data. The three bloodstream C. orthopsilosis strains were confined to a single genotype. Among 81 randomly selected C. parapsilosis strains, two genotypes were detected by IGS1 region analyses, indicating limited genotypic heterogeneity among C. parapsilosis sensu stricto strains. As far as is known, this is the first report on the identification of C. orthopsilosis from a bloodstream infection in the Arabian Gulf region.


Parallel-Serial Memoing: A Novel Approach to Analyzing Qualitative Data.
The mechanisms by which talking therapies exert their beneficial effects are largely unknown. In exploring the process of a talking therapy, motivational interviewing (MI), when used to treat and prevent low mood in stroke survivors, we developed, what we believe to be, a novel approach to analyzing transcripts. We illustrate the method using qualitative data from MI sessions with 10 stroke survivors. The approach, drawing on grounded theory, incorporated processes of parallel and serial memoing among a team of researchers to allow a process of validation. This enabled us to describe session content and to develop theoretical interpretations of what was occurring in and across MI sessions. We found that this process can be used to integrate different perspectives in theory building, allowing for a richer description and more robust theoretical interpretation. Others can use and adapt this approach to develop insights into their own inquiry.


Generalized risk zone: selecting observations for classification.
In this paper, we extend the risk zone concept by creating the Generalized Risk Zone. The Generalized Risk Zone is a model-independent scheme to select key observations in a sample set. The observations belonging to the Generalized Risk Zone have shown comparable, in some experiments even better, classification performance when compared to the use of the whole sample. The main tool that allows this extension is the Cauchy-Schwartz divergence, used as a measure of dissimilarity between probability densities. To overcome the setback concerning pdf's estimation, we used the ideas provided by the Information Theoretic Learning, allowing the calculation to be performed on the available observations only. We used the proposed methodology with Learning Vector Quantization, feedforward Neural Networks, Support Vector Machines, and Nearest Neighbors.


Brevundimonas terrae sp. nov., isolated from an alkaline soil in Korea.
A Gram-negative, rod-shaped, Brevundimonas-like bacterial strain, KSL-145(T), was isolated from an alkaline soil in Korea and subjected to a polyphasic taxonomic investigation. Strain KSL-145(T) grew optimally at pH 7.5-8.0 and 30 degrees C without NaCl. It was characterized chemotaxonomically as containing Q-10 as the predominant ubiquinone and C(18 : 1)omega7c and C(16 : 0) as the major fatty acids. The DNA G+C content was 61.8 mol%. A phylogenetic analysis based on 16S rRNA gene sequences showed that strain KSL-145(T) fell within the radiation of the cluster comprising Brevundimonas species and Mycoplana bullata. The levels of 16S rRNA gene sequence similarity between strain KSL-145(T) and the type strains of Brevundimonas species and M. bullata ranged from 95.3 to 98.7 %. The mean DNA-DNA relatedness values between strain KSL-145(T) and the type strains of Brevundimonas diminuta and M. bullata, the closest phylogenetic relatives, were 26 and 15 %, respectively. Strain KSL-145(T) could be differentiated from Brevundimonas species and M. bullata by differences in several phenotypic characteristics. On the basis of the phenotypic, phylogenetic and genetic data, strain KSL-145(T) represents a novel species in the genus Brevundimonas, for which the name Brevundimonas terrae sp. nov. is proposed. The type strain is KSL-145(T) (=KCTC 12481(T)=JCM 13476(T)).


Atomic and Specificity Details of Mucin 1 O-Glycosylation Process by Multiple Polypeptide GalNAc-Transferase Isoforms Unveiled by NMR and Molecular Modeling.
The large family of polypeptide GalNAc-transferases (GalNAc-Ts) controls with precision how GalNAc O-glycans are added in the tandem repeat regions of mucins (e.g., MUC1). However, the structural features behind the creation of well-defined and clustered patterns of O-glycans in mucins are poorly understood. In this context, herein, we disclose the full process of MUC1 O-glycosylation by GalNAc-T2/T3/T4 isoforms by NMR spectroscopy assisted by molecular modeling protocols. By using MUC1, with four tandem repeat domains as a substrate, we confirmed the glycosylation preferences of different GalNAc-Ts isoforms and highlighted the importance of the lectin domain in the glycosylation site selection after the addition of the first GalNAc residue. In a glycosylated substrate, with yet multiple acceptor sites, the lectin domain contributes to orientate acceptor sites to the catalytic domain. Our experiments suggest that during this process, neighboring tandem repeats are critical for further glycosylation of acceptor sites by GalNAc-T2/T4 in a lectin-assisted manner. Our studies also show local conformational changes in the peptide backbone during incorporation of GalNAc residues, which might explain GalNAc-T2/T3/T4 fine specificities toward the MUC1 substrate. Interestingly, we postulate that a specific salt-bridge and the inverse γ-turn conformation of the PDTRP sequence in MUC1 are the main structural motifs behind the GalNAc-T4 specificity toward this region. In addition, in-cell analysis shows that the GalNAc-T4 isoform is the only isoform glycosylating the Thr of the immunogenic epitope PDTRP in vivo, which highlights the relevance of GalNAc-T4 in the glycosylation of this epitope. Finally, the NMR methodology established herein can be extended to other glycosyltransferases, such as C1GalT1 and ST6GalNAc-I, to determine the specificity toward complex mucin acceptor substrates.


Autologous bone marrow transplantation for the treatment of multiple sclerosis.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and represents one of the leading causes of neurologic disability in young adults. Current treatments for MS have shown limited efficacy in patients with either a progressive or an aggressive disease course. Hematopoietic stem cell transplantation (HSCT) has been proposed to control or even cure refractory cases of MS. Indeed, HSCT is able to temporarily eradicate the autoreactive cells and to reset the aberrant immune response to self-antigens. In the last decade, owing to the growing experience in selecting the most appropriate patients to transplant and the recent advances in chemotherapeutic and support regimens, the transplant-related mortality of autologous HSCT in MS patients dropped down to 1,3 % and the progression-free survival ranges from 47 % to 100 %. Altogether, these data support autologous HSCT as a possible second-line therapy for refractory MS.


Blockchain Technology for Detecting Falsified and Substandard Drugs in Distribution: Pharmaceutical Supply Chain Intervention.
Drug counterfeiting is a global problem with significant risks to consumers and the general public. In the Philippines, 30% of inspected drug stores in 2003 were found with substandard/spurious/falsely-labeled/falsified/counterfeit drugs. The economic burden on the population drug expenditures and on governments is high. The Philippine Food and Drug Administration (FDA) encourages the public to check the certificates of product registration and report any instances of counterfeiting. The National Police of Philippines responds to such reports through a special task force. However, no literature on its impact on the distribution of such drugs were found. Blockchain technology is a cryptographic ledger that is allegedly immutable through repeated sequential hashing and fault-tolerant through a consensus algorithm. This project will develop and test a pharmacosurveillance blockchain system that will support information sharing along the official drug distribution network. This study aims to develop a pharmacosurveillance blockchain system and test its functions in a simulated network. We are developing a Distributed Application (DApp) that will run on smart contracts, employing Swarm as the Distributed File System (DFS). Two instances will be developed: one for Ethereum and another for Hyperledger Fabric. The proof-of-work (PoW) consensus algorithm of Ethereum will be modified into a delegated proof-of-stake (DPoS) or practical Byzantine fault tolerance (PBFT) consensus algorithm as it is scalable and fits the drug supply chain environment. The system will adopt the GS1 pedigree standard and will satisfy the data points in the data standardization guidelines from the US FDA. Simulations will use the following 5 nodes: for FDA, manufacturer, wholesaler, retailer, and the consumer portal. Development is underway. The design of the system will place FDA in a supervisory data verification role, with each pedigree type-specific data source serving a primary data verification role. The supply chain process will be initiated by the manufacturer, with recursive verification for every transaction. It will allow consumers to scan a code printed on the receipt of their purchases to review the drug distribution history. Development and testing will be conducted in a simulated network, and thus, results may differ from actual practice. The project being proposed is disruptive; once tested, the team intends to engage the Philippine FDA to discuss implementation plans and formulate policies to facilitate adoption and sustainability. RR1-10.2196/10163.


Predator and heterospecific stimuli alter behaviour in cattle.
Wild and domestic ungulates modify their behaviour in the presence of olfactory and visual cues of predators but investigations have not exposed a domestic species to a series of cues representing various predators and other ungulate herbivores. We used wolf (Canis lupus), mountain lion (Puma concolor), and mule deer (Odocoileus hemionus) stimuli (olfactory and visual), and a control (no stimuli) to experimentally test for differences in behaviour of cattle (Bos taurus) raised in Arizona. We measured (1) vigilance, (2) foraging rates, (3) giving up density (GUD) of high quality foods and (4) time spent in high quality forage locations in response to location of stimuli treatments. In general, we found a consistent pattern in that wolf and deer treatments caused disparate results in all 4 response variables. Wolf stimuli significantly increased cattle vigilance and decreased cattle foraging rates; conversely, deer stimuli significantly increased cattle foraging rate and increased cattle use of high quality forage areas containing stimuli. Mountain lion stimuli did not significantly impact any of the 4 response variables. Our findings suggest that domestic herbivores react to predatory stimuli, can differentiate between stimuli representing two predatory species, and suggest that cattle may reduce antipredatory behaviour when near heterospecifics.