Randomized controlled trial of oral glutathione supplementation on body stores of glutathione.
Glutathione (GSH), the most abundant endogenous antioxidant, is a critical regulator of oxidative stress and immune function. While oral GSH has been shown to be bioavailable in laboratory animal models, its efficacy in humans has not been established. Our objective was to determine the long-term effectiveness of oral GSH supplementation on body stores of GSH in healthy adults. A 6-month randomized, double-blinded, placebo-controlled trial of oral GSH (250 or 1,000 mg/day) on GSH levels in blood, erythrocytes, plasma, lymphocytes and exfoliated buccal mucosal cells was conducted in 54 non-smoking adults. Secondary outcomes on a subset of subjects included a battery of immune markers. GSH levels in blood increased after 1, 3 and 6 months versus baseline at both doses. At 6 months, mean GSH levels increased 30-35 % in erythrocytes, plasma and lymphocytes and 260 % in buccal cells in the high-dose group (P < 0.05). GSH levels increased 17 and 29 % in blood and erythrocytes, respectively, in the low-dose group (P < 0.05). In most cases, the increases were dose and time dependent, and levels returned to baseline after a 1-month washout period. A reduction in oxidative stress in both GSH dose groups was indicated by decreases in the oxidized to reduced glutathione ratio in whole blood after 6 months. Natural killer cytotoxicity increased >twofold in the high-dose group versus placebo (P < 0.05) at 3 months. These findings show, for the first time, that daily consumption of GSH supplements was effective at increasing body compartment stores of GSH.


Does hyperthermia increase apoptosis in white spot syndrome virus (WSSV)-infected Litopenaeus vannamei?
Apoptosis plays a critical role in development and maintenance of multicellular organisms. It has also been described as an anti-viral mechanism in both insects and vertebrates. In fact, to escape the immune system and to increase their spread, some viruses such as baculovirus produce anti-apoptotic molecules. Conversely, a recent report showing a positive correlation between the number of apoptotic cells and the severity of white spot syndrome virus (WSSV) infection in Penaeus monodon suggested that apoptosis might be the cause of death in viral-infected shrimp. Searching for the mechanisms involved in the beneficial effect of hyperthermia for WSSV-infected Litopenaeus vannamei (also called Penaeus vannamei) and considering that hyperthermia increases apoptosis in other experimental models, we investigated the presence of apoptosis by Tdt-mediated dUTP nick-end label (TUNEL), from 4 of 168 h in 3 groups of 50 L. vannamei juveniles. Group 1 consisted of experimentally infected shrimp (intramuscular injection of 3 x 10(7) viral copies) kept at 25 degrees C, Group 2 of similarly infected shrimp kept at 32 degrees C and Group 3 of uninjected shrimp kept at 32 degrees C. Apoptosis was found only in WSSV-infected individuals. Shrimp at 25 degrees C were positive for apoptotic cells in 48 (16%) of their examined tissues or organs, compared to 62 (21%) for those at 32 degrees C. Moreover, shrimp at 32 degrees C also had a significantly higher overall mean apoptotic index (AI) than shrimp at 25 degrees C (p < 0.05). Comparison of mean AI at 72, 96 and 120 h post-infection showed that individuals at 32 degrees C presented a significantly higher values than those at 25 degrees C. These results suggested that hyperthermia might facilitate apoptosis in WSSV-infected L. vannamei and might be one of the mechanisms responsible for increased survival of infected shrimp maintained at 32 degrees C.


Why nearly all PET of abdominal and pelvic cancers will be performed as PET/CT.
Clinical experience at Johns Hopkins and published literature regarding PET/CT applications in the abdomen and pelvis are reviewed, and the strengths and limitations of this evolving technology are summarized. More than 2,700 whole-body PET/CT scans including the abdomen and pelvis were performed for clinical indications by our nuclear medicine service from June 2001 through September 2003. Indications for these studies are reviewed, and our clinical impressions of diagnostic advantages and limitations of PET/CT are reported. Of the >2,700 whole-body PET/CT scans performed at our institution, >90% were for known or suspected cancers. Primary abdominopelvic indications were second in frequency to thoracic indications. In addition, a comprehensive literature search was performed, and key articles related to PET/CT in the abdomen and pelvis were identified, reviewed, and summarized. Under the search term "PET/CT," 142 articles were identified under the National Library of Medicine Pub Med database, and a number of general findings are summarized. PET/CT allows for the accurate localization of foci of radiotracer uptake and their separation from normal structures. In our experience, the method is quantitatively accurate, rapid, and easily implemented, including contrast studies, in clinical practice in a wide range of abdominopelvic indications. Although artifacts can occur from a variety of causes, close attention to protocol details and patient immobilization reduces their frequency. Where systematically studied, PET/CT improves diagnostic accuracy compared with PET alone. It is anticipated that PET/CT will increasingly become the routine and preferred procedure for abdominopelvic evaluations with PET imaging. It has already become the preferred method at our center.


Dentist-laboratory communication and quality assessment of removable prostheses in Oregon: A cross-sectional pilot study.
When fabricating a removable dental prosthesis, it is unclear if the information received by the dental laboratory technician is clear and sufficient. The purpose of this survey study was to evaluate the dentist's work authorizations for removable prostheses as well as determine common practices used by laboratories during the fabrication of removable prostheses. A 24-item questionnaire was developed based on previously published questionnaires and incorporating new topics. A public uniform resource locator (URL) survey link was generated and sent to the office of the Oregon Association of Dental Laboratories (OADL). The executive director of the board then sent out the link to 163 participants that included members and nonmembers of the OADL who were still active in the state of Oregon. Two reminder e-mails were sent 2 weeks apart. Study data were collected and managed by using the Research Electronic Data Capture (REDCap) software program. Descriptive statistics were tabulated, and responses displayed as a percentage of the total. From the 163 invited participants, 26 responded to the survey representing a 15.9% response rate. Only 11% of the laboratories stated that they routinely receive work authorizations with clear instructions. All participants stated that they always (62.5%) or frequently (37.5%) design the partial prostheses frameworks. Only 37.5% of the laboratories stated that they usually receive adequately extended and accurate definitive casts to fabricate the framework. Fifty percent of the laboratories stated that they very rarely perform altered cast procedures and 50% indicated that half or more of the removable partial prostheses they fabricate were entirely made of acrylic resin. Most laboratories stated that thermoplastic resin partial dentures were less than 25% of their produced volume of removable prostheses. Only 22% of respondents stated that they usually receive adequate information to complete a denture tooth arrangement and most (78%) dentists do not routinely specify the type of occlusal scheme desired for their complete denture tooth arrangements. In most prostheses (77%), posterior palatal seal was marked by the prescribing dentists rarely or very rarely. Work authorizations provided by the dentists were less than adequate and left much decision-making to the dental laboratory technician.


Identification of a gene set to evaluate the potential effects of loud sounds from seismic surveys on the ears of fishes: a study with Salmo salar.
Functional genomic studies were carried out on the inner ear of Atlantic salmon Salmo salar following exposure to a seismic airgun. Microarray analyses revealed 79 unique transcripts (passing background threshold), with 42 reproducibly up-regulated and 37 reproducibly down-regulated in exposed v. control fish. Regarding the potential effects on cellular energetics and cellular respiration, altered transcripts included those with roles in oxygen transport, the glycolytic pathway, the Krebs cycle and the electron transport chain. Of these, a number of transcripts encoding haemoglobins that are important in oxygen transport were up-regulated and among the most highly expressed. Up-regulation of transcripts encoding nicotinamide riboside kinase 2, which is also important in energy production and linked to nerve cell damage, points to evidence of neuronal damage in the ear following noise exposure. Transcripts related to protein modification or degradation also indicated potential damaging effects of sound on ear tissues. Notable in this regard were transcripts associated with the proteasome-ubiquitin pathway, which is involved in protein degradation, with the transcript encoding ubiquitin family domain-containing protein 1 displaying the highest response to exposure. The differential expression of transcripts observed for some immune responses could potentially be linked to the rupture of cell membranes. Meanwhile, the altered expression of transcripts for cytoskeletal proteins that contribute to the structural integrity of the inner ear could point to repair or regeneration of ear tissues including auditory hair cells. Regarding potential effects on hormones and vitamins, the protein carrier for thyroxine and retinol (vitamin A), namely transthyretin, was altered at the transcript expression level and it has been suggested from studies in mammalian systems that retinoic acid may play a role in the regeneration of damaged hair cells. The microarray experiment identified the transcript encoding growth hormone I as up-regulated by loud sound, supporting previous evidence linking growth hormone to hair cell regeneration in fishes. Quantitative (q) reverse transcription (RT) polymerase chain reaction (qRT-PCR) analyses confirmed dysregulation of some microarray-identified transcripts and in some cases revealed a high level of biological variability in the exposed group. These results support the potential utility of molecular biomarkers to evaluate the effect of seismic surveys on fishes with studies on the ears being placed in a priority category for development of exposure-response relationships. Knowledge of such relationships is necessary for addressing the question of potential size of injury zones.


Sympathoneural and adrenomedullary responses to mental stress.
This concept-based review provides historical perspectives and updates about sympathetic noradrenergic and sympathetic adrenergic responses to mental stress. The topic of this review has incited perennial debate, because of disagreements over definitions, controversial inferences, and limited availability of relevant measurement tools. The discussion begins appropriately with Cannon's "homeostasis" and his pioneering work in the area. This is followed by mental stress as a scientific idea and the relatively new notions of allostasis and allostatic load. Experimental models of mental stress in rodents and humans are discussed, with particular attention to ethical constraints in humans. Sections follow on sympathoneural responses to mental stress, reactivity of catecholamine systems, clinical pathophysiologic states, and the cardiovascular reactivity hypothesis. Future advancement of the field will require integrative approaches and coordinated efforts between physiologists and psychologists on this interdisciplinary topic.


Microbubble-mediated ultrasound therapy: a review of its potential in cancer treatment.
The inherently toxic nature of chemotherapy drugs is essential for them to kill cancer cells but is also the source of the detrimental side effects experienced by patients. One strategy to reduce these side effects is to limit the healthy tissue exposure by encapsulating the drugs in a vehicle that demonstrates a very low leak rate in circulation while simultaneously having the potential for rapid release once inside the tumor. Designing a vehicle with these two opposing properties is the major challenge in the field of drug delivery. A triggering event is required to change the vehicle from its stable circulating state to its unstable release state. A unique mechanical actuation type trigger is possible by harnessing the size changes that occur when microbubbles interact with ultrasound. These mechanical actuations can burst liposomes and cell membranes alike allowing for rapid drug release and facilitating delivery into nearby cells. The tight focusing ability of the ultrasound to just a few cubic millimeters allows for precise control over the tissue location where the microbubbles destabilize the vehicles. This allows the ultrasound to highlight the tumor tissue and cause rapid drug release from any carrier present. Different vehicle designs have been demonstrated from carrying drug on just the surface of the microbubble itself to encapsulating the microbubble along with the drug within a liposome. In the future, nanoparticles may extend the circulation half-life of these ultrasound triggerable drug-delivery vehicles by acting as nucleation sites of ultrasound-induced mechanical actuation. In addition to the drug delivery capability, the microbubble size changes can also be used to create imaging contrast agents that could allow the internal chemical environment of a tumor to be studied to help improve the diagnosis and detection of cancer. The ability to attain truly tumor-specific release from circulating drug-delivery vehicles is an exciting future prospect to reduce chemotherapy side effects while increasing drug effectiveness.


Visualizing the determinants of viral RNA recognition by innate immune sensor RIG-I.
Retinoic acid inducible gene-I (RIG-I) is a key intracellular immune receptor for pathogenic RNAs, particularly from RNA viruses. Here, we report the crystal structure of human RIG-I bound to a 5' triphosphorylated RNA hairpin and ADP nucleotide at 2.8 Å resolution. The RNA ligand contains all structural features that are essential for optimal recognition by RIG-I, as it mimics the panhandle-like signatures within the genome of negative-stranded RNA viruses. RIG-I adopts an intermediate, semiclosed conformation in this product state of ATP hydrolysis. The structure of this complex allows us to visualize the first steps in RIG-I recognition and activation upon viral infection.


Hydrophobic gating in BK channels.
The gating mechanism of transmembrane ion channels is crucial for understanding how these proteins control ion flow across membranes in various physiological processes. Big potassium (BK) channels are particularly interesting with large single-channel conductance and dual regulation by membrane voltage and intracellular Ca2+. Recent atomistic structures of BK channels failed to identify structural features that could physically block the ion flow in the closed state. Here, we show that gating of BK channels does not seem to require a physical gate. Instead, changes in the pore shape and surface hydrophobicity in the Ca2+-free state allow the channel to readily undergo hydrophobic dewetting transitions, giving rise to a large free energy barrier for K+ permeation. Importantly, the dry pore remains physically open and is readily accessible to quaternary ammonium channel blockers. The hydrophobic gating mechanism is also consistent with scanning mutagenesis studies showing that modulation of pore hydrophobicity is correlated with activation properties.


A randomized controlled trial of an exercise intervention targeting cardiovascular and metabolic risk factors for prostate cancer patients from the RADAR trial.
Androgen deprivation therapy leads to a number of adverse effects including deterioration of the musculoskeletal system and increased risk factors for cardiovascular and metabolic complications. The purpose of this study is to determine the effects, efficacy, retention and compliance of a physical exercise intervention in a large established cohort of prostate cancer patients from the Randomised Androgen Deprivation and Radiotherapy (RADAR) study. Specifically, we aim to compare short- and long-term effects of a prostate cancer-specific supervised exercise program to a standard public health physical activity strategy utilizing printed resources on cardiovascular and metabolic risk factors. Our primary outcomes are cardiorespiratory capacity, abdominal obesity, and lipid and glycemic control, while secondary outcomes include self-reported physical activity, quality of life and psychological distress. Multi-site randomized controlled trial of 370 men from the RADAR study cohort undergoing treatment or previously treated for prostate cancer involving androgen deprivation therapy in the cities of Perth and Newcastle (Australia), and Wellington (New Zealand). Participants will be randomized to (1) supervised resistance/aerobic exercise or (2) printed material comprising general physical activity recommendations. Participants will then undergo progressive training for 6 months. Measurements for primary and secondary endpoints will take place at baseline, 6 months (end of intervention), and at 6 months follow-up. This study uses a large existent cohort of patients and will generate valuable information as to the continuing effects of exercise specifically targeting cardiovascular function and disease risk, insulin metabolism, abdominal obesity, physical function, quality of life and psychological distress. We expect dissemination of the knowledge gained from this project to reduce risk factors for the development of co-morbid diseases commonly associated with androgen deprivation therapy such as cardiovascular disease, obesity, metabolic disease and diabetes, as well as improvements in physical and functional ability, and quality of life. ACTRN12609000729224.


Early life height and weight production functions with endogenous energy and protein inputs.
We examine effects of protein and energy intakes on height and weight growth for children between 6 and 24 months old in Guatemala and the Philippines. Using instrumental variables to control for endogeneity and estimating multiple specifications, we find that protein intake plays an important and positive role in height and weight growth in the 6-24 month period. Energy from other macronutrients, however, does not have a robust relation with these two anthropometric measures. Our estimates indicate that in contexts with substantial child undernutrition, increases in protein-rich food intake in the first 24 months can have important growth effects, which previous studies indicate are related significantly to a range of outcomes over the life cycle.


Effect of neurolytic celiac plexus block on pain relief, quality of life, and survival in patients with unresectable pancreatic cancer: a randomized controlled trial.
Pancreatic cancer is an aggressive tumor associated with high mortality. Optimal pain control may improve quality of life (QOL) for these patients. To test the hypothesis that neurolytic celiac plexus block (NCPB) vs opioids alone improves pain relief, QOL, and survival in patients with unresectable pancreatic cancer. Double-blind, randomized clinical trial conducted at Mayo Clinic, Rochester, Minn. Enrolled (October 1997 and January 2001) were 100 eligible patients with unresectable pancreatic cancer experiencing pain. Patients were followed up for at least 1 year or until death. Patients were randomly assigned to receive either NCPB or systemic analgesic therapy alone with a sham injection. All patients could receive additional opioids managed by a clinician blinded to the treatment assignment. Pain intensity (0-10 numerical rating scale), QOL, opioid consumption and related adverse effects, and survival time were assessed weekly by a blinded observer. Mean (SD) baseline pain was 4.4 (1.7) for NCPB vs 4.1 (1.8) for opioids alone. The first week after randomization, pain intensity and QOL scores were improved (pain intensity, P< or =.01 for both groups; QOL, P<.001 for both groups), with a larger decrease in pain for the NCPB group (P =.005). From repeated measures analysis, pain was also lower for NCPB over time (P =.01). However, opioid consumption (P =.93), frequency of opioid adverse effects (all P>.10), and QOL (P =.46) were not significantly different between groups. In the first 6 weeks, fewer NCPB patients reported moderate or severe pain (pain intensity rating of > or =5/10) vs opioid-only patients (14% vs 40%, P =.005). At 1 year, 16% of NCPB patients and 6% of opioid-only patients were alive. However, survival did not differ significantly between groups (P =.26, proportional hazards regression). Although NCPB improves pain relief in patients with pancreatic cancer vs optimized systemic analgesic therapy alone, it does not affect QOL or survival.


Recirculating air filtration significantly reduces exposure to airborne nanoparticles.
Airborne nanoparticles from vehicle emissions have been associated with adverse effects in people with pulmonary and cardiovascular disease, and toxicologic studies have shown that nanoparticles can be more hazardous than their larger-scale counterparts. Recirculating air filtration in automobiles and houses may provide a low-cost solution to reducing exposures in many cases, thus reducing possible health risks. We investigated the effectiveness of recirculating air filtration on reducing exposure to incidental and intentionally produced airborne nanoparticles under two scenarios: while driving in traffic, and while generating nanomaterials using gas-phase synthesis. We tested the recirculating air filtration in two commercial vehicles when driving in traffic, as well as in a nonventilation room with a nanoparticle generator, simulating a nanomaterial production facility. We also measured the time-resolved aerosol size distribution during the in-car recirculation to investigate how recirculating air filtration affects particles of different sizes. We developed a recirculation model to describe the aerosol concentration change during recirculation. The use of inexpensive, low-efficiency filters in recirculation systems is shown to reduce nanoparticle concentrations to below levels found in a typical office within 3 min while driving through heavy traffic, and within 20 min in a simulated nanomaterial production facility. Development and application of this technology could lead to significant reductions in airborne nanoparticle exposure, reducing possible risks to health and providing solutions for generating nanomaterials safely.


Can curriculum design influence medical students' attitudes to psychiatry? A comparison of two different approaches.
Medical students with poor attitudes toward psychiatry are unlikely to choose it as a career, and current psychiatry recruitment is inadequate for future NHS needs. Amending medical school curricula has been suggested as one solution. We performed a unique naturalistic mixed-methods cross-sectional survey of two sequential cohorts in a UK medical school, before and after the restructuring of the entire MBChB curriculum. As well as increasing integration with other specialties, the emphasis placed on psychiatry increased throughout the course, but the final psychiatry block reduced from 8 to 6 weeks. Students experiencing the refreshed curriculum had better attitudes to psychiatry and psychiatric patients and were more positive about psychiatry as a career for themselves and others, compared to students on the old curriculum. This was demonstrated both quantitatively using validated rating scales (12/30 questions ATP-30 and 1/6 questions PEAK-6) and qualitatively using free-text responses. Restructuring undergraduate medical curricula to enhance integration may yield added value, including the potential to improve attitudes to specialties previously learned in silos, such as psychiatry. This may improve recruitment and the understanding of mental health for all future doctors.


K-Means Clustering in Monitoring Facility Reporting of HIV Indicator Data: Case of Kenya.
Health management information systems (HMISs) in low- and middle-income countries have been used to collect large amounts of data after years of implementation, especially in support of HIV care services. National-level aggregate reporting data derived from HMISs are essential for informed decision-making. However, the optimal statistical approaches and algorithms for deriving key insights from these data are yet to be fully and adequately utilized. This paper demonstrates use of the k-means clustering algorithm as an approach in supporting monitoring of facility reporting and data-informed decision-making, using the case example of Kenya HIV national reporting data. Results reveal four homogeneous cluster categories that can be used in assessing overall facility performance and rating of that performance.


Production of healthy cloned mice from bodies frozen at -20 degrees C for 16 years.
Cloning animals by nuclear transfer provides an opportunity to preserve endangered mammalian species. However, it has been suggested that the "resurrection" of frozen extinct species (such as the woolly mammoth) is impracticable, as no live cells are available, and the genomic material that remains is inevitably degraded. Here we report production of cloned mice from bodies kept frozen at -20 degrees C for up to 16 years without any cryoprotection. As all of the cells were ruptured after thawing, we used a modified cloning method and examined nuclei from several organs for use in nuclear transfer attempts. Using brain nuclei as nuclear donors, we established embryonic stem cell lines from the cloned embryos. Healthy cloned mice were then produced from these nuclear transferred embryonic stem cells by serial nuclear transfer. Thus, nuclear transfer techniques could be used to "resurrect" animals or maintain valuable genomic stocks from tissues frozen for prolonged periods without any cryopreservation.


Warhead biosynthesis and the origin of structural diversity in hydroxamate metalloproteinase inhibitors.
Metalloproteinase inhibitors often feature hydroxamate moieties to facilitate the chelation of metal ions in the catalytic center of target enzymes. Actinonin and matlystatins are potent metalloproteinase inhibitors that comprise rare N-hydroxy-2-pentyl-succinamic acid warheads. Here we report the identification and characterization of their biosynthetic pathways. By gene cluster comparison and a combination of precursor feeding studies, heterologous pathway expression and gene deletion experiments we are able to show that the N-hydroxy-alkyl-succinamic acid warhead is generated by an unprecedented variation of the ethylmalonyl-CoA pathway. Moreover, we present evidence that the remarkable structural diversity of matlystatin congeners originates from the activity of a decarboxylase-dehydrogenase enzyme with high similarity to enzymes that form epoxyketones. We further exploit this mechanism to direct the biosynthesis of non-natural matlystatin derivatives. Our work paves the way for follow-up studies on these fascinating pathways and allows the identification of new protease inhibitors by genome mining.


Evolution of morphogenesis in 360-million-year-old conodont chordates calibrated in days.
Highly rhythmic increments of crown tissue are identifiable in conodont oral apparatus elements from the Late Devonian of the Holy Cross Mountains, Poland; individual laminae being of thickness comparable with daily increments of vertebrate tooth enamel and fish otoliths. Abundant occurrence of such specimens enables bed-by-bed (stratophenetic) studies of the process of evolution at the population level and quantitative presentation of the evolution of ontogeny in the sampled geological section covering several million years. The morphologic transformation is expressed as expansion of a juvenile asymmetry to later stages of the ontogeny and in decrease of the mature element width, which was due to a change of the mineral tissue secretion rate. It was not just a simple extension of a juvenile character into the later stage of the ontogeny (heterochrony) but rather a true developmental novelty. The evolution was gradual and very slow. The proposed quantitative approach to growth increments in the mineral skeleton of ancient chordates introduces real-time units to evolutionary developmental studies connected with direct paleontological evidence on the course of evolution.


Benthic plastic debris in marine and fresh water environments.
This review provides a discussion of the published literature concerning benthic plastic debris in ocean, sea, lake, estuary and river bottoms throughout the world. Although numerous investigations of shoreline, surface and near-surface plastic debris provide important information on plastic types, distribution, accumulation, and degradation, studies of submerged plastic debris have been sporadic in the past and have become more prominent only recently. The distribution of benthic debris is controlled mainly by combinations of urban proximity and its association with fishing-related activities, geomorphology, hydrological conditions, and river input. High density plastics, biofouled products, polymers with mineral fillers or adsorbed minerals, and plastic-metal composites all have the potential to sink. Once deposited on the bottoms of water basins and channels, plastics are shielded from UV light, thus slowing the degradation process significantly. Investigations of the interactions between benthic plastic debris and bottom-dwelling organisms will help shed light on the potential dangers of submerged plastic litter.


Quantum dynamics study of fulvene double bond photoisomerization: the role of intramolecular vibrational energy redistribution and excitation energy.
The double bond photoisomerization of fulvene has been studied with quantum dynamics calculations using the multi-configuration time-dependent Hartree method. Fulvene is a test case to develop optical control strategies based on the knowledge of the excited state decay mechanism. The decay takes place on a time scale of several hundred femtoseconds, and the potential energy surface is centered around a conical intersection seam between the ground and excited state. The competition between unreactive decay and photoisomerization depends on the region of the seam accessed during the decay. The dynamics are carried out on a four-dimensional model surface, parametrized from complete active space self-consistent field calculations, that captures the main features of the seam (energy and locus of the seam and associated branching space vectors). Wave packet propagations initiated by single laser pulses of 5-25 fs duration and 1.85-4 eV excitation energy show the principal characteristics of the first 150 fs of the photodynamics. Initially, the excitation energy is transferred to a bond stretching mode that leads the wave packet to the seam, inducing the regeneration of the reactant. The photoisomerization starts after the vibrational energy has flowed from the bond stretching to the torsional mode. In our propagations, intramolecular energy redistribution (IVR) is accelerated for higher excess energies along the bond stretch mode. Thus, the competition between unreactive decay and isomerization depends on the rate of IVR between the bond stretch and torsion coordinates, which in turn depends on the excitation energy. These results set the ground for the development of future optical control strategies.


Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial.
The role of nutrition in the treatment of attention-deficit hyperactivity disorder (ADHD) is gaining international attention; however, treatments have generally focused only on diet restriction or supplementing with one nutrient at a time. To investigate the efficacy and safety of a broad-based micronutrient formula consisting mainly of vitamins and minerals, without omega fatty acids, in the treatment of ADHD in adults. This double-blind randomised controlled trial assigned 80 adults with ADHD in a 1:1 ratio to either micronutrients (n = 42) or placebo (n = 38) for 8 weeks (trial registered with the Australian New Zealand Clinical Trials Registry: ACTRN12609000308291). Intent-to-treat analyses showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales. However, clinicians rated those receiving micronutrients as more improved than those on placebo both globally and on ADHD symptoms. Post hoc analyses showed that for those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo. There were no group differences in adverse events. This study provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile.


Opiate substitution treatment and HIV transmission in people who inject drugs: systematic review and meta-analysis.
To quantify the effect of opiate substitution treatment in relation to HIV transmission among people who inject drugs. Systematic review and meta-analysis of prospective published and unpublished observational studies. Search of Medline, Embase, PsychINFO, and the Cochrane Library from the earliest year to 2011 without language restriction. We selected studies that directly assessed the impact of opiate substitution treatment in relation to incidence of HIV and studies that assessed incidence of HIV in people who inject drugs and that might have collected data regarding exposure to opiate substitution treatment but not have reported it. Authors of these studies were contacted. Data were extracted by two reviewers and pooled in a meta-analysis with a random effects model. Twelve published studies that examined the impact of opiate substitution treatment on HIV transmission met criteria for inclusion, and unpublished data were obtained from three additional studies. All included studies examined methadone maintenance treatment. Data from nine of these studies could be pooled, including 819 incident HIV infections over 23,608 person years of follow-up. Opiate substitution treatment was associated with a 54% reduction in risk of HIV infection among people who inject drugs (rate ratio 0.46, 95% confidence interval 0.32 to 0.67; P<0.001). There was evidence of heterogeneity between studies (I(2)=60%, χ(2)=20.12, P=0.010), which could not be explained by geographical region, site of recruitment, or the provision of incentives. There was weak evidence for greater benefit associated with longer duration of exposure to opiate substitution treatment. Opiate substitution treatment provided as maintenance therapy is associated with a reduction in the risk of HIV infection among people who inject drugs. These findings, however, could reflect comparatively high levels of motivation to change behaviour and reduce injecting risk behaviour among people who inject drugs who are receiving opiate substitution treatment.


Variance estimation in single-cell mutation assays: comparison to experimental observations in human lymphoblasts at 4 gene loci.
The performance of mutation assays with single cells involves a series of separate steps beginning with the induction of mutant cells and ending with the counting of mutant and wild-type colonies. The variation among identically treated cultures is here modeled as arising from 3 sources: (1) the number of mutant cells surviving treatment, (2) the number of mutant cells sampled in steps of sampling and growth required in assays involving phenotypic lag, and (3) the number of mutant and nonmutant colonies actually observed. The arithmetical statements describing the expectation of variance from each step are presented and used to provide means to calculate an expected overall variance for typical experiments. The model is then tested by comparing its predictions with the observed mutant fractions in human lymphoblastoid cells at the loci coding for 6-thioguanine, ouabain, podophyllotoxin, and 5,6-dichlororibofuranosyl benzimidazole resistances. The model is found to have excellent predictive qualities and should be useful in experimental design of studies involving induction of rare variants in single-cell systems.


Factors affecting the most recent fertility rates in urban-rural Bangladesh.
This paper reports on a study which has been undertaken using data from the 1989 Bangladesh Fertility Survey (BFS) to determine the significance of influences on the probability of birth in the year preceding the survey. In the survey a total of 11905 ever-married women of reproductive age were asked a battery of questions relating to fertility aspects of women. Variables selected in this study were grouped into demographic, socio-economic, cultural and decision-making variables. Findings from the study indicate that the mother's age, whether contraception has ever been used, the death of a child at any time, whether the woman has ever worked, religion, region of residence, and female independence are the important covariates for explaining recent fertility in Bangladesh. Models are developed for the probabilities of a woman giving birth in urban and rural areas, dependent on her demographic and socio-economic conditions. Also developed are models for contraceptive use in urban-rural Bangladesh. This modelling contributes to a better understanding of fertility changes in Bangladesh and the differentials between urban and rural fertility. It is indicated that a continued fertility decline is likely.


Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation.
Triple antithrombotic therapy with warfarin plus two antiplatelet agents is the standard of care after percutaneous coronary intervention (PCI) for patients with atrial fibrillation, but this therapy is associated with a high risk of bleeding. In this multicenter trial, we randomly assigned 2725 patients with atrial fibrillation who had undergone PCI to triple therapy with warfarin plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and aspirin (for 1 to 3 months) (triple-therapy group) or dual therapy with dabigatran (110 mg or 150 mg twice daily) plus a P2Y12 inhibitor (clopidogrel or ticagrelor) and no aspirin (110-mg and 150-mg dual-therapy groups). Outside the United States, elderly patients (≥80 years of age; ≥70 years of age in Japan) were randomly assigned to the 110-mg dual-therapy group or the triple-therapy group. The primary end point was a major or clinically relevant nonmajor bleeding event during follow-up (mean follow-up, 14 months). The trial also tested for the noninferiority of dual therapy with dabigatran (both doses combined) to triple therapy with warfarin with respect to the incidence of a composite efficacy end point of thromboembolic events (myocardial infarction, stroke, or systemic embolism), death, or unplanned revascularization. The incidence of the primary end point was 15.4% in the 110-mg dual-therapy group as compared with 26.9% in the triple-therapy group (hazard ratio, 0.52; 95% confidence interval [CI], 0.42 to 0.63; P<0.001 for noninferiority; P<0.001 for superiority) and 20.2% in the 150-mg dual-therapy group as compared with 25.7% in the corresponding triple-therapy group, which did not include elderly patients outside the United States (hazard ratio, 0.72; 95% CI, 0.58 to 0.88; P<0.001 for noninferiority). The incidence of the composite efficacy end point was 13.7% in the two dual-therapy groups combined as compared with 13.4% in the triple-therapy group (hazard ratio, 1.04; 95% CI, 0.84 to 1.29; P=0.005 for noninferiority). The rate of serious adverse events did not differ significantly among the groups. Among patients with atrial fibrillation who had undergone PCI, the risk of bleeding was lower among those who received dual therapy with dabigatran and a P2Y12 inhibitor than among those who received triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. Dual therapy was noninferior to triple therapy with respect to the risk of thromboembolic events. (Funded by Boehringer Ingelheim; RE-DUAL PCI ClinicalTrials.gov number, NCT02164864 .).


Protein and amino acid metabolism during and after exercise and the effects of nutrition.
Sustained dynamic exercise stimulates amino acid oxidation, chiefly of the branched-chain amino acids, and ammonia production in proportion to exercise intensity; if the exercise is intense enough, there is a net loss of muscle protein (as a result of decreased protein synthesis, increased breakdown, or both); some of the amino acids are oxidized as fuel, whereas the rest provide substrates for gluconeogenesis and possibly for acid-based regulation. Protein balance is restored after exercise, but no hypertrophy occurs with habitual dynamic exercise. Resistance exercise causes little change in amino acid oxidation but probably depresses protein synthesis and elevates breakdown acutely. After exercise, protein synthesis rebounds for </=48 h, but breakdown remains elevated, and net positive balance is achieved only if amino acid availability is increased. There is no evidence that habitual exercise increases protein requirements; indeed protein metabolism may become more efficient as a result of training.


Cancer prevention interdisciplinary education program at Purdue University: overview and preliminary results.
Cancer prevention is a broad field that crosses many disciplines; therefore, educational efforts to enhance cancer prevention research focused on interdisciplinary approaches to the field are greatly needed. In order to hasten progress in cancer prevention research, the Cancer Prevention Internship Program (CPIP) at Purdue University was designed to develop and test an interdisciplinary curriculum for undergraduate and graduate students. The hypothesis was that course curriculum specific to introducing interdisciplinary concepts in cancer prevention would increase student interest in and ability to pursue advanced educational opportunities (e.g., graduate school, medical school). Preliminary results from the evaluation of the first year which included ten undergraduate and five graduate students suggested that participation in CPIP is a positive professional development experience, leading to a significant increase in understanding of interdisciplinary research in cancer prevention. In its first year, the CPIP project has created a successful model for interdisciplinary education in cancer prevention research.


Experimental and theoretical studies of the aureole about a point source that is due to atmospheric scattering in the middle ultraviolet.
In the atmosphere, pointlike sources are surrounded by aureoles because of molecular and aerosol scattering. In various meteorological conditions, this variance field can be a nonnegligible part of the signal detected by a large-field-of-view sensor. A model based on a Monte Carlo technique has been developed to simulate the propagation of radiation coming from a UV point source. The model was validated with an experimental comparison by a photon-counting technique, and good agreement between experimental and theoretical results was found.


Matrilysin/matrix metalloproteinase-7(MMP7) cleavage of perlecan/HSPG2 creates a molecular switch to alter prostate cancer cell behavior.
Perlecan/HSPG2, a large heparan sulfate (HS) proteoglycan, normally is expressed in the basement membrane (BM) underlying epithelial and endothelial cells. During prostate cancer (PCa) cell invasion, a variety of proteolytic enzymes are expressed that digest BM components including perlecan. An enzyme upregulated in invasive PCa cells, matrilysin/matrix metalloproteinase-7 (MMP-7), was examined as a candidate for perlecan proteolysis both in silico and in vitro. Purified perlecan showed high sensitivity to MMP-7 digestion even when fully decorated with HS or when presented in native context connected with other BM proteins. In both conditions, MMP-7 produced discrete perlecan fragments corresponding to an origin in immunoglobulin (Ig) repeat region domain IV. While not predicted by in silico analysis, MMP-7 cleaved every subpart of recombinantly generated perlecan domain IV. Other enzymes relevant to PCa that were tested had limited ability to cleave perlecan including prostate specific antigen, hepsin, or fibroblast activation protein α. A long C-terminal portion of perlecan domain IV, Dm IV-3, induced a strong clustering phenotype in the metastatic PCa cell lines, PC-3 and C4-2. MMP-7 digestion of Dm IV-3 reverses the clustering effect into one favoring cell dispersion. In a C4-2 Transwell® invasion assay, perlecan-rich human BM extract that was pre-digested with MMP-7 showed loss of barrier function and permitted a greater level of cell penetration than untreated BM extract. We conclude that enzymatic processing of perlecan in the BM or territorial matrix by MMP-7 as occurs in the invasive tumor microenvironment acts as a molecular switch to alter PCa cell behavior and favor cell dispersion and invasiveness.


The effects of 17alpha-ethynylestradiol, 4-nonylphenol and phenol red on vitellogenin synthesis in juvenile Chalcalburnus tarichi primary hepatocyte culture.
In this study, the effects of the endocrine-disrupting chemicals known as 17α-ethynylestradiol (EE2), 4-nonylphenol (NP) and phenol red on vitellogenin (Vtg) synthesis in juvenile Chalcalburnus tarichi primary hepatocyte culture were investigated depending on dose and time. Hepatocytes were isolated by collagenase perfusion method and the cells were kept alive in cell culture for more than 2 weeks without using serum. As a result, it was determined that EE2 increased the Vtg synthesis depending on dose and time (p < 0.05), while NP and phenol red did not have any effect on the Vtg synthesis in the Chalcalburnus tarichi primary hepatocyte culture. Besides that, it was observed that high doses of NP (10( -3) and 10(-4)M) had toxic effects to the hepatocyte culture, too.


DMEK lenticule preparation from donor corneas using a novel 'SubHyS' technique followed by anterior corneal dissection.
To describe a novel submerged hydro-separation (SubHyS) technique followed by anterior corneal dissection to prepare a Descemet endothelial graft (DEG) for Descemet's membrane endothelial keratoplasty from human donor corneas. 30 human donor corneas were immersed in liquid (organ culture (OC) storage medium). Using a 25-gauge needle, approximately 0.3 mL of OC was injected (SubHyS) in the posterior stroma to create a liquid bubble. The bubbled cornea was mounted onto a modified artificial chamber with the epithelial side facing the air. The endothelium was protected with a viscoelastic solution. The anterior cornea was excised with a Barron radial vacuum trephine and the residual peripheral stroma was removed manually using micro-scissors. The DEG was dismounted and washed. The endothelial cell density (ECD) and mortality of the prepared DEG was determined. All the DEGs were preserved in deturgescent medium for 7 days using a cornea claw which was fixed to the sclera. ECD and mortality were checked post preservation. Complete detachment of Descemet's membrane and stroma was achieved in all 30 cases. Bubble burst was observed in five cases (excluded from the study) due to overfilling of the liquid. The average diameter of the excised DEG was 10.96 mm. The average endothelial cell loss post preservation was 27.69%. Histological analysis confirmed elimination of the residual stroma (n=13). The DEGs can be preserved in a deturgescent medium for up to 7 days. The procedure provides a standardised, pre-validated (quality assured), pre-separated, no-touch, ready-to-use tissue and also reduces the preparation time. Further, the tissues can be trephined as per the surgeon's convenience and can either be rolled or a contact lens could be used for final delivery of the DEG using a surgical glide.


Templated dewetting: designing entirely self-organized platforms for photocatalysis.
Formation and dispersion of metal nanoparticles on oxide surfaces in site-specific or even arrayed configuration are key in various technological processes such as catalysis, photonics, electrochemistry and for fabricating electrodes, sensors, memory devices, and magnetic, optical, and plasmonic platforms. A crucial aspect towards an efficient performance of many of these metal/metal oxide arrangements is a reliable fabrication approach. Since the early works on graphoepitaxy in the 70s, solid state dewetting of metal films on patterned surfaces has been much explored and regarded as a most effective tool to form defined arrays of ordered metal particles on a desired substrate. While templated dewetting has been studied in detail, particularly from a mechanistic perspective on lithographically patterned Si surfaces, the resulting outstanding potential of its applications on metal oxide semiconductors, such as titania, has received only limited attention. In this perspective we illustrate how dewetting and particularly templated dewetting can be used to fabricate highly efficient metal/TiO2 photocatalyst assemblies e.g. for green hydrogen evolution. A remarkable advantage is that the synthesis of such photocatalysts is completely based on self-ordering principles: anodic self-organized TiO2 nanotube arrays that self-align to a highest degree of hexagonal ordering are an ideal topographical substrate for a second self-ordering process, that is, templated-dewetting of sputter-deposited metal thin films. The controllable metal/semiconductor coupling delivers intriguing features and functionalities. We review concepts inherent to dewetting and particularly templated dewetting, and outline a series of effective tools that can be synergistically interlaced to reach fine control with nanoscopic precision over the resulting metal/TiO2 structures (in terms of e.g. high ordering, size distribution, site specific placement, alloy formation) to maximize their photocatalytic efficiency. These processes are easy to scale up and have a high throughput and great potential to be applied to fabricate not only (photo)catalytic materials but also a large palette of other functional nanostructured elements and devices.


[Hoflund syndrome due to anterior functional stenosis in 20 cows].
This study gives a comprehensive survey on 20 cows with vagus indigestion due to cranial functional stenosis (failure of omasal transport). The most important clinical findings were distension of the entire lateral abdominal wall on the left side and partially of the right ventral area as well, severely distended rumen, reduced or missing appetite and reduced defaecation. Nine animals had bradycardia. The dominant laboratory findings were increased concentrations of total protein and fibrinogen. Sixteen cows were slaughtered at the clinic. Six of these had signs of peritonitis in the cranial part of the abdomen, which had started from foreign body peritonitis. Six cows had abscesses between reticulum and liver, also starting from a foreign body, one cow had one isolated abscess in the liver and one cow severe fatty degeneration of the liver. In 2 cows no pathological changes could be found on the occasion of slaughter.


Fibroblast-derived dermal matrix drives development of aggressive cutaneous squamous cell carcinoma in patients with recessive dystrophic epidermolysis bullosa.
Patients with the genetic skin blistering disease recessive dystrophic epidermolysis bullosa (RDEB) develop aggressive cutaneous squamous cell carcinoma (cSCC). Metastasis leading to mortality is greater in RDEB than in other patient groups with cSCC. Here we investigate the dermal component in RDEB using mRNA expression profiling to compare cultured fibroblasts isolated from individuals without cSCC and directly from tumor matrix in RDEB and non-RDEB samples. Although gene expression of RDEB normal skin fibroblasts resembled that of cancer-associated fibroblasts, RDEB cancer-associated fibroblasts exhibited a distinct and divergent gene expression profile, with a large proportion of the differentially expressed genes involved in matrix and cell adhesion. RDEB cancer-associated fibroblasts conferred increased adhesion and invasion to tumor and nontumor keratinocytes. Reduction of COL7A1, the defective gene in RDEB, in normal dermal fibroblasts led to increased type XII collagen, thrombospondin-1, and Wnt-5A, while reexpression of wild type COL7A1 in RDEB fibroblasts decreased type XII collagen, thrombospondin-1, and Wnt-5A expression, reduced tumor cell invasion in organotypic culture, and restricted tumor growth in vivo. Overall, our findings show that matrix composition in patients with RDEB is a permissive environment for tumor development, and type VII collagen directly regulates the composition of matrix proteins secreted by dermal and cancer-associated fibroblasts.


Paleomagnetic age for hominid fossils at Atapuerca archaeological site, Spain.
A paleomagnetic investigation at the Gran Dolina site excavation (Atapuerca, Spain) shows that the sediments containing the recently discovered human occupation were deposited more than 780,000 years ago, near the time of the Matuyama-Brunhes boundary. Forty-one oriented samples were obtained from 22 sites along an 18-meter section of the Gran Dolina karst filling. The lower 16 sites displayed reversed-polarity magnetizations whereas the upper six sites were normal. The reversal spans the hominid finds at stratigraphic level TD6 (the Aurora stratum), and these hominid fossils are therefore the oldest in southern Europe.


Body mass index and waist circumference cut-points in multi-ethnic populations from the UK and India: the ADDITION-Leicester, Jaipur heart watch and New Delhi cross-sectional studies.
To derive cut-points for body mass index (BMI) and waist circumference (WC) for minority ethnic groups that are risk equivalent based on endogenous glucose levels to cut-points for white Europeans (BMI 30 kg/m2; WC men 102 cm; WC women 88 cm). Cross-sectional data from participants aged 40-75 years: 4,672 white and 1,348 migrant South Asian participants from ADDITION-Leicester (UK) and 985 indigenous South Asians from Jaipur Heart Watch/New Delhi studies (India). Cut-points were derived using fractional polynomial models with fasting and 2-hour glucose as outcomes, and ethnicity, objectively-measured BMI/WC, their interaction and age as covariates. Based on fasting glucose, obesity cut-points were 25 kg/m2 (95% Confidence Interval: 24, 26) for migrant South Asian, and 18 kg/m2 (16, 20) for indigenous South Asian populations. For men, WC cut-points were 90 cm (85, 95) for migrant South Asian, and 87 cm (82, 91) for indigenous South Asian populations. For women, WC cut-points were 77 cm (71, 82) for migrant South Asian, and 54 cm (20, 63) for indigenous South Asian populations. Cut-points based on 2-hour glucose were lower than these. These findings strengthen evidence that health interventions are required at a lower BMI and WC for South Asian individuals. Based on our data and the existing literature, we suggest an obesity threshold of 25 kg/m2 for South Asian individuals, and a very high WC threshold of 90 cm for South Asian men and 77 cm for South Asian women. Further work is required to determine whether lower cut-points are required for indigenous, than migrant, South Asians.


Acupuncture in living liver and kidney donors: a feasibility study.
The purpose of this study was to test the feasibility of integrating acupuncture into the routine care of living liver and kidney donors during the process of donation and recovery. This is a pilot study on the feasibility of a brief acupuncture intervention for living liver and kidney donors. Participants received acupuncture immediately prior to organ donation surgery, every day as inpatients, while recovering from donation, and at a 2-week follow-up. Prior to surgery, questionnaires were completed on acupuncture outcome expectations and the State-Trait Anxiety Inventory. After participating, those who received acupuncture provided feedback. Following the active intervention, a retrospective chart review was conducted, using donors who did not receive acupuncture as a comparison cohort. Forty donor candidates were approached and recruited, 32 consented and ultimately 25 donors participated in the acupuncture intervention (15 of kidney, 10 of liver), 68% female, and 88% Caucasian; only one had prior experience with acupuncture. Participants received an average of 4 sessions while inpatient (range 2-8). Those who expected acupuncture to be more helpful prior to the intervention reported lower inpatient pain scores (P = 0.04). Qualitative feedback from patients was predominantly positive, indicating acupuncture was helpful for relaxation and pain. However, a few patients reported feeling overburdened during postdonation recovery, and that the study was viewed as additional obligation. Preliminary findings suggest it is feasible to integrate acupuncture into inpatient recovery for living organ donation. Tailoring interventions to the specific needs of patients is important to address ongoing concerns. Larger studies are needed to further ascertain benefits of peri-operative acupuncture.


[Correlation analysis on changes between cognitive ability and brain fMRI after acupoint thread embedding in Alzheimer's disease patients].
To explore the mechanism of acupoint thread embedding (ATE) in treating Alzheimer's disease (AD) by means of brain functional magnetic resonance imaging (fMRI). Twenty-six patients with mild to moderate AD were assigned to the tested group and the control group in pairing, 13 in each group. ATE was performed in patients of the tested group at Shenmen (HT7), Fenglong (ST40), Taixi (KI3) and Zusanli (ST36) acupoints, once every month for 6 times in total; but for patients of the control group only sham operation was done at the same acupoints. The correlation between cognitive ability and fMRI were assessed by comparing the scores of Mini-Mental State Examination (MMSE) and Alzhemer's Disease Assessment Scale-Cognitive section (ADAS-Cog), monitored at two time points, namely, in one week before starting treatment and 1 week after terminating 6-month treatment. Furthermore, fMRI was detected to obtain the data of the cerebral blood oxygen content before treatment and 6 months after completing the 6-month therapeutic course. Correlation analysis was conducted on the obtained data using software SPM. After treatment, changes of MMSE score significently increased in the test group (P < 0.01) and decreased in the control group (P < 0.01), and ADAS-Cog decreased in the test group (P < 0.01) and increased in the control group (P < 0.05), showing statistical significance between the two groups (P < 0.01, P < 0.05). The activated regions related with the change of MMSE were mainly inferior frontal gyrus, middle frontal gyrus, superior frontal gyrus, transverse temporal gyrus, on the left cerebrum and superior frontal gyrus, middle frontal gyrus, precentral gyrus, hippocampal gyrus, cingulate gyrus, postcentral gyrus, paracentral lobule on the right cerebrum; those related with change of ADAS-Cog were superior frontal gyrus, middle frontal gyrus, fusiform gyrus, inferior temporal gyrus, hippocampal gyrus on the left cerebrum, and superior frontal gyrus, middle frontal gyrus, precentral gyrus, fusiform gyrus, transverse temporal gyrus, postcentral gyrus, middle occipital gyrus on the right cerebrum. ATE could improve the cognitive ability of AD patients, its possible mechanism may be through the activation on the cognition related regions of frontal, temporal lobe and marginal system, as well as those of cerebellum.


Evaluation of stroke incidence with duty-cycled multielectrode-phased radiofrequency ablation of persistent atrial fibrillation results of the VICTORY AF Study.
The VICTORY AF Study was designed to evaluate the risk of the procedure and/or device-related strokes in patients with PersAF on warfarin undergoing ablation with a phased radiofrequency (RF) system. The VICTORY AF trial was a prospective, multicenter, single-arm, investigational study. PersAF patients on vitamin K antagonism without major structural heart disease or history of stroke/transient ischemic attack undergoing phased RF ablation for atrial fibrillation (AF) were included. The primary outcome was the incidence of the procedure and/or device-related stroke within 30 days of the ablation by a board-certified neurologist's assessment. The secondary outcomes were an acute procedural success, 6 months effectiveness (defined as the reduction in AF/atrial flutter episodes lasting ≥10 minutes by 48-hour Holter 6 months postablation) and the number of patients with pulmonary vein (PV) stenosis. A total of 129 (108 PersAF, 21 long-standing PersAF) patients were treated (mean age: 60.6 ± 7.7; 79.8% male, 54.3% CHA2Ds2-VASc score ≥ 2). Two nondisabling strokes were reported (1.6%); one before discharge and the second diagnosed at the 30-day visit. Due to slow enrollment, the study was terminated before reaching the 95% one-sided upper confidence boundary for stroke incidence. Acute procedural success was 93.8%, and at 6 months, 72.8% of patients demonstrated ≥90% reduction in AF burden, 78.9% were off all antiarrhythmic drugs. There were no patients with PV stenosis of greater than 70%. VICTORY AF demonstrated a 1.6% incidence of stroke in PersAF undergoing ablation with a phased RF system which did not meet statistical confidence due to poor enrollment. The secondary outcomes suggest comparable efficacy to phased RF in the tailored treatment of permanent AF trial. Rigorous clinical evaluation of the stroke risk of new AF ablation technologies as well as restriction to Vitamin K antagonist anticoagulation appears to be unachievable goals in a clinical multicenter IDE trial of AF ablation in the current era.


Effects of nutrient deprivation on Vibrio cholerae.
Environmental and clinical strains of Vibrio cholerae were exposed to nutrient-free artificial seawater and filtered natural seawater microcosms for selected time intervals and examined for changes in cell morphology and number. Cells observed by transmission electron and epifluorescence microscopy were found to undergo gross alterations in cell morphology with time of exposure. The vibroid cells decreased in volume by 85% and developed into small coccoid forms surrounded by remnant cell walls. The initial number of cells inoculated into nutrient-free microcosms (culturable count and direct viable count) increased 2.5 log10 within 3 days, and even after 75 days the number of viable cells was still 1 to 2 log10 higher than the initial inoculum size. Nutrient-depleted coccoid-shaped cells were restored to normal size and assumed a bacillary shape within 3 h and began to divide within 5 h after nutrient supplementation. The increase in cell number and decrease in cell volume under nutrient-depleted conditions, as well as the rapid growth response after nutrient supplementation, may describe some of the survival mechanisms of V. cholerae in the aquatic environment.


Diffuse ultrasonic backscatter using a multi-Gaussian beam model.
Diffuse ultrasonic backscatter is widely used to evaluate microstructural parameters of heterogeneous materials. Recent singly scattered response (SSR) models utilize a single-Gaussian beam (SGB) assumption which is expected to have limitations. Following a similar formalism, a model is presented using a multi-Gaussian beam (MGB) assumption to characterize the transducer beam for longitudinal-to-longitudinal scattering at normal incidence through an interface with arbitrary curvature. First, the Wigner transform of the transducer field is defined using conjugate double-layer MGB expressions. The theoretical analysis shows that ten groups of Gaussian beams are sufficient for convergence. Compared with the SGB-SSR curve, the shape of MGB-SSR curve is positive skewed. Differences between the MGB-SSR model and the SGB-SSR model are quantified and shown to be complex functions of frequency, sample curvature, transducer parameters, and focal depth in the material. Finally, both models are used to fit experimental spatial variance data from a 304 stainless steel pipe with planar, convex, and concave surfaces. The results show that the MGB-SSR has some characteristics suggesting a better fit to the experiments. However, both models result in grain size estimates within the uncertainty of the optical microscopy suggesting that the SGB is sufficient for normal incidence pulse-echo measurements.


Deep-tissue reporter-gene imaging with fluorescence and optoacoustic tomography: a performance overview.
A primary enabling feature of near-infrared fluorescent proteins (FPs) and fluorescent probes is the ability to visualize deeper in tissues than in the visible. The purpose of this work is to find which is the optimal visualization method that can exploit the advantages of this novel class of FPs in full-scale pre-clinical molecular imaging studies. Nude mice were stereotactically implanted with near-infrared FP expressing glioma cells to from brain tumors. The feasibility and performance metrics of FPs were compared between planar epi-illumination and trans-illumination fluorescence imaging, as well as to hybrid Fluorescence Molecular Tomography (FMT) system combined with X-ray CT and Multispectral Optoacoustic (or Photoacoustic) Tomography (MSOT). It is shown that deep-seated glioma brain tumors are possible to visualize both with fluorescence and optoacoustic imaging. Fluorescence imaging is straightforward and has good sensitivity; however, it lacks resolution. FMT-XCT can provide an improved rough resolution of ∼1 mm in deep tissue, while MSOT achieves 0.1 mm resolution in deep tissue and has comparable sensitivity. We show imaging capacity that can shift the visualization paradigm in biological discovery. The results are relevant not only to reporter gene imaging, but stand as cross-platform comparison for all methods imaging near infrared fluorescent contrast agents.


Introducing research initiatives into healthcare: what do doctors think?
Current national and international policies emphasize the need to develop research initiatives within our health care system. Institutional biobanking represents a modern, large-scale research initiative that is reliant upon the support of several aspects of the health care organization. This research project aims to explore doctors' views on the concept of institutional biobanking and to gain insight into the factors which impact the development of research initiatives within healthcare systems. Qualitative research study using semi-structured interviews. The research was conducted across two public teaching hospitals in Sydney, Australia where institutional biobanking was being introduced. Twenty-five participants were interviewed, of whom 21 were medical practitioners at the specialist trainee level or above in a specialty directly related to biobanking; four were key stakeholders responsible for the design and implementation of the biobanking initiative. All participants strongly supported the concept of institutional biobanking. Participants highlighted the discordance between the doctors who work to establish the biobank (the contributors) and the researchers who use it (the consumers). Participants identified several barriers that limit the success of research initiatives in the hospital setting including: the 'resistance to change' culture; the difficulties in engaging health professionals in research initiatives; and the lack of incentives offered to doctors for their contribution. Doctors positively valued the opportunity to advise the implementation team, and felt that the initiative could benefit from their knowledge and expertise. Successful integration of research initiatives into hospitals requires early collaboration between the implementing team and the health care professionals to produce a plan that is sensitive to the needs of the health professionals and tailored to the hospital setting. Research initiatives must consider incentives that encourage doctors to adopt operational responsibility for hospital research initiatives.


Definitions of healing and healing interventions across different cultures.
For centuries healing has been embedded in non-Western cultures. Traditional cultures believe that healing is derived from the divine and utilize a holistic approach to healing including the body, mind, and spirit. The community and environment are key elements in individual healing along with herbal remedies and ceremonies. Western cultures have accepted some traditional methods of relaxation and exercise, such as yoga and tai chi. In this paper we will examine some similar themes of traditional practices to better understand traditional patients' healing paradigm and find new tools as practitioners of Western medicine.


The genomic and epigenomic landscape in thymic carcinoma.
Thymic carcinoma (TC) is a rare cancer whose genomic features have been examined in only a limited number of patients of European descent. Here, we characterized both genomic and epigenomic aberrations by whole exome sequencing, RNA sequencing, methylation array and copy number analyses in TCs from Asian patients and compared them with those in TCs from USA/European patients. Samples analyzed were 10 pairs of snap-frozen surgical specimens of cancerous and non-cancerous thymic tissue. All 10 cases were Japanese patients treated at the National Cancer Center Hospital, Japan, between 1994 and 2010. Mutational signature analysis indicated that the accumulation of age-related mutations drive TC development. We identified recurrent somatic mutations in TET2, CYLD, SETD2, TP53, FBXW7, HRAS and RB1, and no mutations in GTF2I, supporting the hypothesis that TC and thymoma are distinguishable by their genetic profiles. TCs with TET2 mutations had more hypermethylated genes than those without, and hyper-methylation was associated with downregulation of gene expression. Focal genome copy number gains, associated with elevated gene expression, were observed at the KIT (which is known to drive thymic carcinogenesis) and AHNAK2 gene loci. Taken together, the results suggest that the molecular processes leading to TC depend on the accumulation of genetic and epigenetic aberrations. In addition, epigenetic dysregulation as a result of the TET2 mutation was observed in a subset of TCs.


Paradoxical Expectation: Oscillatory Brain Activity Reveals Social Interaction Impairment in Schizophrenia.
People with schizophrenia show social impairments that are related to functional outcomes. We tested the hypothesis that social interaction impairments in people with schizophrenia are related to alterations in the predictions of others' behavior and explored their underlying neurobiological mechanisms. Electroencephalography was performed in 20 patients with schizophrenia and 25 well-matched control subjects. Participants played as proposers in the repeated version of the Ultimatum Game believing that they were playing with another human or with a computer. The power of oscillatory brain activity was obtained by means of the wavelet transform. We performed a trial-by-trial correlation between the oscillatory activity and the risk of the offer. Control subjects adapted their offers when playing with computers and tended to maintain their offers when playing with humans, as such revealing learning and bargaining strategies, respectively. People with schizophrenia presented the opposite pattern of behavior in both games. During the anticipation of others' responses, the power of alpha oscillations correlated with the risk of the offers made, in a different way in both games. Patients with schizophrenia presented a greater correlation in computer games than in human games; control subjects showed the opposite pattern. The alpha activity correlated with positive symptoms. Our results reveal an alteration in social interaction in patients with schizophrenia that is related to oscillatory brain activity, suggesting maladjustment of expectation when patients face social and nonsocial agents. This alteration is related to psychotic symptoms and could guide further therapies for improving social functioning in patients with schizophrenia.


Sudemycin E influences alternative splicing and changes chromatin modifications.
Sudemycin E is an analog of the pre-messenger RNA splicing modulator FR901464 and its derivative spliceostatin A. Sudemycin E causes the death of cancer cells through an unknown mechanism. We found that similar to spliceostatin A, sudemycin E binds to the U2 small nuclear ribonucleoprotein (snRNP) component SF3B1. Native chromatin immunoprecipitations showed that U2 snRNPs physically interact with nucleosomes. Sudemycin E induces a dissociation of the U2 snRNPs and decreases their interaction with nucleosomes. To determine the effect on gene expression, we performed genome-wide array analysis. Sudemycin E first causes a rapid change in alternative pre-messenger RNA splicing, which is later followed by changes in overall gene expression and arrest in the G2 phase of the cell cycle. The changes in alternative exon usage correlate with a loss of the H3K36me3 modification in chromatin encoding these exons. We propose that sudemycin E interferes with the ability of U2 snRNP to maintain an H3K36me3 modification in actively transcribed genes. Thus, in addition to the reversible changes in alternative splicing, sudemycin E causes changes in chromatin modifications that result in chromatin condensation, which is a likely contributing factor to cancer cell death.


Survey of psychological disturbance in patients attending a sexually transmitted diseases clinic.
A survey of psychological disturbance was conducted in a sexually transmitted disease (STD) clinic, using the general health questionnaire, the Crown-Crisp experiential index, and the illness concern questionnaire. Of 381 patients who completed the questionnaire, 158 (43%) had general health questionnaire scores indicating that they were psychiatric cases. Psychological disturbance was more common in women. The association between general health questionnaire caseness and patients' reports of concerns and worries about illness in relation to their presenting complaint was significant. The Crown-Crisp experiential index scores of cases were lower than those characteristic of patients attending psychiatric clinics, and much of the psychological disturbance found by this and other surveys of STD clinics may therefore represent distress in relation to the presenting problem. Of the 381 patients, 14 (4%) appeared to have an abnormal or unwarranted level of distress in relation to their presenting complaint.


Chiasma derived genetic maps and recombination fractions: chromosome 13 with reference to the proposed 13q14 retinoblastoma locus.
Provided that there is no chromatid interference, no movement of chiasmata, and no discrepancies between meiotic and mitotic chromosome lengths, then genetic maps and recombination fractions may be directly derived from our meiotic chiasma distribution data. This is illustrated by male chiasma derived genetic lengths and recombination fractions along chromosome 13. The recombination fraction between 13p fluorescent markers and the proposed retinoblastoma locus at 13q14 is estimated at 0.27 to 0.37 and preliminary female chiasma studies suggest a recombination fraction of 0.5 between these two sites. Therefore, it seems unlikely that 13p fluorescent markers may be of any practical help in identifying retinoblastoma gene carriers. This is also borne out by the discordant segregation which has been found in six out of seven retinoblastoma families, which gives a calculated recombination fraction of 0.39 (SE 0.15), not significantly different from 0.5.


Absence of p53 in Clara cells favours multinucleation and loss of cell cycle arrest.
The p53 oncosuppressor protein is a critical mediator of the response to injury in mammalian cells and is mutationally inactivated in the majority of lung malignancies. In this analysis, the effects of p53-deficiency were investigated in short-term primary cultures of murine bronchiolar Clara cells. Clara cells, isolated from gene-targeted p53-deficient mice, were compared to cells derived from wild type littermates. p53 null cultures displayed abnormal morphology; specifically, a high incidence of multinucleation, which increased with time in culture. Multinucleated cells were proficient in S phase DNA synthesis, as determined by BrdU incorporation. However, multinucleation did not reflect altered rates of S phase synthesis, which were similar between wild type and p53-/- cultures. Nucleation defects in p53-/- Clara cells associated with increased centrosome number, as determined by confocal microscopy of pericentrin-stained cultures, and may highlight a novel role of p53 in preserving genomic integrity in lung epithelial cells. Effects of p53-deficiency were also studied following exposure to DNA damage. A p53-dependent reduction in the BrdU index was observed in Clara cells following ionizing radiation. The reduction in BrdU index in wild type cells displayed serum-dependency, and occurred only in the absence of serum. Taken together, these findings demonstrate that in murine primary Clara cell culture, cell cycle arrest is a p53-mediated response to DNA damage, and that extracellular factors, such as serum, influence this response. These findings highlight functions of wild type p53 protein in bipolar spindle formation, centrosome regulation, and growth control in bronchiolar Clara cells.


Mental and physical activities delay cognitive decline in older persons with dementia.
To examine the effects of cognitive stimulation (mahjong) and physical exercise (tai chi [TC]) on cognitive performance in persons with dementia. Cluster-randomized open-label controlled design. Nursing homes. One hundred ten residents, most of whom were cholinesterase-inhibitor naive. Inclusion criteria were Mini-Mental State Examination (MMSE) = 10-24 and suffering from at least very mild dementia (Clinical Dementia Rating ≥ 0.5). Exclusion criteria were being bedbound, audio/visual impairment, regular activity participation before study, or contraindications for physical or group activities. Homes were randomized into three conditions (mahjong, TC, and simple handicrafts [control]). Activities were conducted three times weekly for 12 weeks. Primary outcome was MMSE. Secondary outcomes were immediate/delayed recall, categorical fluency, and digit span. Various biological risk factors, including apolipoprotein E ε4 allele, were included as covariates. Measures were collected at 0 (baseline), 3 (posttreatment), 6, and 9 months. Intent-to-treat analyses were performed using mixed-effects regression. Mahjong's effect varied by time for MMSE, delayed recall, and forward digit span. TC had similar effects but not for delayed recall. The typical pattern was that control participants deteriorated while mahjong and TC participants maintained their abilities over time, leading to enlarged treatment effects as time progressed. By 9 months, mahjong and TC differed from control by 4.5 points (95% confidence interval: 2.0-6.9; d = 0.48) and 3.7 points (95% confidence interval: 1.4-6.0; d = 0.40), respectively, on MMSE. No treatment effects were observed for immediate recall and backward digit span. Mahjong and TC can preserve functioning or delay decline in certain cognitive domains, even in those with significant cognitive impairment.


The attraction of yellow corn: reduced attentional constraints on coding learned conjunctive relations.
Physiological evidence indicates that different visual features are computed quasi-independently. The subsequent step of binding features, to generate coherent perception, is typically considered a major rate-limiting process, confined to one location at a time and taking 25 ms per item or longer (A. Treisman & S. Gormican, 1988, Feature analysis in early vision: Evidence from search asymmetries, Psychological Review, Vol. 95, pp. 15-48). We examined whether these processing limitations remain once bindings are learned for familiar objects. Participants searched for objects that could appear either in familiar or unfamiliar colors. Objects in familiar colors were detected efficiently at rates consistent with simultaneous binding across multiple stimuli. Processing limitations were evident for objects in unfamiliar colors. The advantage for the learned color for known targets was eliminated when participants searched for geometric shapes carrying the object colors and when the colors fell in local background areas around the shapes. The effect occurred irrespective of whether the nontargets had familiar colors, but was largest when nontargets had incorrect colors. The efficient search for targets in familiar colors held, even when the search was biased to favor objects in unfamiliar colors. The data indicate that learned bindings can be computed with minimal attentional limitations, consistent with the direct activation of learned conjunctive representations in vision.


The PurR regulon in Lactococcus lactis - transcriptional regulation of the purine nucleotide metabolism and translational machinery.
Purine nucleotides are either synthesized de novo from 5-phosphoribosyl-1-pyrophosphate (PRPP) or salvaged from the environment. In Lactococcus lactis, transcription of the de novo synthesis operons, purCSQLF and purDEK, has genetically been shown to be activated by the PurR protein when bound to a conserved PurBox motif present on the DNA at a fixed distance from the promoter -10 element. PurR contains a PRPP-binding site, and activation occurs when the intracellular PRPP pool is high as a consequence of low exogenous purine nucleotide pools. By an iterative approach of bioinformatics searches and motif optimization, 21 PurR-regulated genes were identified and used in a redefinition of the PurBox consensus sequence. In the process a new motif, the double-PurBox, which is present in a number of promoters and contains two partly overlapping PurBox motifs, was established. Transcriptional fusions were used to analyse wild-type promoters and promoters with inactivating PurBox mutations to confirm the relevance of the PurBox motifs as PurR-binding sites. The promoters of several operons were shown to be devoid of any -35 sequence, and found to be completely dependent on PurR-mediated activation. This suggests that binding of the PurR protein to the PurBox takes over the role of the -35 sequence. The study has expanded the PurR regulon to include promoters in nucleotide metabolism, C(1) compound metabolism, phosphonate transport, pyrophosphatase activity, (p)ppGpp metabolism, and translation-related functions. Of special interest is the presence of PurBox motifs in rrn promoters, suggesting a novel connection between nucleotide availability and the translational machinery.


Leptin, MUC2 and mTOR in appendiceal mucinous neoplasms.
Leptin contributes to mucin production in colonic epithelium and regulates carcinogenesis via various signalling pathways. We evaluated the proteins involved in mucin-producing carcinogenesis and putative targets for molecular therapy in appendiceal mucinous neoplasms. Immunohistochemistry and fluorescence in situ hybridization were performed in 22 cases of appendiceal mucinous adenoma, 20 mucinous neoplasms of uncertain malignant potential and 14 mucinous adenocarcinomas. Leptin, MUC2, MUC5AC, mTOR and ERK were more frequently immunopositive in mucinous adenocarcinomas compared with mucinous adenomas or mucinous neoplasms of uncertain malignant potential (p < 0.05). STAT3 revealed immunopositivity in 82% of tumours, regardless of tumour category. MUC2 immunopositivity was associated with pseudomyxoma peritonei (p < 0.05). None of the tumours exhibited c-kitimmunoexpression, amplification of Her2 or EGFR, or translocation of ALK. The mTOR-immunopositive group of patients had a lower rate of disease-free survival compared with the mTOR-immunonegative group (p < 0.05). Leptin may collaborate with MUC2 and MUC5AC in mucin-producing carcinogenesis in an mTOR-, STAT3- and ERK-dependent manner. STAT3 may be activated early during tumorigenesis. MUC2 and mTOR (but not c-kit, Her2, EGFR and ALK) may represent targets for molecular therapy in pseudomyxoma peritonei and appendiceal mucinous adenocarcinoma, respectively.


Inverse changes in plasma tetranectin and titin levels in patients with type 2 diabetes mellitus: a potential predictor of acute myocardial infarction?
An early intervention using biomarkers to predict acute myocardial infarction (AMI) will effectively reduce global heart attack incidence, particularly among high-risk patients with type 2 diabetes mellitus (T2DM). This study attempted to identify potential biomarkers by detecting changes in the levels of plasma proteins in T2DM patients following onset of AMI in comparison with those without AMI. Volunteer T2DM patients without AMI (control; n=10) and T2DM patients with AMI (n=10) were recruited. Plasma samples from these patients were evaluated via two-dimensional gel electrophoresis (2DE) to screen for proteins with level changes between the two groups. The abundance of spots on gel images was analyzed using Progenesis SameSpots and subjected to false discovery rate (FDR) analysis. Protein spots with statistically significant changes of at least 1.5 fold were selected for mass spectrometry (MS) analysis. Due to strong cardiac connections, tetranectin and titin were evaluated by enzymelinked immunosorbent assay (ELISA). The adjusted P-values and fold changes between the two groups resulted in identification of 34 protein spots with significantly altered abundance. Upon MS analysis, 17 plasma proteins were identified: tetranectin, titin, clusterin, haptoglobin, myosin-13, zinc fnger protein 445, DNA repair protein RAD50, serum albumin, apolipoprotein A-IV, caspase-6, aminoacyl tRNA synthase complex-interacting multifunctional protein 1, serotransferrin, retinol-binding protein 4, transthyretin, alpha-1-antitrypsin, apolipoprotein A-I and serum amyloid A. Comparable patterns of changes in tetranectin and titin between the control and AMI groups were confirmed using ELISA. In summary, tetranectin and titin in plasma appeared to be closely associated with the onset of AMI among T2DM patients and can be used as potential biomarkers for prediction of a cardiac event, though this requires validation in a prospective cohort study.


Information related to prenatal genetic counseling: interpretation by adolescents, effects on risk perception and ethical implications.
Being raised in the genomic era may not only increase knowledge of available genetic testing but may also have an impact on how genetic information is perceived. However, little is known about how current adolescents react to the language commonly used by health care professionals providing prenatal counseling. In addition, as risk communication is related to numbers and figures, having different educational backgrounds may be associated with variability in risk perceptions. In order to investigate these issues, a previously developed questionnaire studying different ways of being told about hypothetical anomalies in a baby and corresponding risks (Abramsky and Fletcher Prenatal Diagnosis 22(13):1188-1194, 2002) was administered to high-school students in Sweden. A total of 344 questionnaires were completed by students belonging to a natural science or a social science program. The data show that teenage participants found technical jargon and words such as rare and abnormal more worrying than the presented comparison terms. Negative framing effects and perception differences related to numeric risk formats were also present. Additionally, participants' gender and educational program did not seem to have an effect on risk assessment. In addition to reporting the questionnaire results, we discuss the ethical implications of the data based on the norm of non-directiveness and make some recommendations for practice. In general, genetic counselors should be aware that the language used within clinical services can be influential on this group of upcoming counselees.


ForVizor: Visualizing Spatio-Temporal Team Formations in Soccer.
Regarded as a high-level tactic in soccer, a team formation assigns players different tasks and indicates their active regions on the pitch, thereby influencing the team performance significantly. Analysis of formations in soccer has become particularly indispensable for soccer analysts. However, formations of a team are intrinsically time-varying and contain inherent spatial information. The spatio-temporal nature of formations and other characteristics of soccer data, such as multivariate features, make analysis of formations in soccer a challenging problem. In this study, we closely worked with domain experts to characterize domain problems of formation analysis in soccer and formulated several design goals. We design a novel spatio-temporal visual representation of changes in team formation, allowing analysts to visually analyze the evolution of formations and track the spatial flow of players within formations over time. Based on the new design, we further design and develop ForVizor, a visual analytics system, which empowers users to track the spatio-temporal changes in formation and understand how and why such changes occur. With ForVizor, domain experts conduct formation analysis of two games. Analysis results with insights and useful feedback are summarized in two case studies.


Running to stand still: adaptation and the response of plants to rapid climate change.
Climate is a potent selective force in natural populations, yet the importance of adaptation in the response of plant species to past climate change has been questioned. As many species are unlikely to migrate fast enough to track the rapidly changing climate of the future, adaptation must play an increasingly important role in their response. In this paper we review recent work that has documented climate-related genetic diversity within populations or on the microgeographical scale. We then describe studies that have looked at the potential evolutionary responses of plant populations to future climate change. We argue that in fragmented landscapes, rapid climate change has the potential to overwhelm the capacity for adaptation in many plant populations and dramatically alter their genetic composition. The consequences are likely to include unpredictable changes in the presence and abundance of species within communities and a reduction in their ability to resist and recover from further environmental perturbations, such as pest and disease outbreaks and extreme climatic events. Overall, a range-wide increase in extinction risk is likely to result. We call for further research into understanding the causes and consequences of the maintenance and loss of climate-related genetic diversity within populations.


Quit Methods Used by US Adult Cigarette Smokers, 2014-2016.
To quantify the prevalence of 10 quit methods commonly used by adult cigarette smokers, we used data from a nationally representative longitudinal (2014-2016) online survey of US adult cigarette smokers (n = 15,943). Overall, 74.7% of adult current cigarette smokers used multiple quit methods during their most recent quit attempt. Giving up cigarettes all at once (65.3%) and reducing the number of cigarettes smoked (62.0%) were the most prevalent methods. Substituting some cigarettes with e-cigarettes was used by a greater percentage of smokers than the nicotine patch, nicotine gum, or other cessation aids approved by the US Food and Drug Administration. Further research into the effectiveness of e-cigarettes as a cessation aid is warranted.


Intrasphincteric injection of botulinum toxin for suspected sphincter of Oddi dysfunction.
Botulinum toxin is a potent inhibitor of the release of acetylcholine from nerve endings. It has previously been shown that it can effectively reduce lower oesophageal sphincter pressures both in animals and humans with achalasia. This study examined the hypothesis that locally injected botulinum toxin could also reduce sphincter of Oddi pressure in patients with sphincter of Oddi dysfunction. Two patients with postcholecystectomy pain syndrome were diagnosed with sphincter of Oddi dysfunction (by biliary manometry in one patient and by hepatobiliary scanning criteria in the other). Botulinum toxin was injected into the sphincter of Oddi, by a sclerotherapy needle passed through a duodenoscope. In the first patient, intrasphincteric injection of botulinum toxin reduced sphincter pressure by about 50%, an effect that was sustained for at least four months. In the second patient, intrasphincteric injection caused about a 50% improvement in bile flow, with normalisation of scintigraphy. Neither patient showed any sustained improvement in pain despite these objective findings. Both patients eventually had endoscopic sphincterotomy, which also did not result in symptomatic improvement in either patient. No side effects were seen. Intrasphincteric botulinum toxin is a simple and effective means of lowering sphincter of Oddi pressure. This technique has potential for being useful clinically.


Prognostic value of the morning blood pressure surge in 5645 subjects from 8 populations.
Previous studies on the prognostic significance of the morning blood pressure surge (MS) produced inconsistent results. Using the International Database on Ambulatory Blood Pressure in Relation to Cardiovascular Outcome, we analyzed 5645 subjects (mean age: 53.0 years; 54.0% women) randomly recruited in 8 countries. The sleep-through and the preawakening MS were the differences in the morning blood pressure with the lowest nighttime blood pressure and the preawakening blood pressure, respectively. We computed multivariable-adjusted hazard ratios comparing the risk in ethnic- and sex-specific deciles of the MS relative to the average risk in the whole study population. During follow-up (median: 11.4 years), 785 deaths and 611 fatal and nonfatal cardiovascular events occurred. While accounting for covariables and the night:day ratio of systolic pressure, the hazard ratio of all-cause mortality was 1.32 (95% CI: 1.09 to 1.59; P=0.004) in the top decile of the systolic sleep-through MS (>or=37.0 mm Hg). For cardiovascular and noncardiovascular death, these hazard ratios were 1.18 (95% CI: 0.87 to 1.61; P=0.30) and 1.42 (95% CI: 1.11 to 1.80; P=0.005). For all cardiovascular, cardiac, coronary, and cerebrovascular events, the hazard ratios in the top decile of the systolic sleep-through MS were 1.30 (95% CI: 1.06 to 1.60; P=0.01), 1.52 (95% CI: 1.15 to 2.00; P=0.004), 1.45 (95% CI: 1.04 to 2.03; P=0.03), and 0.95 (95% CI: 0.68 to 1.32; P=0.74), respectively. Analysis of the preawakening systolic MS and the diastolic MS generated consistent results. In conclusion, a MS above the 90th percentile significantly and independently predicted cardiovascular outcome and might contribute to risk stratification by ambulatory blood pressure monitoring.


The fine structure of the renal glomerulus of the mouse.
Sections of mouse renal glomerulus fixed by perfusion with buffered osmium tetroxide solution have been studied with the electron microscope. Four components are recognized in the mouse glomerulus: epithelium, basement membrane, endothelium, and intercapillary cell. The three cellular components all display in their cytoplasm mitochondria, Golgi bodies, endoplasmic reticulum, and uncharacterized vesicles. The concepts of Hall, of Pease, and of Rhodin regarding the glomerular filtration surface are confirmed. The epithelial cells are characterized by intricate, branching, interdigitating ridge-like processes or pedicels, the summits of which press against the urinary surface of the basement membrane, covering the glomerular capillary tuft almost completely except for narrow spaces about 200 to 300 A wide between the processes. These spaces are termed the epithelial filtration slits, and are bridged by a very delicate gossamer-like membrane about 30 A thick,-the filtration slit membrane. The basement membrane is interposed everywhere between epithelial processes and endothelium, and between epithelial and intercapillary cells. The basement membrane of the filtration surface of the glomerular capillary has smooth surfaces and is about 800 A thick. It consists of three layers-a thick central lamina densa, appearing to have a very delicate felt-like structure, flanked on each side by thinner lamina rara externa and lamina rara interna. This membrane continues to the intercapillary space and makes a complicated sponge-work of varying thickness in which the intercapillary cells are enmeshed. The endothelial cells are of moderate thickness in the nuclear region, but send out thin sheet-like extensions over the filtration surface. These extensions are about 300 to 400 A thick and are characterized by numerous round endothelial filtration pores about 500 to 1000 A in diameter. The intercapillary tissue or mesangium is composed of the network of the basement membrane and the intercapillary cells. The intercapillary cells, with characteristic fine fibrillar cytoplasm, make contact with epithelial and endothelial cells and are enmeshed within the network of the basement membrane. Rounded processes of intercapillary cells penetrate into the endothelial cell through the basement membrane, and may even perforate entirely through the endothelium. Such processes are called (after Zimmermann) the intracapillary colliculi. In the endothelial cytoplasm close to the intracapillary colliculi are many dense endothelial juxtacollicular vesicles and caveolae. The cell boundaries of the endothelial cell resemble terminal bars. Some physiological speculations relating to glomerular structure are advanced. The description of Zimmermann (54), based on a light microscope study, is confirmed in many respects.