The efficiency of a volumetric alcohol tax in Australia.
In Australia and elsewhere, fiscal measures such as alcohol taxation are a commonly used intervention and cost-effective strategy to reduce alcohol consumption and associated harm. However, alcohol taxation policies distort the market for alcohol, specifically increasing the marginal cost of alcohol. It is proposed that a volumetric tax, which taxes alcohol equally across all beverage types, is less distortive of consumer preferences and more efficient at reducing alcohol consumption than the current Australian tax model, where taxes are charged at varying amounts per litre of pure alcohol, depending on the beverage type. This paper quantifies the effect of four different alcohol taxation systems, relative to the current Australian system: two different types of volumetric taxation (deadweight loss neutral and tax revenue neutral); the recent strategy trialled in Australia of increasing the tax only on ready-to-drink alcoholic beverages (i.e. premixed spirits); and a tiered tax system, which may be more politically acceptable. A partial equilibrium approach was used to measure taxation revenue, consumer welfare and consumption in alcohol markets. Estimates of taxation revenue, consumer welfare and consumption were first calculated for 2008 and then compared with the four scenarios considered. Relative to the previous alcohol taxation scheme in Australia, the taxation strategy that increased the tax solely on ready-to-drink alcoholic beverages increased taxation revenue by 479 million Australian dollars ($A), reduced pure alcohol consumption by 754 000 litres and increased the net deadweight loss of taxation by $A62 million. For a tax-neutral approach, for the same level of taxation revenue as is currently generated, a volumetric tax could substantially reduce the cost of taxation (as described by the net loss in consumer welfare) by $A177 million and reduce pure alcohol consumption by 4 68 000 litres. Under a deadweight loss-neutral scenario, for the same amount of deadweight loss generated from the previous taxation scenario, taxation revenue could be increased by $A1153 million, in addition to reducing pure alcohol consumption by 4 316 000 litres. A tiered taxation regime, as modelled here, could decrease pure alcohol consumption by 2 616 000 litres whilst increasing taxation revenue by $A1101 million. However, this scenario would also increase the deadweight loss of taxation by $A113 million. From these scenarios, it can be shown that, for the same tax revenue, consumer welfare can be reduced or, for the same level of loss to consumer welfare, taxation revenue can be increased. Both these scenarios result in a reduction of pure alcohol consumption.


Cabazitaxel for Hormone-Relapsed Metastatic Prostate Cancer Previously Treated With a Docetaxel-Containing Regimen: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.
As part of its single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the company that manufactures cabazitaxel (Jevtana®, Sanofi, UK) to submit evidence for the clinical and cost effectiveness of cabazitaxel for treatment of patients with metastatic hormone-relapsed prostate cancer (mHRPC) previously treated with a docetaxel-containing regimen. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the company's submission to NICE. Clinical evidence for cabazitaxel was derived from a multinational randomised open-label phase III trial (TROPIC) of cabazitaxel plus prednisone or prednisolone compared with mitoxantrone plus prednisone or prednisolone, which was assumed to represent best supportive care. The NICE final scope identified a further three comparators: abiraterone in combination with prednisone or prednisolone; enzalutamide; and radium-223 dichloride for the subgroup of people with bone metastasis only (no visceral metastasis). The company did not consider radium-223 dichloride to be a relevant comparator. Neither abiraterone nor enzalutamide has been directly compared in a trial with cabazitaxel. Instead, clinical evidence was synthesised within a network meta-analysis (NMA). Results from TROPIC showed that cabazitaxel was associated with a statistically significant improvement in both overall survival and progression-free survival compared with mitoxantrone. Results from a random-effects NMA, as conducted by the company and updated by the ERG, indicated that there was no statistically significant difference between the three active treatments for both overall survival and progression-free survival. Utility data were not collected as part of the TROPIC trial, and were instead taken from the company's UK early access programme. Evidence on resource use came from the TROPIC trial, supplemented by both expert clinical opinion and a UK clinical audit. List prices were used for mitoxantrone, abiraterone and enzalutamide as directed by NICE, although commercial in-confidence patient-access schemes (PASs) are in place for abiraterone and enzalutamide. The confidential PAS was used for cabazitaxel. Sequential use of the advanced hormonal therapies (abiraterone and enzalutamide) does not usually occur in clinical practice in the UK. Hence, cabazitaxel could be used within two pathways of care: either when an advanced hormonal therapy was used pre-docetaxel, or when one was used post-docetaxel. The company believed that the former pathway was more likely to represent standard National Health Service (NHS) practice, and so their main comparison was between cabazitaxel and mitoxantrone, with effectiveness data from the TROPIC trial. Results of the company's updated cost-effectiveness analysis estimated a probabilistic incremental cost-effectiveness ratio (ICER) of £45,982 per quality-adjusted life-year (QALY) gained, which the committee considered to be the most plausible value for this comparison. Cabazitaxel was estimated to be both cheaper and more effective than abiraterone. Cabazitaxel was estimated to be cheaper but less effective than enzalutamide, resulting in an ICER of £212,038 per QALY gained for enzalutamide compared with cabazitaxel. The ERG noted that radium-223 is a valid comparator (for the indicated sub-group), and that it may be used in either of the two care pathways. Hence, its exclusion leads to uncertainty in the cost-effectiveness results. In addition, the company assumed that there would be no drug wastage when cabazitaxel was used, with cost-effectiveness results being sensitive to this assumption: modelling drug wastage increased the ICER comparing cabazitaxel with mitoxantrone to over £55,000 per QALY gained. The ERG updated the company's NMA and used a random effects model to perform a fully incremental analysis between cabazitaxel, abiraterone, enzalutamide and best supportive care using PASs for abiraterone and enzalutamide. Results showed that both cabazitaxel and abiraterone were extendedly dominated by the combination of best supportive care and enzalutamide. Preliminary guidance from the committee, which included wastage of cabazitaxel, did not recommend its use. In response, the company provided both a further discount to the confidential PAS for cabazitaxel and confirmation from NHS England that it is appropriate to supply and purchase cabazitaxel in pre-prepared intravenous-infusion bags, which would remove the cost of drug wastage. As a result, the committee recommended use of cabazitaxel as a treatment option in people with an Eastern Cooperative Oncology Group performance status of 0 or 1 whose disease had progressed during or after treatment with at least 225 mg/m2 of docetaxel, as long as it was provided at the discount agreed in the PAS and purchased in either pre-prepared intravenous-infusion bags or in vials at a reduced price to reflect the average per-patient drug wastage.


Scrotal reconstruction in female-to-male transsexuals: a novel scrotoplasty.
One of the goals of genital construction in female-to-male transsexuals is the creation of an aesthetically acceptable result, both for phallus and scrotum, leaving minimal morbidity and recreating function. In the last 15 years, transsexuals have become more demanding, and scrotoplasty has received more attention than before. Traditional flaps for scrotal reconstruction in a biological male do not really apply in transsexuals: the labia majora seem to achieve the best results; still, they may not provide enough tissue and can be located much too posteriorly. Since November of 1993, more than 300 scrotal reconstructions (and radial forearm flap phalloplasties) have been performed in female-to-male transsexuals by the authors' gender team. Based on the authors' large experience, they modified previous techniques and developed a novel scrotoplasty consisting of a V-Y advancement of the major labia together with a rotation of these superiorly based labial flaps. Refinements (to achieve better sensation and shaping) are described. Twelve months after the original operation, one testicle implant and erection prosthesis procedures were performed. No major complications related to scrotoplasty occurred in the authors' series. Patients were all pleased at short- or long-term follow-up with their scrotum, located in its natural position in front of the legs. The authors' novel scrotoplasty can become the ultimate surgical technique to reconstruct the scrotum in female-to-male transsexual patients, further improving the final cosmetic result, with the possibility of enhanced erogenous sensitivity.


Metformin improves ovarian insulin signaling alterations caused by fetal programming.
Insulin resistance is the decreased ability of insulin to mediate metabolic actions. In the ovary, insulin controls ovulation and oocyte quality. Alterations in ovarian insulin signaling pathway could compromise ovarian physiology. Here, we aimed to investigate the effects of fetal programming on ovarian insulin signaling and evaluate the effect of metformin treatment. Pregnant rats were hyperandrogenized with testosterone and female offspring born to those dams were employed; at adulthood, prenatally hyperandrogenized (PH) offspring presented two phenotypes: irregular ovulatory (PHiov) and anovulatory (PHanov). Half of each group was orally treated with metformin. Metformin treatment improved the estrous cyclicity in both PH groups. Both PH groups showed low mRNA levels of IR, IRS1 and Glut4. IRS2 was decreased only in PHanov. Metformin upregulated the mRNA levels of some of the mediators studied. Protein expression of IR, IRS1/2 and GLUT4 was decreased in both PH groups. In PHiov, metformin restored the expression of all the mediators, whereas, in PHanov, metformin restored only that of IR and IRS1/2. IRS1 phosphorylation was measured in tyrosine residues, which activates the pathway, and in serine residues, which impairs insulin action. PHiov presented high IRS1 phosphorylation on tyrosine and serine residues, whereas PHanov showed high serine phosphorylation and low tyrosine phosphorylation. Metformin treatment lowered serine phosphorylation only in PHanov rats. Our results suggest that PHanov rats have a defective insulin action, partially restored with metformin. PHiov rats had less severe alterations, and metformin treatment was more effective in this phenotype.


Molecular flow resonance Raman effect from retinal and rhodopsin.
We have performed resonance enhanced Raman measurements of retinal isomers in solution (all-trans, 11-cis, 9-cis, and 13-cis) and cetyltrimethylammonium bromide (CTAB) detergent extracts of bovine rhodopsin near physiological temperatures (17 degrees C). In order to measure these photolabile systems, we have developed a general technique which allows Raman measurements of any photosensitive material. This technique involves imposing a molecular velocity transverse to the Raman exciting laser beam sufficient to ensure that any given molecule moves through the beam so that it has little probability of absorbing a photon. We have also measured the resonance Raman spectra of crystals of the same retinal isomers. The data show that each isomer has a distinct and characteristic Raman spectra and that the spectrum of 11-cis-retinal is quite similar but not identical with that of rhodopsin and similarly for 9-cis-retinal compared with isorhodopsin. In agreement with previous work, the Raman data demonstrate that retinal and opsin are joined by a protonated Schiff base. Due to the fact that the Raman spectra of 11-cis-retinal (solution) and rhodopsin show bands near 998 and 1018 cm(-1), a spectral region previously assigned to C-Me stretching motions, it is suggested that 11-cis-retinal in solution is compased of a mixture of 12-s-trans and 12-s-cis, and that the conformation of rhodopsin is (perhaps distorted) 12-s-trans.


Screening digital rectal examination and prostate cancer mortality: a population-based case-control study.
Although digital rectal examination (DRE) for the detection of prostate cancer has been recommended by many professional groups and has become part of the general physical examination, no randomized clinical trial has demonstrated the efficacy or effectiveness of this practice. We conducted a population-based case-control study to evaluate the association between DRE and prostate cancer mortality. With the resources of the Rochester Epidemiology Project, all 173 men who died of prostate cancer in Olmsted County from 1976 to 1991, who were resident at the time of diagnosis, were identified. For each case, two control patients were drawn from the population, matched for residence at the time of diagnosis in the case, birth date, and duration of medical record in Olmsted County. Trained nurse abstractors reviewed the community medical records for up to 10 years before the date of diagnosis in the case for mention of DRE and specific findings associated with each mention. Case subjects were less likely than control subjects to have had any DRE in the 10 years before diagnosis (matched odds ratio [OR] = 0.51; 95% confidence interval [CI] = 0.31, 0.84). When limited to DREs without mention of signs or symptoms that might raise suspicion of prostate cancer, the association was even stronger (OR = 0.31; 95% CI = 0.19, 0.49). Adjustment for educational attainment, marital status, and comorbid conditions did little to alter the associations. These results demonstrate a strong inverse association between DRE and prostate cancer mortality. If further research concludes this association to be causal, screening DREs may have prevented as many as 50% to 70% of deaths due to prostate cancer that might have occurred in the absence of screening.


Using Gene Transcription to Assess Ecological and Anthropological Stressors in Brown Bears.
Increasingly, population- and ecosystem-level health assessments are performed using sophisticated molecular tools. Advances in molecular technology enable the identification of synergistic effects of multiple stressors on the individual physiology of different species. Brown bears (Ursus arctos) are an apex predator; thus, they are ideal candidates for detecting potentially ecosystem-level systemic perturbations using molecular-based tools. We used gene transcription to analyze 130 brown bear samples from three National Parks and Preserves in Alaska. Although the populations we studied are apparently stable in abundance and exist within protected and intact environments, differences in transcript profiles were noted. The most prevalent differences were among locations. The transcript patterns among groups reflect the influence of environmental factors, such as nutritional status, disease, and xenobiotic exposure. However, these profiles also likely represent baselines for each unique environment by which future measures can be made to identify early indication of population-level changes due to, for example, increasing Arctic temperatures. Some of those environmental changes are predicted to be potentially positive for brown bears, but other effects such as the manifestation of disease or indirect effects of oceanic acidification may produce negative impacts.


Non-rod, non-cone photoreception in the vertebrates.
When reflected from a surface, light can provide a representation of the spatial environment, whilst gross changes in environment light can signal the time of day. The differing sensory demands of using light to detect environmental space and time appear to have provided the selection pressures for the evolution of different photoreceptor systems in the vertebrates, and probably all animals. This point has been well recognised in the non-mammals, which possess multiple opsin/vitamin A-based photoreceptor populations in a variety of sites distributed both within and outside the CNS. By contrast, eye loss in mammals abolishes all responses to light, and as a result, all photoreception was attributed to the rods and cones of the retina. However, studies over the past decade have provided overwhelming evidence that the mammalian eye contains a novel photoreceptor system that does not depend upon the input from the rods and cones. Mice with eyes but lacking rod and cone photoreceptors can still detect light to regulate their circadian rhythms, suppress pineal melatonin, modify locomotor activity, and modulate pupil size. Furthermore, action spectra for some of these responses in rodents and humans have characterised at least one novel opsin/vitamin A-based photopigment, and molecular studies have identified a number of candidate genes for this photopigment. Parallel studies in fish showing that VA opsin photopigment is expressed within sub-sets of inner retina neurones, demonstrates that mammals are not alone in having inner retinal photoreceptors. It therefore seems likely that inner retinal photoreception will be a feature of all vertebrates. Current studies are directed towards an understanding of their mechanisms, determining the extent to which they contribute to physiology and behaviour in general, and establishing how they may interact with other photoreceptors, including the rods and cones. Progress on each of these topics is moving very rapidly. As a result, we hope this review will serve as an introduction to the cascade of papers that will emerge on these topics in the next few years. We also hope to convince the more casual reader that there is much more to vertebrate photoreceptors than the study of retinal rods and cones.


ASCEND-Eye: Effects of Omega-3 Fatty Acids on Diabetic Retinopathy.
Preclinical studies support a protective role for omega-3 fatty acids (FAs) on diabetic retinopathy (DR), but these observations have not been confirmed in randomized trials. We present randomized evidence for the effects of omega-3 FAs on DR outcomes. A sub-study of the ASCEND (A Study of Cardiovascular Events iN Diabetes) double-blind, randomized, placebo-controlled trial of 1g omega-3 fatty acids (containing 460mg eicosapentaenoic acid and 380mg docosahexaenoic acid) daily for the primary prevention of serious cardiovascular events, in 15,480 UK adults at least 40 years of age, with diabetes. Linkage to electronic NHS Diabetic Eye Screening Programme records in England and Wales, and confirmation of participant-reported eye events via medical record review. Logrank and stratified logrank methods were used for intention-to-treat analyses of time until the main outcomes of interest. The primary efficacy endpoint was time to the first post-randomization recording of referable disease, a composite of referable retinopathy (R2 or R3a/s) or referable maculopathy (M1) based on the grading criteria defined by the UK National Screening Committee. Secondary and tertiary outcomes included the referable disease outcome stratified by the severity of DR at baseline, any progression in retinopathy grade, and incident diabetic maculopathy. Linkage data were obtained for 7360 participants (48% of those who were randomized in ASCEND). During their mean follow-up of 6.5 years, 548 [14.8%] had a referable disease event in the omega-3 FAs group, compared to 513 [13.9%] in the placebo group (rate ratio 1.07; 95% confidence interval: 0.95-1.20; P = 0.29). There were no statistically significant between-group differences in the proportion of events for either of the secondary or tertiary outcomes. Representing the first large-scale, prospective test of its kind, these data exclude any clinically meaningful benefits of 1g daily omega-3 FAs on DR.


Agents of Change for Mental Health: A Survey of Young People's Aspirations for Participation Across Five Low- and Middle-Income Countries.
Effective intervention, policy, and research in mental health and well-being (MHWB) require young people to be understood not only as beneficiaries, but also as active agents in codesigning and implementing initiatives. To identify pathways for young people's participation in promoting MHWB in low- and middle-income countries (LMICs), this study surveyed young people's aspirations for engagement, their spheres of influence, capacity building needs, and key barriers to participation. Using U-Report, United Nations Children's Emergency Fund's social messaging tool and data collection platform, we distributed a short quantitative survey to a nonrepresentative, but large sample of young people aged 15-29 across five LMICs: Nigeria, Brazil, Jamaica, South Africa, and Burundi. A total of 42,689 young people responded, with representation from most or all provinces within each country. Participants' average age was 23.8 years (SD = 3.77). Young people's core aspirations were to join a mental health awareness project and to support their peers. Participants considered schools and community settings to be the most important spheres for engagement. Lack of information about mental health was the main perceived barrier to participation, and mental health classes the main training need. In many countries, MHWB is not taught or discussed in schools and youth-led mental health interventions are rare. Findings from this study reveal clear aspirations for participatory engagement to promote MHWB among young people in LMICs. To support meaningful participation, policymakers and youth service providers must ensure that young people have access to mental health literacy training and opportunities to raise awareness in schools or community settings.


beta-Adrenergic receptor regulation by agonists and membrane depolarization in rat brain slices.
Rat cerebral cortex slices exposed to (-)-isoproterenol and then washed accumulated significantly less cyclic AMP when rechallenged with isoproterenol than did control slices. The isoproterenol-induced desensitization was associated with a concurrent reduction in [3H]dihydroalprenolol membrane binding but with no change in the affinity of [3H]dihydroalprenolol or isoproterenol for the binding sites. beta-Adrenergic receptor desensitization was rapidly reversed by slice depolarization with high-[K+] buffers, batrachotoxin, grayanotoxin, or veratridine, even in the continued presence of isoproterenol. Restoration of binding by grayanotoxin was prevented by tetrodotoxin or by removing Na+ from the buffer. These data demonstrate partial participation of the membrane receptor in beta-adrenergic desensitization of rat brain slices and suggest that brain beta-adrenergic receptors, like cholinergic receptors in skeletal muscle and alpha-adrenergic receptors in rat parotid, are regulated in part by membrane voltage.


A genome-wide survey of human short-term memory.
Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.


Data on projections of surface water withdrawal, consumption, and availability in the conterminous United States through the 21st century.
We report data on the projections of annual surface water demand and supply in the conterminous United States at a high spatial resolution from 2010s to the end of the 21st century, including: 1) water withdrawal and consumption in the water-use sectors of domestic, thermoelectric power generation, and irrigation; 2) availability of surface water generated from local watershed runoff, accumulated from upstream areas, and artificially transferred from other basins. These data were derived from the projected changes in climate, population, energy structure, technology and water uses. These data are related to the original article "Understanding the role of regional water connectivity in mitigating climate change impacts on surface water supply stress in the United States" (Duan et al., 2019) [1].


Zero-power infrared digitizers based on plasmonically enhanced micromechanical photoswitches.
State-of-the-art sensors use active electronics to detect and discriminate light, sound, vibration and other signals. They consume power constantly, even when there is no relevant data to be detected, which limits their lifetime and results in high costs of deployment and maintenance for unattended sensor networks. Here we propose a device concept that fundamentally breaks this paradigm-the sensors remain dormant with near-zero power consumption until awakened by a specific physical signature associated with an event of interest. In particular, we demonstrate infrared digitizing sensors that consist of plasmonically enhanced micromechanical photoswitches (PMPs) that selectively harvest the impinging electromagnetic energy in design-defined spectral bands of interest, and use it to create mechanically a conducting channel between two electrical contacts, without the need for any additional power source. Our zero-power digitizing sensor prototypes produce a digitized output bit (that is, a large and sharp off-to-on state transition with an on/off conductance ratio >1012 and subthreshold slope >9 dec nW-1) when exposed to infrared radiation in a specific narrow spectral band (∼900 nm bandwidth in the mid-infrared) with the intensity above a power threshold of only ∼500 nW, which is not achievable with any existing photoswitch technologies.


How external and internal resources influence user action: the case of infusion devices.
Human error can have potentially devastating consequences in contexts such as healthcare, but there is a rarely a simple dichotomy between errors and correct behaviour. Furthermore, there has been little consideration of how the activities of users (erroneous and otherwise) relate to the conceptual fit between user and device, despite the fact that healthcare technologies are becoming increasingly prevalent and complex. In this article, we present a study in which nurses' conceptions of infusion device practice were elicited to identify misfits. By focusing on key concepts that users work with when setting up infusions and the extent to which the system supports them, our analysis highlights how actions are influenced by the different resources available to users including: the device itself; supporting artefacts; the conceptual understanding of the user; and the community of practice the user is part of. The findings reveal the ways in which users are resourceful in their day-to-day activities and also suggest potential vulnerabilities within the wider system that could threaten patient safety. Our approach is able to make previously under-explored aspects of practice visible, thus enabling insight into how users act and why.


Tailor-made polyamide membranes for water desalination.
Independent control of the extrinsic and intrinsic properties of the polyamide (PA) selective layer is essential for designing thin-film composite (TFC) membranes with performance characteristics required for water purification applications besides seawater desalination. Current commercial TFC membranes fabricated via the well-established interfacial polymerization (IP) approach yield materials that are far from ideal because their layer thickness, surface roughness, polymer chemistry, and network structure cannot be separately tailored. In this work, tailor-made PA-based desalination membranes based on molecular layer-by-layer (mLbL) assembly are presented. The mLbL technique enables the construction of an ultrathin and highly cross-linked PA selective layer in a precisely and independently controlled manner. The mLbL-assembled TFC membranes exhibit significant enhancements in performance compared to their IP-assembled counterparts. A maximum sodium chloride rejection of 98.2% is achieved along with over 2.5 times higher water flux than the IP-assembled counterpart. More importantly, this work demonstrates the broad applicability of mLbL in fabricating a variety of PA-based TFC membranes with nanoscale control of the selective layer thickness and roughness independent of the specific polyamide chemistry.


Controlled formation of the two-dimensional TTBC J-aggregates in an aqueous solution.
Strong experimental and theoretical evidence was provided on the controlled formation of the two-dimensional J-aggregates that were assembled in the herringbone morphology. The exciton-band structure formation of 1,1',3,3'-tetraethyl-5,5',6,6'-tetrachlorobenzimidazolocarbocyanine (TTBC) J-aggregates was investigated in ionic (NaOH) aqueous solution at room temperature. The control was achieved by changing the [TTBC] at a given [NaOH], or vice versa, and was monitored through the changes in the absorption, fluorescence excitation, and emission spectra. Specific attention was paid to expose the excited-state structure and dynamics through simulations of the excitonic properties, which included diagonal energetic disorder and phonon-assisted exciton relaxation. Aggregates were characterized by an asymmetrically split Davydov pair, an H-band (approximately 500 nm, 1300 cm(-1) wide, Lorentzian-like) and a J-band (approximately 590 nm, 235 cm(-1) wide, with a band shape typical of a one-dimensional J-aggregate), whose relative intensities showed a strong dependence on the [TTBC]/[NaOH]. The H-band is favored by high [TTBC] or high [NaOH]. An explanation of the control on the aggregate formation was given by correlating the changes in the absorption with the structural modifications and the subsequent changes in the dynamics, which were induced by variations in the dye and NaOH concentrations. The J-band shape/width was attributed to disorder and disorder-induced intraband phonon-assisted exciton relaxation. The intraband processes in both bands were estimated to occur in the same time scale (about a picosecond). It has been suggested that the wide energetic gap between the Davydov split bands (3000 cm(-1)) could get bridged by the excitonic states of the loosely coupled chains, in addition to the monomeric species at low [TTBC]. Phonon-assisted interband relaxation, through the band gap states and/or directly from the H- to the J-band, are suggested for accounting the difference between the bandwidths and shapes of the two bands. Energy transfer between the H-band and the monomeric species is suggested as crucial for tuning the relative strengths of the two bands.


Dr. Haifan Lin. Interviewed by Han Lee and Rachel Rosenstein.
Dr. Haifan Lin is professor of Cell Biology at Yale University, where he studies the mechanism of stem cell self-renewal in fruit flies, mice, and human cancer cells. Recently named director of the Yale Stem Cell Center, Dr. Lin has made seminal contributions to the stem cell field, most notably his demonstration of the stem cell niche theory using the fruit fly model, his discovery of the PIWI/AGO gene family that is essential for stem cell division in diverse organisms, and his recent finding of a group of small RNAs called PIWI-interacting, or piRNAs, which may play a crucial role in stem cell proliferation and germline development. Dr. Lin's work on piRNAs was recognized by Science Magazine as a top scientific breakthrough of 2006. Recently, the Lin lab has begun exploring the role of these molecules in stem cell division and oncogenesis.


Prolonging herd immunity to cholera via vaccination: Accounting for human mobility and waning vaccine effects.
Oral cholera vaccination is an approach to preventing outbreaks in at-risk settings and controlling cholera in endemic settings. However, vaccine-derived herd immunity may be short-lived due to interactions between human mobility and imperfect or waning vaccine efficacy. As the supply and utilization of oral cholera vaccines grows, critical questions related to herd immunity are emerging, including: who should be targeted; when should revaccination be performed; and why have cholera outbreaks occurred in recently vaccinated populations? We use mathematical models to simulate routine and mass oral cholera vaccination in populations with varying degrees of migration, transmission intensity, and vaccine coverage. We show that migration and waning vaccine efficacy strongly influence the duration of herd immunity while birth and death rates have relatively minimal impacts. As compared to either periodic mass vaccination or routine vaccination alone, a community could be protected longer by a blended "Mass and Maintain" strategy. We show that vaccination may be best targeted at populations with intermediate degrees of mobility as compared to communities with very high or very low population turnover. Using a case study of an internally displaced person camp in South Sudan which underwent high-coverage mass vaccination in 2014 and 2015, we show that waning vaccine direct effects and high population turnover rendered the camp over 80% susceptible at the time of the cholera outbreak beginning in October 2016. Oral cholera vaccines can be powerful tools for quickly protecting a population for a period of time that depends critically on vaccine coverage, vaccine efficacy over time, and the rate of population turnover through human mobility. Due to waning herd immunity, epidemics in vaccinated communities are possible but become less likely through complementary interventions or data-driven revaccination strategies.


Parathyroid adenoma diagnosed on the basis of a giant cell tumor of parieto-occipital region and multifocal bone injuries.
Brown tumors are rare skeletal manifestations of hyperparathyroidism (HPT) that may mimic cancer metastases. Histopathologically, they are difficult to differentiate from other giant cell lesions. A case is presented of 41-year-old woman with giant cell tumor in parieto-occipital region with injury of external bone lamina, growing into the skull cavity. The mass was suspected of being neoplastic. Numerous osteolytic lesions in the skull skeleton and multifocal bone injuries were observed, also. Elevation in calcium (5.91 mEq/L) and parathormone (1188 ng/mL) concentrations and hypercalciuria (52 mEq/24 h) suggested the diagnosis of HPT initially manifesting as a brown tumor of the skull. Further exploration confirmed the existence of parathyroid adenoma as a cause of the disease. The key treatment for the condition was surgical excision of the adenoma followed by the normalization of parathyroid function and significant reduction in size of skull tumor and other lesions.


The validation of Implicit Association Test measures for smartphone and Internet addiction in at-risk children and adolescents.
Background Potential concerns are increasing that smartphone and Internet addictions may have deleterious effects on the mental health. Despite the recognition of the important role that implicit associations may have over explicit processes in addiction, such implicit associations have not been comprehensively investigated with respect to Internet addiction. Therefore, we modified the Implicit Association Test (IAT) for smartphone and Internet addictions and investigated its validity in children and adolescents. Methods In this experimental study, 78 at-risk children and adolescents ranging in age from 7 to 17 years completed an IAT modified with pictures captured from the most popular Internet games among youth. Furthermore, measures of Internet and smartphone addictions, mental health and problem behaviors, impulsive tendencies, self-esteem, daily stress, and quality of life were assessed simultaneously. Results Significant correlations were found between IAT D2SD scores and standardized scales for Internet (r = .28, p < .05) and smartphone (r = .33, p < .01) addictions. There were no significant correlations between IAT parameters and other scales measuring the constructs that are less relevant to the features of addiction, such as daily stress levels, impulsivity, and quality of life. Multiple regression analysis revealed that the IAT D2SD was independently and positively associated with smartphone addiction (p = .03) after controlling for other clinical correlates. Conclusions This study demonstrated good convergent and discriminant validity of this IAT as a novel measurement relating to Internet and smartphone addictions. Further longitudinal and prospective studies are needed to evaluate its potential utility in clinical and community settings.


Caloric restriction and aging: studies in mice and monkeys.
It is widely accepted that caloric restriction (CR) without malnutrition delays the onset of aging and extends lifespan in diverse animal models including yeast, worms, flies, and laboratory rodents. The mechanism underlying this phenomenon is still unknown. We have hypothesized that a reprogramming of energy metabolism is a key event in the mechanism of CR (Anderson and Weindruch 2007). Data will be presented from studies of mice on CR, the results of which lend support to this hypothesis. Effects of long-term CR (but not short-term CR) on gene expression in white adipose tissue (WAT) are overt. In mice and monkeys, a chronic 30% reduction in energy intake yields a decrease in adiposity of approximately 70%. In mouse epididymal WAT, long-term CR causes overt shifts in the gene expression profile: CR increases the expression of genes involved in energy metabolism (Higami et al. 2004), and it down-regulates the expression of more than 50 pro-inflammatory genes (Higami et al. 2006). Whether aging retardation occurs in primates on CR is unknown. We have been investigating this issue in rhesus monkeys subjected to CR since 1989 and will discuss the current status of this project. A new finding from this project is that CR reduces the rate of age-associated muscle loss (sarcopenia) in monkeys (Colman et al. 2008).


Bortezomib stabilizes mitotic cyclins and prevents cell cycle progression via inhibition of UBE2C in colorectal carcinoma.
Substantial evidence implicates the ubiquitin-conjugating enzyme E2C (UBE2C) gene, in several human cancers, including colorectal carcinoma (CRC). We therefore investigated the prognostic value of UBE2C alterations in CRC and UBE2C signaling in CRC cell lines. UBE2C protein expression and UBE2C gene copy number were evaluated on clinical samples by immunohistochemistry and fluorescence in situ hybridization in a TMA format. The effect of the proteasome inhibitor bortezomib and small-interfering RNA knockdown was assessed by apoptotic assays and immunoblotting. UBE2C dysregulation was associated with proliferative marker Ki-67, accumulation of cyclin A and B1, and a poor overall survival. UBE2C expression was an independent prognostic marker in early-stage (I and II) CRC. UBE2C depletion resulted in suppression of cellular growth and accumulation of cyclin A and B1. In vitro, bortezomib treatment of CRC cells caused inhibition of cell viability via down-regulation of UBE2C. UBE2C knockdown by bortezomib or transfection with specific small-interfering RNA against UBE2C also caused cells to be arrested at the G2/M level, leading to accumulation of cyclin A and cyclin B1. In vivo, a significant reduction in tumor volume and weight was noted in mice treated with a combination of subtoxic doses of oxaliplatin and bortezomib compared with treatment with oxaliplatin or bortezomib alone. Altogether, our results suggest that UBE2C and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention in CRC.


Minimum energy configurations of the 2-dimensional HP-model of proteins by self-organizing networks.
We use self-organizing maps (SOM) as an efficient tool to find the minimum energy configurations of the 2-dimensional HP-models of proteins. The usage of the SOM for the protein folding problem is similar to that for the Traveling Salesman Problem. The lattice nodes represent the cities whereas the neurons in the network represent the amino acids moving towards the closest cities, subject to the HH interactions. The valid path that maximizes the HH contacts corresponds to the minimum energy configuration of the protein. We report promising results for the cases when the protein completely fills a lattice and discuss the current problems and possible extensions. In all the test sequences up to 36 amino acids, the algorithm was able to find the global minimum and its degeneracies.


Kinetics of mRNA delivery and protein translation in dendritic cells using lipid-coated PLGA nanoparticles.
Messenger RNA (mRNA) has gained remarkable attention as an alternative to DNA-based therapies in biomedical research. A variety of biodegradable nanoparticles (NPs) has been developed including lipid-based and polymer-based systems for mRNA delivery. However, both systems still lack in achieving an efficient transfection rate and a detailed understanding of the mRNA transgene expression kinetics. Therefore, quantitative analysis of the time-dependent translation behavior would provide a better understanding of mRNA's transient nature and further aid the enhancement of appropriate carriers with the perspective to generate future precision nanomedicines with quick response to treat various diseases. A lipid-polymer hybrid system complexed with mRNA was evaluated regarding its efficiency to transfect dendritic cells (DCs) by simultaneous live cell video imaging of both particle uptake and reporter gene expression. We prepared and optimized NPs consisting of poly (lactid-co-glycolid) (PLGA) coated with the cationic lipid 1, 2-di-O-octadecenyl-3-trimethylammonium propane abbreviated as LPNs. An earlier developed polymer-based delivery system (chitosan-PLGA NPs) served for comparison. Both NPs types were complexed with mRNA-mCherry at various ratios. While cellular uptake and toxicity of either NPs was comparable, LPNs showed a significantly higher transfection efficiency of ~ 80% while chitosan-PLGA NPs revealed only ~ 5%. Further kinetic analysis elicited a start of protein translation after 1 h, with a maximum after 4 h and drop of transgene expression after 48 h post-transfection, in agreement with the transient nature of mRNA. Charge-mediated complexation of mRNA to NPs enables efficient and fast cellular delivery and subsequent protein translation. While cellular uptake of both NP types was comparable, mRNA transgene expression was superior to polymer-based NPs when delivered by lipid-polymer NPs.


Trends in rates of primary angle closure glaucoma and cataract surgery in England from 1968 to 2004.
Eyes that are predisposed to primary angle closure usually have a shallow anterior chamber secondary to a relatively forward position of the lens and progressive lens thickening with ageing. The aim of this study was to examine trends over time in rates of primary angle closure glaucoma (PACG) in England, and to compare these rates with rates of cataract surgery. Hospital episode statistics and the hospital inpatient inquiry were analyzed for PACG as the main diagnosis between the years 1968 and 2004, and for cataract surgery over the same period. Age-specific and sex-specific rates of PACG and cataract surgery were calculated over 3 representative time periods. Annual rates of patients with PACG did not change significantly from the late 1960s to the mid-1980s and then increased until the early 1990s before reaching a plateau; from 1999 to 2004, rates of patients with PACG declined significantly. From the 1980s to 2004, annual rates of patients undergoing cataract surgery increased significantly and substantially. In the recent period of decline in PACG, the decline was greatest in older age groups, whereas rates of cataract surgery increased significantly in all age groups for both men and women throughout the whole time period. Rates of patients with PACG have started to decline in recent years, after a long period of increases in rates of patients undergoing cataract surgery. Although other explanations are possible, this lends support to the hypothesis that cataract surgery may reduce the likelihood of acute angle closure.


Geographical differences in cancer incidence in the Amazon basin of Ecuador in relation to residence near oil fields.
Since 1972, oil companies have extracted more than 2 billion barrels of crude oil from the Ecuadorian Amazon, releasing billions of gallons of untreated wastes and oil directly into the environment. This study aimed to determine if there was any difference in overall and specific cancer incidence rates between populations living in proximity to oil fields and those who live in areas free from oil exploitation. Cancer cases from the provinces of Sucumbios, Orellana, Napo and Pastaza during the period 1985-1998 were included in the study. The exposed population was defined as those living in a county (n = 4) where oil exploitation had been ongoing for a minimum of 20 years up to the date of the study. Non-exposed counties were identified as those (n = 11) without oil development activities. Relative risks (RR) along with 95% CI were calculated for men and women as ratios of the age-adjusted incidence rates in the exposed versus non-exposed group. The RR of all cancer sites combined was significantly elevated in both men and women in exposed counties. Significantly elevated RR were observed for cancers of the stomach, rectum, skin melanoma, soft tissue and kidney in men and for cancers of the cervix and lymph nodes in women. An increase in haematopoietic cancers was also observed in the population under 10 years in the exposed counties in both males and females. Study results are compatible with a relationship between cancer incidence and living in proximity to oil fields. An environmental monitoring and cancer surveillance system in the area is recommended.


Nanoscale Assembly of Cellulose Nanocrystals during Drying and Redispersion.
We have followed the structural evolution during evaporation-induced self-assembly of sulfonated cellulose nanocrystal (CNC) in the presence of H+ and Li+ counterions by small-angle X-ray scattering. Drying of CNC-H dispersions results in ordered films that could not be readily redispersed, while the CNC-Li films were disordered and prone to reswelling and redispersion. The scaling of the separation distance (d) between CNC particles and the particle concentration (c) shows that the CNC-H dispersions display a unidimensional contraction of the nematic structure (d ∝ c-1) during drying, while the CNC-Li dispersions consolidate isotropically (d ∝ c-1/3), which is characteristic for hydrogels with no preferential orientation. Temporal evolution of the structure factor and complementary dynamic light-scattering measurements show that CNC-Li is more aggregated than CNC-H during evaporation-induced assembly. Insights on the structural evolution during CNC assembly and redispersion can promote development of novel and optimized processing routes of nanocellulose-based materials.


Association of car ownership and physical activity across the spectrum of human development: Modeling the Epidemiologic Transition Study (METS).
Variations in physical activity (PA) across nations may be driven by socioeconomic position. As national incomes increase, car ownership becomes within reach of more individuals. This report characterizes associations between car ownership and PA in African-origin populations across 5 sites at different levels of economic development and with different transportation infrastructures: US, Seychelles, Jamaica, South Africa, and Ghana. Twenty-five hundred adults, ages 25-45, were enrolled in the study. A total of 2,101 subjects had valid accelerometer-based PA measures (reported as average daily duration of moderate to vigorous PA, MVPA) and complete socioeconomic information. Our primary exposure of interest was whether the household owned a car. We adjusted for socioeconomic position using household income and ownership of common goods. Overall, PA levels did not vary largely between sites, with highest levels in South Africa, lowest in the US. Across all sites, greater PA was consistently associated with male gender, fewer years of education, manual occupations, lower income, and owning fewer material goods. We found heterogeneity across sites in car ownership: after adjustment for confounders, car owners in the US had 24.3 fewer minutes of MVPA compared to non-car owners in the US (20.7 vs. 45.1 minutes/day of MVPA); in the non-US sites, car-owners had an average of 9.7 fewer minutes of MVPA than non-car owners (24.9 vs. 34.6 minutes/day of MVPA). PA levels are similar across all study sites except Jamaica, despite very different levels of socioeconomic development. Not owning a car in the US is associated with especially high levels of MVPA. As car ownership becomes prevalent in the developing world, strategies to promote alternative forms of active transit may become important.


The relationship between cardiac endothelium and fibroblasts: it's complicated.
Coronary revascularization is an effective means of treating ischemic heart disease; however, current therapeutic revascularization strategies are limited to large caliber vessels. Because the mammalian heart scars following cardiac injury, recent work showing that cardiac fibroblasts can transdifferentiate into new coronary endothelium raises a new and exciting approach to promoting endogenous revascularization following cardiac injury. In this issue of the JCI, He et al. report on their employment of a battery of lineage-tracing tools to address the developmental origins of fibroblasts that give rise to new endothelial cells. Surprisingly, cardiac fibroblasts did not appear to contribute appreciably to regeneration of cardiac endothelium. Instead, cardiac endothelial cells were likely to proliferate and generate new endothelium following injury. As these conclusions diverge from prior findings, additional work will be required to understand the sources that generate cardiac endothelium in new blood vessels after injury. Clarification of the origins of coronary endothelial cells during cardiac repair is essential for identifying improved approaches to revascularizing damaged myocardium in patients with ischemic heart disease.


The mapping model: a cognitive theory of quantitative estimation.
How do people make quantitative estimations, such as estimating a car's selling price? Traditionally, linear-regression-type models have been used to answer this question. These models assume that people weight and integrate all information available to estimate a criterion. The authors propose an alternative cognitive theory for quantitative estimation. The mapping model, inspired by the work of N. R. Brown and R. S. Siegler (1993) on metrics and mappings, offers a heuristic approach to decision making. The authors test this model against established alternative models of estimation, namely, linear regression, an exemplar model, and a simple estimation heuristic. With 4 experimental studies the authors compare the models under different environmental conditions. The mapping model proves to be a valid model to predict people's estimates.


Influence of Ethanol on Oxycodone-induced Respiratory Depression: A Dose-escalating Study in Young and Elderly Individuals.
Respiratory depression is a potentially fatal complication of opioid use, which may be exacerbated by simultaneous ethanol intake. In this three-way sequential crossover dose-escalating study, the influence of coadministration of oral oxycodone and intravenous ethanol was assessed on resting ventilation, apneic events and the hypercapnic ventilatory response in healthy young and older volunteers. Twelve young (21 to 28 yr) and 12 elderly (66 to 77 yr) opioid-naive participants ingested one 20 mg oxycodone tablet combined with an intravenous infusion of 0, 0.5, or 1 g/l ethanol. Resting respiratory variables and the primary outcome, minute ventilation at isohypercapnia (end-tidal partial pressure of carbon dioxide of 55 mmHg or VE55), were obtained at regular intervals during treatment. Oxycodone reduced baseline minute ventilation by 28% (P < 0.001 vs. control). Ethanol caused a further decrease of oxycodone-induced respiratory depression by another 19% at 1 g/l ethanol plus oxycodone (P < 0.01 vs. oxycodone). Ethanol combined with oxycodone caused a significant increase in the number of apneic events measured in a 6-min window with a median (range) increase from 1 (0 to 3) at 0 g/l ethanol to 1 (0 to 11) at 1 g/l ethanol (P < 0.01). Mean (95% CI) VE55 decreased from 33.4 (27.9 to 39.0) l/min (control) to 18.6 (15.6 to 21.6) l/min (oxycodone, P < 0.01 vs. control) and to 15.7 (12.7 to 18.6) l/min (oxycodone combined with ethanol, 1 g/l; P < 0.01 vs. oxycodone). Ethanol together with oxycodone causes greater ventilatory depression than either alone, the magnitude of which is clinically relevant. Elderly participants were more affected than younger volunteers.


The Immune Response to Mycobacterium tuberculosis in HIV-1-Coinfected Persons.
Globally, about 36.7 million people were living with HIV infection at the end of 2015. The most frequent infection co-occurring with HIV-1 is Mycobacterium tuberculosis-374,000 deaths per annum are attributable to HIV-tuberculosis, 75% of those occurring in Africa. HIV-1 infection increases the risk of tuberculosis by a factor of up to 26 and alters its clinical presentation, complicates diagnosis and treatment, and worsens outcome. Although HIV-1-induced depletion of CD4+ T cells underlies all these effects, more widespread immune deficits also contribute to susceptibility and pathogenesis. These defects present a challenge to understand and ameliorate, but also an opportunity to learn and optimize mechanisms that normally protect people against tuberculosis. The most effective means to prevent and ameliorate tuberculosis in HIV-1-infected people is antiretroviral therapy, but this may be complicated by pathological immune deterioration that in turn requires more effective host-directed anti-inflammatory therapies to be derived.


A combination intervention addressing sexual risk-taking behaviors among vulnerable women in Uganda: study protocol for a cluster randomized clinical trial.
Sub-Saharan Africa (SSA) has the highest number of people living with HIV/AIDS, with Nigeria, South Africa, and Uganda accounting for 48% of new infections. A systematic review of the HIV burden among women engaged in sex work (WESW) in 50 low- and middle-income countries found that they had increased odds of HIV infection relative to the general female population. Social structural factors, such as the sex work environment, violence, stigma, cultural issues, and criminalization of sex work are critical in shaping sexually transmitted infection (STI)/HIV risks among WESW and their clients in Uganda. Poverty is the most commonly cited reason for involvement in sex work in SSA. Against this backdrop, this study protocol describes a randomized controlled trial (RCT) that tests the impact of adding economic empowerment to traditional HIV risk reduction (HIVRR) to reduce new incidence of STIs and HIV among WESW in Rakai and the greater Masaka regions in Uganda. This three-arm RCT will evaluate the efficacy of adding savings, financial literacy and vocational training/mentorship to traditional HIVRR on reducing new incidence of STI infections among 990 WESW across 33 hotspots. The three arms (n = 330 each) are: 1) Control group: only HIVRR versus 2) Treatment group 1: HIVRR plus Savings plus Financial Literacy (HIVRR + S + FL); and 3) Treatment group 2: HIVRR plus S plus FL plus Vocational Skills Training and Mentorship (V) (HIVRR + S + FL + V). Data will be collected at baseline (pre-test), 6, 12, 18 and 24-months post-intervention initiation. This study will use an embedded experimental mixed methods design where qualitative data will be collected post-intervention across all conditions to explore participant experiences. When WESW have access to more capital and/or alternative forms of employment and start earning formal income outside of sex work, they may be better able to improve their skills and employability for professional advancement, thereby reducing their STI/HIV risk. The study findings may advance our understanding of how best to implement gender-specific HIV prevention globally, engaging women across the HIV treatment cascade. Further, results will provide evidence for the intervention's efficacy to reduce STIs and inform implementation sustainability, including costs and cost-effectiveness. ClinicalTrials.gov , ID: NCT03583541 .


Isoflavone soy protein supplementation and atherosclerosis progression in healthy postmenopausal women: a randomized controlled trial.
Although epidemiological and experimental studies suggest that dietary intake of soy may be cardioprotective, use of isoflavone soy protein (ISP) supplementation as a primary preventive therapy remains unexplored. We determined whether ISP reduces subclinical atherosclerosis assessed as carotid artery intima-media thickness progression. In a double-blind, placebo-controlled trial, 350 postmenopausal women 45 to 92 years of age without diabetes and cardiovascular disease were randomized to 2 evenly divided daily doses of 25 g soy protein containing 91 mg aglycon isoflavone equivalents or placebo for 2.7 years. Overall, mean (95% CI) carotid artery intima-media thickness progression rate was 4.77 (3.39-6.16) μm/year in the ISP group and 5.68 (4.30-7.06) μm/year in the placebo group. Although carotid artery intima-media thickness progression was reduced on average by 16% in the ISP group relative to the placebo group, this treatment effect was not statistically significant (P=0.36). Among the subgroup of women who were randomized within 5 years of menopause, ISP participants had on average a 68% lower carotid artery intima-media thickness progression rate than placebo participants 2.16 (-1.10 to 5.43) versus 6.79 (3.56-10.01) μm/year (P=0.05). ISP supplementation had a null effect on women who were >5 years beyond menopause when randomized. There were no major adverse events from ISP supplementation. ISP supplementation did not significantly reduce subclinical atherosclerosis progression in postmenopausal women. Subgroup analysis suggests that ISP supplementation may reduce subclinical atherosclerosis in healthy young (median age, 53 years) women at low-risk for cardiovascular disease who were <5 years postmenopausal. These first trial results of their kind warrant further investigation.


A standardized protocol to reduce pediatric baclofen pump infections: a quality improvement initiative.
OBJECTIVE Intrathecal baclofen pumps are generally placed in children for the treatment of spasticity and dystonia. Use of implants in this pediatric population with comorbidities is reported to have a high risk of complications and infections. With the aim of reducing baclofen pump-related infections, a quality improvement project was instituted at the authors' institution. METHODS A workflow paradigm unique to baclofen pump implantation aimed at decreasing implant-related infections was implemented. All baclofen pump operations performed at the authors' institution between August 2012 and June 2016 were reviewed. An infection prevention protocol was created and implemented in August 2014 based on a literature review and the consensus opinion of the pediatric neurosurgeons in the group. Compliance with the prevention bundle was tracked. Case outcomes before and after implementation of the protocol with a minimum of 3 months of follow-up were retrospectively reviewed. Univariate and multivariate analyses were performed to assess the association of the steps in the prevention bundle with infection and complication outcomes. RESULTS A total of 128 baclofen pump surgeries were performed (64 preprotocol and 64 postprotocol). The patient age range was 3 to 27 years. The overall compliance rate with the infection prevention bundle was 82%. The pre- and postimplementation infection rates were 12.5% and 6.3%, respectively (p = 0.225). The total pre- and postimplementation complication rates were 23.4% and 9.4%, respectively (p = 0.032). The absolute and relative risk reductions for infections were 6.3% (95% CI 3.8%-16.3%) and 50%, respectively; for complications, the absolute and relative risk reductions were 14.1% (95% CI 1.5%-26.7%) and 60%, respectively. CONCLUSIONS The total complication rate following intrathecal baclofen pump surgery was significantly lower after implementation of the quality improvement protocol. This study is an example of using checklist standardization to diminish special cause variability.


Modulation of swimming in the gastropod Melibe leonina by nitric oxide.
Nitric oxide (NO) is a gaseous intercellular messenger produced by the enzyme nitric oxide synthase. It has been implicated as a neuromodulator in several groups of animals, including gastropods, crustaceans and mammals. In this study, we investigated the effects of NO on the swim motor program produced by isolated brains and by semi-intact preparations of the nudibranch Melibe leonina. The NO donors sodium nitroprusside (SNP, 1 mmol x l(-1)) and S-nitroso-N-acetylpenicillamine (SNAP, 1 mmol x l(-1)) both had a marked effect on the swim motor program expressed in isolated brains, causing an increase in the period of the swim cycle and a more erratic swim rhythm. In semi-intact preparations, the effect of NO donors was manifested as a significant decrease in the rate of actual swimming. An NO scavenger, reduced oxyhemoglobin, eliminated the effects of NO donors on isolated brains, supporting the assumption that the changes in swimming induced by donors were actually due to NO. The cGMP analogue 8-bromoguanosine 3',5'-cyclic monophosphate (1 mmol x l(-1)) produced effects that mimicked those of NO donors, suggesting that NO is working via a cGMP-dependent mechanism. These results, in combination with previous histological studies indicating the endogenous presence of nitric oxide synthase, suggest that NO is used in the central nervous system of Melibe leonina to modulate swimming.


A retrospective study of Babesia macropus associated with morbidity and mortality in eastern grey kangaroos (Macropus giganteus) and agile wallabies (Macropus agilis).
This is a retrospective study of 38 cases of infection by Babesia macropus, associated with a syndrome of anaemia and debility in hand-reared or free-ranging juvenile eastern grey kangaroos (Macropus giganteus) from coastal New South Wales and south-eastern Queensland between 1995 and 2013. Infection with B. macropus is recorded for the first time in agile wallabies (Macropus agilis) from far north Queensland. Animals in which B. macropus infection was considered to be the primary cause of morbidity had marked anaemia, lethargy and neurological signs, and often died. In these cases, parasitised erythrocytes were few or undetectable in peripheral blood samples but were sequestered in large numbers within small vessels of visceral organs, particularly in the kidney and brain, associated with distinctive clusters of extraerythrocytic organisms. Initial identification of this piroplasm in peripheral blood smears and in tissue impression smears and histological sections was confirmed using transmission electron microscopy and molecular analysis. Samples of kidney, brain or blood were tested using PCR and DNA sequencing of the 18S ribosomal RNA and heat shock protein 70 gene using primers specific for piroplasms. The piroplasm detected in these samples had 100% sequence identity in the 18S rRNA region with the recently described Babesia macropus in two eastern grey kangaroos from New South Wales and Queensland, and a high degree of similarity to an unnamed Babesia sp. recently detected in three woylies (Bettongia penicillata ogilbyi) in Western Australia.


Identification and activities in situ of Nitrosospira and Nitrospira spp. as dominant populations in a nitrifying fluidized bed reactor.
Bacterial aggregates from a chemolithoautotrophic, nitrifying fluidized bed reactor were investigated with microsensors and rRNA-based molecular techniques. The microprofiles of O2, NH4+, NO2-, and NO3- demonstrated the occurrence of complete nitrification in the outer 125 microgram of the aggregates. The ammonia oxidizers were identified as members of the Nitrosospira group by fluorescence in situ hybridization (FISH). No ammonia- or nitrite-oxidizing bacteria of the genus Nitrosomonas or Nitrobacter, respectively, could be detected by FISH. To identify the nitrite oxidizers, a 16S ribosomal DNA clone library was constructed and screened by denaturing gradient gel electrophoresis and selected clones were sequenced. The organisms represented by these sequences formed two phylogenetically distinct clusters affiliated with the nitrite oxidizer Nitrospira moscoviensis. 16S rRNA-targeted oligonucleotide probes were designed for in situ detection of these organisms. FISH analysis showed that the dominant populations of Nitrospira spp. and Nitrosospira spp. formed separate, dense clusters which were in contact with each other and occurred throughout the aggregate. A second, smaller, morphologically and genetically different population of Nitrospira spp. was restricted to the outer nitrifying zones.


Embryonic and larval staging of summer flounder (Paralichthys dentatus).
Early development of flatfishes such as the summer flounder Paralichthys dentatus (Pleuronectiformes) has not been extensively documented, largely because of a dearth of material; however, the recent expansion of flatfish aquaculture has made embryos of P. dentatus readily available for developmental studies. We divide development of P. dentatus embryos and larvae into two main periods, pre- and posthatching, and assign stages within each of those primary divisions. Stages from fertilization to hatching loosely follow the general teleost staging scheme suggested by Shardo ([1995] J Morphol 225:125-167); stages from hatching through metamorphosis are aligned with the series used for Japanese flounder, P. olivaceus (Minami [1982] Nippon Suisan Gakkaishi 48:1581-1588; Fukuhara [1986] Nippon Suisan Gakkaishi 52:81-91). Although length, width, and age may serve as approximate indicators of developmental progression in summer flounder, these characteristics are too variable to form the sole basis of a staging table. Therefore, we define stages by morphological criteria drawn from the development of the jaw apparatus and digestive system, eye migration, and notochord tip flexion. Examination of these morphological features in hatched larvae allows accurate and consistent assessment of developmental stage despite variation in timing and size. The staging scheme for flounder embryonic and larval development presented here should facilitate both experimental and comparative research on summer flounder and other flatfish species.


Congenital diaphragmatic hernia: 2D lung area and 3D lung volume measurements of the contralateral lung to predict postnatal outcome.
The aim of the study was to evaluate the prognostic utility of 2D lung area and 3D lung volume measurements of the contralateral lung in infants with congenital diaphragmatic hernia. At 18-37 weeks' gestation between 1 and 5 scans of the contralateral fetal lung were obtained in 6 pregnancies complicated by congenital diaphragmatic hernia (5 left- and 1 right-sided). Lung volume measurements were compared with reference curves for gestational age and estimated fetal weight obtained from uncomplicated pregnancies. Lung area measurements were compared with reference nomograms. Three infants survived and 3 died. Lung volume measurements versus gestational age were beneath the 5th percentile for the nonsurviving infants and within the normal ranges for the surviving infants. When comparing the observed/expected lung volume and lung area ratios of the first measurements with the ratios at the last visit before birth, the ratios of the infants who subsequently died decreased whereas the ratios of the infants who survived remained unchanged or increased. In the case of congenital diaphragmatic hernia, 3D lung volume measurements seem to be a good predictor of outcome but longitudinal measurement also provides important additional information. Larger studies are necessary to confirm these results.


Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNFalpha, anti-IL-1alpha/beta and IL-1Ra.
To examine the role of tumor necrosis factor alpha (TNF alpha), interleukin-1 alpha (IL-1 alpha), and IL-1 beta in collagen-induced arthritis (CIA), immediately after onset and during the phase of established arthritis. Male DBA/1 mice with collagen-induced arthritis were treated with antibodies against murine TNF alpha and IL-1 alpha/beta at different time points of the disease. IL-1 receptor antagonist (IL-1Ra) was administered using Alzet osmotic minipumps. The effect of anticytokine treatment was monitored by visual scoring. Histology and cytokine reverse transcription polymerase chain reaction (RT-PCR) analyses were performed at the end of the treatment period. Anti-TNF alpha treatment showed efficacy shortly after onset of the disease, but had little effect on fully established CIA. Histologic analysis after early treatment revealed that anti-TNF alpha significantly reduced joint pathology, as determined by infiltration of inflammatory cells and cartilage damage. Anti-IL-1 alpha/beta treatment ameliorated both early and full-blown CIA. This clear suppression of established arthritis was confirmed by administration of high doses of IL-1Ra. Dose-response experiments showed that a continuous supply of 1 mg/day was needed for optimal suppression. Histologic analysis showed markedly reduced cartilage destruction both in the knee and the ankle joints. Autoradiography demonstrated full recovery of chondrocyte synthetic function of articular cartilage. In addition, we found that the IL-1 beta isoform plays a dominant role in established CIA. Profound suppression of CIA was observed with anti-IL-1 beta, although elimination of both IL-1 alpha and IL-1 beta still gave better protection. Analysis of messenger RNA with RT-PCR revealed that IL-1 beta was highly upregulated in synovium and cartilage at late stages of CIA, whereas anti-IL-1 beta treatment markedly reduced IL-1 beta message in the synovium. The present study identified different TNF alpha/IL-1 dependencies in various stages of CIA and revealed that blocking of TNF alpha does not necessarily eliminate IL-1. Continuous, high doses of IL-1Ra are needed to block CIA.


Mutation analysis of the SLC26A4, FOXI1 and KCNJ10 genes in individuals with congenital hearing loss.
Pendred syndrome (PDS) and DFNB4 comprise a phenotypic spectrum of sensorineural hearing loss disorders that typically result from biallelic mutations of the SLC26A4 gene. Although PDS and DFNB4 are recessively inherited, sequencing of the coding regions and splice sites of SLC26A4 in individuals suspected to be affected with these conditions often fails to identify two mutations. We investigated the potential contribution of large SLC26A4 deletions and duplications to sensorineural hearing loss (SNHL) by screening 107 probands with one known SLC26A4 mutation by Multiplex Ligation-dependent Probe Amplification (MLPA). A heterozygous deletion, spanning exons 4-6, was detected in only one individual, accounting for approximately 1% of the missing mutations in our cohort. This low frequency is consistent with previously published MLPA results. We also examined the potential involvement of digenic inheritance in PDS/DFNB4 by sequencing the coding regions of FOXI1 and KCNJ10. Of the 29 probands who were sequenced, three carried nonsynonymous variants including one novel sequence change in FOXI1 and two polymorphisms in KCNJ10. We performed a review of prior studies and, in conjunction with our current data, conclude that the frequency of FOXI1 (1.4%) and KCNJ10 (3.6%) variants in PDS/DFNB4 individuals is low. Our results, in combination with previously published reports, indicate that large SLC26A4 deletions and duplications as well as mutations of FOXI1 and KCNJ10 play limited roles in the pathogenesis of SNHL and suggest that other genetic factors likely contribute to the phenotype.


Massive multiplication of genome and ribosomes in dormant cells (akinetes) of Aphanizomenon ovalisporum (Cyanobacteria).
Akinetes are dormancy cells commonly found among filamentous cyanobacteria, many of which are toxic and/or nuisance, bloom-forming species. Development of akinetes from vegetative cells is a process that involves morphological and biochemical modifications. Here, we applied a single-cell approach to quantify genome and ribosome content of akinetes and vegetative cells in Aphanizomenon ovalisporum (Cyanobacteria). Vegetative cells of A. ovalisporum were naturally polyploid and contained, on average, eight genome copies per cell. However, the chromosomal content of akinetes increased up to 450 copies, with an average value of 119 genome copies per akinete, 15-fold higher than that in vegetative cells. On the basis of fluorescence in situ hybridization, with a probe targeting 16S rRNA, and detection with confocal laser scanning microscopy, we conclude that ribosomes accumulated in akinetes to a higher level than that found in vegetative cells. We further present evidence that this massive accumulation of nucleic acids in akinetes is likely supported by phosphate supplied from inorganic polyphosphate bodies that were abundantly present in vegetative cells, but notably absent from akinetes. These results are interpreted in the context of cellular investments for proliferation following a long-term dormancy, as the high nucleic acid content would provide the basis for extended survival, rapid resumption of metabolic activity and cell division upon germination.


Hyperploidy induced by drugs that inhibit formation of microtubule promotes chromosome instability.
Antimicrotubule drugs (AMDs), such as taxol and vincristine, are the most important addition to the chemotherapeutic armamentarium against human cancers. It has been shown that prolonged AMD treatment induces hyperploidy in G1-checkpoint-defective cancer cells and that these hyperploid cells subsequently undergo apoptosis. However, a fraction of these hyperploid cells are able to survive the prolonged mitotic stress and resume cell-cycle progression. We established hyperploid clones that escaped from cell death after AMD treatment from two glioma cell lines, U251MG and U87MG. Subtractive comparative genomic hybridization (CGH) analysis revealed that clones derived from U87MG mainly had chromosome number changes, but that those from U251MG showed both numerical and structural chromosomal changes. Furthermore, numerous aberrations identified in U251MG clones were remarkably chromosome-specific, which may have been due to clonal selection for cells that have an advantage in growth and/or survival. All clones derived from both cell lines had abnormalities in chromosome segregation, and karyotypes of clones were more heterogeneous than those of parental cells, suggesting that cells having a higher chromosome number are subject to asymmetric chromosome segregation, resulting in a heterogeneous karyotype. All clones derived from U87MG and U251MG increased both centric and acentromeric micronuclei, suggesting the presence of chromosome structural abnormality. AMD treatment induces hyperploid formation and chromosome instability in checkpoint-deficient cancer cells.


A Multisite Initiative to Increase the Use of Alcohol Screening and Brief Intervention Through Resident Training and Clinic Systems Changes.
Screening and brief intervention (SBI) is a seldom-used evidence-based practice for reducing unhealthy alcohol use among primary care patients. This project assessed the effectiveness of a regional consortium's training efforts in increasing alcohol SBI. Investigators combined alcohol SBI residency training efforts with clinic SBI implementation processes and used chart reviews to assess impact on SBI rates in four residency clinics. Data were derived from a random sample of patient charts collected before (2010; n = 662) and after (2011; n = 656) resident training/clinic implementation. Patient charts were examined for evidence that patients were asked about alcohol use by a validated screening instrument, the screening result (positive or negative), evidence that patients received a brief intervention, prescriptions for medications to assist abstinence, and referrals to alcohol treatment. Chi-square analyses identified differences in pre- and posttraining implementation of SBI practices. Following program implementation, screening with validated instruments increased from 151/662 (22.8%) at baseline to 543/656 (82.8%, P < .01), and identification of unhealthy alcohol use increased from 12/662 (1.8%) to 41/656 (6.3%, P < .01). Performance of brief interventions more than doubled (10/662 [1.5%] versus 24/656 [3.7%], P < .01). There were no increases in the use of medications or referrals to treatment. Resident training combined with clinic implementation efforts can increase the delivery of evidence-based practices such as alcohol SBI in residency clinics.


Insights into the development and evolution of exaggerated traits using de novo transcriptomes of two species of horned scarab beetles.
Scarab beetles exhibit an astonishing variety of rigid exo-skeletal outgrowths, known as "horns". These traits are often sexually dimorphic and vary dramatically across species in size, shape, location, and allometry with body size. In many species, the horn exhibits disproportionate growth resulting in an exaggerated allometric relationship with body size, as compared to other traits, such as wings, that grow proportionately with body size. Depending on the species, the smallest males either do not produce a horn at all, or they produce a disproportionately small horn for their body size. While the diversity of horn shapes and their behavioural ecology have been reasonably well studied, we know far less about the proximate mechanisms that regulate horn growth. Thus, using 454 pyrosequencing, we generated transcriptome profiles, during horn growth and development, in two different scarab beetle species: the Asian rhinoceros beetle, Trypoxylus dichotomus, and the dung beetle, Onthophagus nigriventris. We obtained over half a million reads for each species that were assembled into over 6,000 and 16,000 contigs respectively. We combined these data with previously published studies to look for signatures of molecular evolution. We found a small subset of genes with horn-biased expression showing evidence for recent positive selection, as is expected with sexual selection on horn size. We also found evidence of relaxed selection present in genes that demonstrated biased expression between horned and horn-less morphs, consistent with the theory of developmental decoupling of phenotypically plastic traits.


Metronidazole for the prevention of dry socket after removal of partially impacted mandibular third molar: a randomised controlled trial.
We randomised 119 patients who had been referred for removal of partially impacted mandibular third molars to be given either metronidazole 1600 mg or placebo as a single dose 45 min before operation. Ten of the fifty-nine patients who were given metronidazole and 13 of the 60 given placebo developed dry sockets. Two variables were significantly associated with the development of a dry socket: pericoronitis and oral contraceptives.


Influence of flow rate on transport of bacteriophage in shale saprolite.
The objective of this study was to investigate the influence of flow rate on transport and retention of bacteriophage tracers in a fractured shale saprolite, which is a highly weathered, fine-grained subsoil that retains much of the fabric of the parent bedrock. Synthetic ground water containing PRD-1, MS-2, and bromide was passed through a saturated column of undisturbed shale saprolite at rates ranging from 0.0075 to 0.96 m d '. First arrival of the bacteriophage tracers in effluent samples in each of the experiments occurred within 0.01 to 0.04 pore volumes (PV) of the start of injection, indicating that bacteriophage were advectively transported mainly through fractures or macropores. Bacteriophage transport velocities, based on first arrival in the effluent, were very similar to fracture flow velocities calculated using the cubic law for flow in a fractured material. For MS-2, maximum concentration and mass of tracer recovered both increased steadily as flow rate increased. For PRD-1, these values initially increased, but were nearly constant at flow rates above 0.039 m d(-1), indicating that approximately 50% of the observed losses were independent of flow rate. Evaluation of the data indicates that physical straining and electrostatic or hydrophobic attachment to fracture or macropore walls were the dominant retention processes. Inactivation and gravitational settling playing secondary roles, except at the slowest flow rates. The study suggests that microbial contamination from sources such as septic fields and sewage ponds may pose a threat to the quality of ground water and surface water in areas with saprolitic subsoils.


Risk factors for dental caries in Latin American and Caribbean countries.
Identifying the risk factors for dental caries is vital in epidemiology and clinical practices for developing effective preventive strategies, both, at the individual and collective levels. Different causality/determination models have been proposed to understand the development process of dental caries. In the present review, we designed a model inspired by the world-known social determinants models proposed in the 90s and more recently in the 10s, wherein the contextual factors are placed more externally and encompass the individual factors. The contextual factors included those related to the cultural and societal values, as well as the social and health government policies. The individual factors were classified into the following categories: socioeconomic (social class, occupation, income, and education level), demographic characteristics (age, sex, and ethnicity), behavioral factors (non-use of fluoride dentifrice, sugar consumption, poor oral hygiene, and lack of preventive dental care), and biological factors (recent caries experience/active caries lesions, biofilm retentive factors, developmental defects of the enamel, disabilities, saliva amount and quality, cariogenic biofilm). Each of these variables was addressed, while focusing on the current evidence from studies conducted in Latin American and Caribbean countries (LACC). Based on the proposed model, educational aspects were addressed, and individual caries risk assessment and management decisions were proposed; further, implications for public health policies and clinical practice were described. The identification of modifiable risk factors for dental caries should be the basis for multi-strategy actions that consider the diversity of Latin American communities.


An absolute and restricted requirement for IL-12 in natural killer cell IFN-gamma production and antiviral defense. Studies of natural killer and T cell responses in contrasting viral infections.
IL-12 is a potent induce of IFN-gamma and is associated with a wide variety of immunoregulatory activities. Using murine CMV (MCMV) and lymphocytic choriomeningitis virus (LCMV) models of acute viral infection, we show here that IL-12 is integrally involved in certain aspects of antiviral immunity. Experiments evaluating the production and function of IL-12 demonstrated the induction of biologically active factor early during Smith strain MCMV, but not Armstrong strain LCMV, infection. The MCMV-induced IL-12 was responsible for early NK cell IFN-gamma production and viral control, as in vivo IL-12 neutralization by Ab treatment blocked both of these. In contrast, NK cell IFN-gamma production could not be detected during LCMV infection, and IL-12 neutralization had no effect on early LCMV replication. In both infections, treatments neutralizing IL-12 failed to alter either early NK cell cytotoxicity or later T cell responses, including IFN-gamma production and viral clearance on days 7 and 9 after infection. These data demonstrate the induction of IL-12 production during certain viral infections and the function of IL-12 for eliciting NK cell IFN-gamma production and antiviral defense. Furthermore, they suggest the existence of IL-12-independent mechanisms for IFN-gamma induction and viral control by T cells.


Hyaluronic acid fragments enhance the inflammatory and catabolic response in human intervertebral disc cells through modulation of toll-like receptor 2 signalling pathways.
Intervertebral disc (IVD) degeneration is characterized by extracellular matrix breakdown and is considered to be a primary cause of discogenic back pain. Although increases in pro-inflammatory cytokine levels within degenerating discs are associated with discogenic back pain, the mechanisms leading to their overproduction have not yet been elucidated. As fragmentation of matrix components occurs during IVD degeneration, we assessed the potential involvement of hyaluronic acid fragments (fHAs) in the induction of inflammatory and catabolic mediators. Human IVD cells isolated from patient biopsies were stimulated with fHAs (6 to 12 disaccharides) and their effect on cytokine and matrix degrading enzyme production was assessed using quantitative real-time polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA). The involvement of specific cell surface receptors and signal transduction pathways in mediating the effects of fHAs was tested using small interfering RNA (siRNA) approaches and kinase inhibition assays. Treatment of IVD cells with fHAs significantly increased mRNA expression levels of interleukin (IL)-1β, IL-6, IL-8, cyclooxygenase (COX)-2, matrix metalloproteinase (MMP)-1 and -13. The stimulatory effects of fHAs on IL-6 protein production were significantly impaired when added to IVD cells in combination with either Toll-like receptor (TLR)-2 siRNA or a TLR2 neutralizing antibody. Furthermore, the ability of fHAs to enhance IL-6 and MMP-3 protein production was found to be dependent on the mitogen-activated protein (MAP) kinase signaling pathway. These findings suggest that fHAs may have the potential to mediate IVD degeneration and discogenic back pain through activation of the TLR2 signaling pathway in resident IVD cells.


Acoustic terahertz graphene plasmons revealed by photocurrent nanoscopy.
Terahertz (THz) fields are widely used for sensing, communication and quality control. In future applications, they could be efficiently confined, enhanced and manipulated well below the classical diffraction limit through the excitation of graphene plasmons (GPs). These possibilities emerge from the strongly reduced GP wavelength, λp, compared with the photon wavelength, λ0, which can be controlled by modulating the carrier density of graphene via electrical gating. Recently, GPs in a graphene/insulator/metal configuration have been predicted to exhibit a linear dispersion (thus called acoustic plasmons) and a further reduced wavelength, implying an improved field confinement, analogous to plasmons in two-dimensional electron gases (2DEGs) near conductive substrates. Although infrared GPs have been visualized by scattering-type scanning near-field optical microscopy (s-SNOM), the real-space imaging of strongly confined THz plasmons in graphene and 2DEGs has been elusive so far-only GPs with nearly free-space wavelengths have been observed. Here we demonstrate real-space imaging of acoustic THz plasmons in a graphene photodetector with split-gate architecture. To that end, we introduce nanoscale-resolved THz photocurrent near-field microscopy, where near-field excited GPs are detected thermoelectrically rather than optically. This on-chip detection simplifies GP imaging as sophisticated s-SNOM detection schemes can be avoided. The photocurrent images reveal strongly reduced GP wavelengths (λp ≈ λ0/66), a linear dispersion resulting from the coupling of GPs with the metal gate below the graphene, and that plasmon damping at positive carrier densities is dominated by Coulomb impurity scattering.


Exertional heat cramps: recovery and return to play.
In contrast to muscle cramps that are brought on by muscle overload or fatigue, exertional heat cramps seem to be prompted by extensive sweating and a significant sweat-induced whole-body sodium deficit. As a result of a consequent contracted interstitial compartment, axon terminals of selected motor neurons can become hyper-excitable and spontaneously discharge. Barely detectable muscle fasciculations or "twitches" in the affected muscles can rapidly progress to debilitating muscle cramps in just 20 to 30 minutes. To aid recovery, salt (NaCl) and water lost from sweating should be sufficiently replaced so as to restore the extracellular volume and interstitial fluid spaces. Sweat sodium, chloride, and fluid losses incurred during training and competition need to be closely matched by daily salt and fluid intake, in order to prevent an excessive sodium deficit, maintain sufficient fluid balance, and avoid exertional heat cramps.


Fatal farm injuries among young children.
Death certificate data concerning farm-related injury deaths among children 0 to 9 years of age in Wisconsin and Illinois for the period of 1979 to 1985 were reviewed. Average annual farm-related injury death rates were 3.2 per 100,000 rural children in Wisconsin (62 deaths) and 1.5 per 100,000 in Illinois (32 deaths). Rates were three times higher among boys than girls. The occurrence of two harvest-related peaks and the absence of fatality in children less than 1 year of age suggest that presence of children on the farm when supervision is diminished is a key factor in farm-related fatalities. Moving machinery (tractors, wagons, and trucks) was the source of injury in approximately 55% of all deaths. Drowning accounted for 15% of all farm-related deaths. Two fatalities related to gravity box wagons could have easily been prevented with simple safety devices. These findings suggest a need for developing environmental interventions in farms. This will require the allocation of more resources to farm safety programs and a revision of current farm safety legislation.


Deep learning extends de novo protein modelling coverage of genomes using iteratively predicted structural constraints.
The inapplicability of amino acid covariation methods to small protein families has limited their use for structural annotation of whole genomes. Recently, deep learning has shown promise in allowing accurate residue-residue contact prediction even for shallow sequence alignments. Here we introduce DMPfold, which uses deep learning to predict inter-atomic distance bounds, the main chain hydrogen bond network, and torsion angles, which it uses to build models in an iterative fashion. DMPfold produces more accurate models than two popular methods for a test set of CASP12 domains, and works just as well for transmembrane proteins. Applied to all Pfam domains without known structures, confident models for 25% of these so-called dark families were produced in under a week on a small 200 core cluster. DMPfold provides models for 16% of human proteome UniProt entries without structures, generates accurate models with fewer than 100 sequences in some cases, and is freely available.


Interstitial retinol-binding protein and cellular retinal-binding protein in the mammalian pineal.
Antibodies against bovine interstitial retinol-binding protein (IRBP) and cellular retinal-binding protein (CRA1BP) were used in immunochemical and immunocytochemical studies of the pineal glands of cattle, hamsters and rats (RCS and RCS-rdy+). On immunoblots, IRBP (Mr 144,000) was identified in cattle, hamster and rat pineal extracts. The abundance of IRBP in bovine pineals was 33 +/- 6 ng.mg-1 (mean +/- SD, n = 12) soluble protein. RCS (Royal College of Surgeons) rat pineals gave a strong IRBP reaction on immunoblots, even when virtually no IRBP could be found in the eye due to photoreceptor degeneration. In the hamster retina IRBP immunostaining was distributed throughout the entire interphotoreceptor matrix and the outer segment layer. The pineal also showed strong IRBP-like immunostaining scattered uniformly throughout the gland. Other hamster brain regions showed no specific immunostaining; however, an immunoreactive protein with the same Mr as IRBP was detected on Western blots of bovine cerebral cortex, spinal cord and brainstem soluble proteins. Immunoreactive proteins at lower Mr were also detected in these tissues. CRA1BP immunoreactivity (Mr about 32,000) was observed in immunoblots of bovine, hamster and rat pineal proteins. These findings suggest that some mammalian pinealocytes are related to the retinal cells that contain CRA1BP (i.e. pigment epithelium, Muller cells) while others are related to the photoreceptors, which synthesize IRBP.


Inhibitory effect of melatonin on homocysteine-induced lipid peroxidation in rat brain homogenates.
Oxidative damage is implicated in several pathologies including cardiovascular disease. As a model system to study the response of cells to oxidative insults, homocysteine toxicity was examined since it is an independent risk factor for atherosclerotic disease. The levels of malondialdehyde and 4-hydroxyalkenals were assayed as an index of oxidatively damaged lipid. In in vitro experiments, the increase of lipid peroxidation products induced by homocysteine were concentration- and time-dependent. To study the protective effect of melatonin on homocystine induced lipid peroxidation, brain homogenates were treated with different concentrations of melatonin. The accumulation of malondialdehyde and 4-hydroxyalkenals induced by homocysteine was significantly reduced by melatonin in a concentration-dependent manner. Additionally, a melatonin concentration of 1.5 mM reduced the levels of oxidatively damaged lipid products below those measured in control homogenates (no homocysteine, no melatonin). These data suggest that melatonin, an endogenous antioxidant may have a role in protecting cells from oxidative damage due to homocysteine and they support the idea that pharmacological concentrations could be used as a therapeutic agent in reducing cardiovascular disease where homocysteine may be a causative or contributing agent.


Transient storage of electrical charge in biofilms of Shewanella oneidensis MR-1 growing in a microbial fuel cell.
Current output of microbial fuel cells (MFCs) depends on a number of engineering variables mainly related to the design of the fuel cell reactor and the materials used. In most cases the engineering of MFCs relies on the premise that for a constant biomass, current output correlates well with the metabolic activity of the cells. In this study we analyze to what extent, MFC output is also affected by the mode of operation, emphasizing how discontinuous operation can affect temporal patterns of current output. The experimental work has been carried out with Shewanella oneidensis MR-1, grown in conventional two-chamber MFCs subject to periodic interruptions of the external circuit. Our results indicate that after closure of the external circuit, current intensity shows a peak that decays back to basal values. The result suggests that the MFC has the ability to store charge during open circuit situations. Further studies using chronoamperometric analyses were carried out using isolated biofilms of Shewanella oneidensis MR-1 developed in a MFC and placed in an electrochemistry chamber in the presence of an electron donor. The results of these studies indicate that the amount of excess current over the basal level released by the biofilm after periods of circuit disconnection is proportional to the duration of the disconnection period up to a maximum of approximately 60 min. The results indicate that biofilms of Shewanella oneidensis MR-1 have the ability to store charge when oxidizing organic substrates in the absence of an external acceptor.