delta-Opioid receptor immunoreactivity: distribution in brainstem and spinal cord, and relationship to biogenic amines and enkephalin.
We have recently developed antisera which recognize epitopes of the cloned delta-opioid receptor (DOR; Dado et al., 1993). In the present report we have further characterized these antisera, and raised additional antisera in rats. We used these antisera to determine the distribution of DOR-like immunoreactivity (-Ll) in rat spinal cord and brainstem in relation to serotoninergic, noradrenergic, and enkephalinergic neurons. We found DOR-Ll in fibers and varicosities distributed throughout the spinal cord gray matter, with highest densities in the superficial dorsal horn, in autonomic regions, around the central canal as well as in the ventral horn motor nuclei. In the brainstem a dense innervation of DOR-immunoreactive (-IR) fibers was found in several nuclei such as spinal trigeminal nuclei, midline raphe nuclei, parabrachial nuclei, periaqueductal gray matter (PAG), interpeduncular nucleus, ans substantia nigra. A group of DOR-positive cells was seen in the laterodorsal tegmental nucleus. In addition, a few DOR-IR cell bodies were demonstrated in the parabrachial nuclei, interpeduncular nucleus, PAG, and superior and inferior colliculi as well as around the central canal in the spinal cord. All DOR-positive cells showed a punctuate staining pattern within the cytoplasm of the cell body and in primary dendrites. No plasma membrane staining of cells or dendrites could be demonstrated using the DOR antisera. Double-labeling experiments for DOR and 5-hydroxytryptamine (5HT, serotonin) revealed that some 5HT-IR neurons in the raphe complex were surrounded by DOR-IR fibers. In the spinal cord a high degree of coexistence was found between DOR and 5HT in nerve fibers and varicosities in the neuropil around the motoneurons and in lamina V of the dorsal horn. In autonomic regions of the spinal cord, a low degree of colocalization was seen between DOR and 5HT; in the superficial dorsal horn no coexistence was found. Tyrosine hydroxylase (TH)-positive neurons in the brainstem (in the A5 area, locus coeruleus, and A7 area) were apposed by DOR-positive fibers. However, no coexistence could be seen between DOR and TH in any part of the spinal cord. A close relation, but no coexistence, was observed between DOR- and enkephalin (ENK)-IR fibers in the spinal cord ventral horn; in the intermediolateral nucleus a low degree of colocalization was observed. Thus, a delta-opioid receptor may affect the activity of descending serotoninergic and noradrenergic neurons by means of modulating the release of neurotransmitters from afferents to these neurons.(ABSTRACT TRUNCATED AT 400 WORDS)


Early Implant Failures Related to Individual Surgeons: An Analysis Covering 11,074 Operations Performed during 28 Years.
Compared with knowledge on patient and implant component factors, little knowledge is available on surgeons' role in early implant failures. To report incidence of early implant failures related to total number of operations performed by individual surgeons. Early implant failures (≤1 year of implant prosthesis function) were reported after a total of 11,074 implant operations at one specialist clinic during 28 years of surgery. Altogether, 8,808 individual patients were treated by 23 different dentists, of whom 21 surgeons were specialists in oral surgery or periodontology. Recorded failures were related to total numbers of performed operations per surgeon, followed by statistical comparisons (χ2 ) between surgeons with regard to type of treated jaw and implant surface. Altogether, 616 operations were recorded with early implant failures (5.6%), most often observed in edentulous upper jaws after placing implants with a turned surface (p < .05). Significant differences between surgeons, gender of surgeon, type of treated jaws by the surgeon, and implant surface used by the surgeon could be observed (p < .05). Early implant failures are complex, multifactorial problems associated with many aspects in the surgical procedure. A stochastic variation of failures for individual surgeons could be observed over the years. Different levels of failure rate could be observed between the surgeons, occasionally reaching significant levels as a total or for different jaw situations (p < .05). The surgeons reduced their failure rates when using implants with moderately rough surfaces (p < .5), but the relationship of failure rate between the surgeons was maintained.


Glial modulation of synaptic transmission: Insights from the supraoptic nucleus of the hypothalamus.
Astrocytes clear synaptically released glutamate from the extracellular space through high-affinity transporters present on their plasma membrane. By controlling the extracellular level of the main excitatory transmitter in the central nervous system, astrocytes thus contribute prominently to the regulation of overall cellular excitability and synaptic information processing. We recently investigated the influence of the glial environment on glutamatergic and GABAergic neurotransmission in the supraoptic nucleus of the rat hypothalamus under physiological conditions such as lactation that significantly reduce astrocytic coverage of its neurons. By performing electrophysiological analyses on this unique model of dynamic neuronal-glial interactions, we have been able to show that the fine astrocytic processes normally enwrapping synapses serve two important functions. First, they govern the level of activation of presynaptic metabotropic glutamate receptors on glutamatergic terminals, thereby regulating synaptic efficacy at excitatory synapses. Second, they act as a physical and functional barrier to diffusion in the extracellular space, limiting spillover of glutamate and other neuroactive substances and therefore contributing to the regulation of heterosynaptic transmission and intercellular communication.


Neural and Behavioral Evidence for Vibrotactile Beat Perception and Bimodal Enhancement.
The ability to synchronize movements to a rhythmic stimulus, referred to as sensorimotor synchronization (SMS), is a behavioral measure of beat perception. Although SMS is generally superior when rhythms are presented in the auditory modality, recent research has demonstrated near-equivalent SMS for vibrotactile presentations of isochronous rhythms [Ammirante, P., Patel, A. D., & Russo, F. A. Synchronizing to auditory and tactile metronomes: A test of the auditory-motor enhancement hypothesis. Psychonomic Bulletin & Review, 23, 1882-1890, 2016]. The current study aimed to replicate and extend this study by incorporating a neural measure of beat perception. Nonmusicians were asked to tap to rhythms or to listen passively while EEG data were collected. Rhythmic complexity (isochronous, nonisochronous) and presentation modality (auditory, vibrotactile, bimodal) were fully crossed. Tapping data were consistent with those observed by Ammirante et al. (2016), revealing near-equivalent SMS for isochronous rhythms across modality conditions and a drop-off in SMS for nonisochronous rhythms, especially in the vibrotactile condition. EEG data revealed a greater degree of neural entrainment for isochronous compared to nonisochronous trials as well as for auditory and bimodal compared to vibrotactile trials. These findings led us to three main conclusions. First, isochronous rhythms lead to higher levels of beat perception than nonisochronous rhythms across modalities. Second, beat perception is generally enhanced for auditory presentations of rhythm but still possible under vibrotactile presentation conditions. Finally, exploratory analysis of neural entrainment at harmonic frequencies suggests that beat perception may be enhanced for bimodal presentations of rhythm.


γ-Tocotrienol as a Promising Countermeasure for Acute Radiation Syndrome: Current Status.
The hazard of ionizing radiation exposure due to nuclear accidents or terrorist attacks is ever increasing. Despite decades of research, still, there is a shortage of non-toxic, safe and effective medical countermeasures for radiological and nuclear emergency. To date, the U.S. Food and Drug Administration (U.S. FDA) has approved only two growth factors, Neupogen (granulocyte colony-stimulating factor (G-CSF), filgrastim) and Neulasta (PEGylated G-CSF, pegfilgrastim) for the treatment of hematopoietic acute radiation syndrome (H-ARS) following the Animal Efficacy Rule. Promising radioprotective efficacy results of γ-tocotrienol (GT3; a member of the vitamin E family) in the mouse model encouraged its further evaluation in the nonhuman primate (NHP) model. These studies demonstrated that GT3 significantly aided the recovery of radiation-induced neutropenia and thrombocytopenia compared to the vehicle controls; these results particularly significant after exposure to 5.8 or 6.5 Gray (Gy) whole body γ-irradiation. The stimulatory effect of GT3 on neutrophils and thrombocytes (platelets) was directly and positively correlated with dose; a 75 mg/kg dose was more effective compared to 37.5 mg/kg. GT3 was also effective against 6.5 Gy whole body γ-irradiation for improving neutrophils and thrombocytes. Moreover, a single administration of GT3 without any supportive care was equivalent, in terms of improving hematopoietic recovery, to multiple doses of Neupogen and two doses of Neulasta with full supportive care (including blood products) in the NHP model. GT3 may serve as an ultimate radioprotector for use in humans, particularly for military personnel and first responders. In brief, GT3 is a promising radiation countermeasure that ought to be further developed for U.S. FDA approval for the ARS indication.


Developing a claim-based version of the ACE-27 comorbidity index: a comparison with medical record review.
The adult comorbidity evaluation (ACE-27) is a medical record-based comorbidity index that predicts survival among various types of cancer patients. The purpose of this study was to compare the medical record-based ACE-27 instrument to a newly developed administrative claim-based ACE-27 measure. Cross-sectional study of 4,300 breast and prostate cancer patients from the Centers for Disease Control and Prevention Patterns of Care Study. Comorbidities with the highest concordance were diabetes (sensitivity=84.6%, κ=0.58 for breast cancer patients; sensitivity=0.764, κ=0.54 for prostate cancer patients), and hypertension (sensitivity=78.5%, κ=0.32 for breast cancer patients; sensitivity=69.6%, κ=0.28 for prostate cancer patients). Diseases with fair or moderate agreement in one or both cancer sites include congestive heart failure, arrhythmia, hypertension, respiratory diseases, hepatic disease, renal disease, dementia, and neuromuscular disease. For overall indices, agreement was fair but with high sensitivities in the collapsed indices, and the highest sensitivities in the lowest level of decompensation. The ACE-27 comorbidity score derived from administrative claims data provides a tool to examine the relationship between comorbidity, cancer diagnosis, and outcomes in future epidemiologic research, particularly when medical record review is logistically impossible. The classification of most comorbidities into 2 or 3 levels of severity within a claim-based measure is a major development. Future research should be directed toward refining the measure with a longer review period or different paradigms for diagnosis identification, and testing the predictive ability of the measure in terms of survival, complications, or other outcomes of care.


Indicators for occupational health surveillance.
Each year, millions of the estimated 140 million U.S. workers are injured on the job or become ill from exposure to hazards at work. These work-related injuries and illnesses result in substantial human and economic costs for workers, employers, and society; estimated direct and indirect costs of work-related injuries and illnesses are approximately $170 billion annually. In 1998, the Council of State and Territorial Epidemiologists (CSTE) and CDC's National Institute for Occupational Safety and Health (NIOSH) convened a work group that identified priority occupational health conditions to be placed under surveillance, addressed cross-cutting surveillance concerns, and made recommendations regarding the role of states in a comprehensive nationwide surveillance system for work-related disease, injuries, and hazards. CSTE recommendations led to the generation of 19 occupational health indicators (OHIs) and one Employment Demographic Profile, which were developed during 2001-2003. The OHIs complement other guidelines for state-based occupational health surveillance to address overall state and national goals to improve public health. These OHIs are intended to help states build occupational health capacity by providing them with tools to collect and generate important, basic information concerning the occupational health status of the state population and to identify areas in which to focus prevention efforts. In 2005, CSTE released a report compiling OHI data from 13 states. NIOSH provides funding for the OHIs because they are now a required component of state-based cooperative agreements for occupational health surveillance. This report introduces the OHIs and describes CSTE's approach to developing this new occupational health surveillance tool.


Professionalism and nonprofit organizations.
Many professionals prefer to work in nonprofit organizations, rather than in either for-profit or bureaucratic organizations. This preference suggests that nonprofits may be successful in reducing the tension between professional principles and institutional requirements. Professionals in for-profit organizations must submit to the control of a manager who is motivated to overrule them whenever their decisions come into conflict with the goal of profit maximization. Bureaucratic organizations stress predictability of results and adherence to rules as the overriding criteria of evaluation and control. This paper argues that nonprofits are on the whole superior from the point of view of professional ideology and practice. Thus, given a commitment to the values of professionalism, the preference for the nonprofit form becomes understandable, even without the usual assumptions about income-maximizing behavior.


Enteroviral RNA sequences detected by polymerase chain reaction in muscle of patients with postviral fatigue syndrome.
To determine the presence of enteroviral sequences in muscle of patients with the postviral fatigue syndrome. Detection of sequences with the polymerase chain reaction in a well defined group of patients with the syndrome and controls over the same period. Institute of Neurological Sciences, Glasgow. 60 consecutive patients admitted to the institute with the postviral fatigue syndrome who had undergone extensive investigation to exclude other conditions. 41 controls from the same catchment area without evidence of fatigue, all undergoing routine surgery. Routine investigations, serological screen for antibodies to a range of viruses, and presence of enteroviral RNA sequences in muscle biopsy specimens. 15 (25%) patients and 10 (24.4%) controls had important serological findings. 12 patients had neutralising antibody titres of greater than or equal to 256 to coxsackieviruses B1-5 (six positive for enteroviral RNA sequences, six negative); three were positive for Epstein-Barr virus specific IgM (two positive, one negative). Six controls had similar neutralising antibody titres to coxsackieviruses (all negative); one was positive for Epstein-Barr virus specific IgM (negative); and three had titres of complement fixing antibody greater than or equal to 256 to cytomegalovirus (all negative). Overall, significantly more patients than controls had enteroviral RNA sequences in muscle (32/60, 53% v 6/41, 15%; odds ratio 6.7, 95% confidence interval 2.4 to 18.2). This was not correlated with duration of disease, patient and age, or to raised titres of antibodies to coxsackieviruses B1-5. Persistent enteroviral infection of muscle may occur in some patients with postviral fatigue syndrome and may have an aetiological role.


Socio-ecological costs of Amazon nut and timber production at community household forests in the Bolivian Amazon.
The Bolivian Amazon holds a complex configuration of people and forested landscapes in which communities hold secure tenure rights over a rich ecosystem offering a range of livelihood income opportunities. A large share of this income is derived from Amazon nut (Bertholletia excelsa). Many communities also have long-standing experience with community timber management plans. However, livelihood needs and desires for better living conditions may continue to place these resources under considerable stress as income needs and opportunities intensify and diversify. We aim to identify the socioeconomic and biophysical factors determining the income from forests, husbandry, off-farm and two keystone forest products (i.e., Amazon nut and timber) in the Bolivian Amazon region. We used structural equation modelling tools to account for the complex inter-relationships between socioeconomic and biophysical factors in predicting each source of income. The potential exists to increase incomes from existing livelihood activities in ways that reduce dependency upon forest resources. For example, changes in off-farm income sources can act to increase or decrease forest incomes. Market accessibility, social, financial, and natural and physical assets determined the amount of income community households could derive from Amazon nut and timber. Factors related to community households' local ecological knowledge, such as the number of non-timber forest products harvested and the number of management practices applied to enhance Amazon nut production, defined the amount of income these households could derive from Amazon nut and timber, respectively. The (inter) relationships found among socioeconomic and biophysical factors over income shed light on ways to improve forest-dependent livelihoods in the Bolivian Amazon. We believe that our analysis could be applicable to other contexts throughout the tropics as well.


Family Caregiving and Place of Death: Insights From Cross-national Analysis of the Harmonized End-of-Life Data.
Family is largely overlooked in research on factors associated with place of death among older adults. We determine if family caregiving at the end of life is associated with place of death in the United States and Europe. We use the Harmonized End of Life data sets developed by the Gateway to Global Aging Data for the Survey of Health, Ageing and Retirement in Europe (SHARE) and the Health and Retirement Study (HRS). We conducted multinomial logistic regression on 7,113 decedents from 18 European countries and 3,031 decedents from the United States to determine if family caregiving, defined based on assistance with activities of daily living, was associated with death at home versus at a hospital or nursing home. Family caregiving was associated with reduced odds of dying in a hospital and nursing home, relative to dying at home in both the United States and Europe. Care from a spouse/partner or child/grandchild was both more common and more strongly associated with place of death than care from other relatives. Associations between family caregiving and place of death were generally consistent across European welfare regimes. This cross-national examination of family caregiving indicates that family-based support is universally important in determining where older adults die. In both the United States and in Europe, most care provided during a long-term illness or disability is provided by family caregivers, and it is clear families exert tremendous influence on place of death.


What's Preventing Us to Get More Attraction: The Fear of Aesthetic Surgery.
Nowadays, with the help of cosmetic surgery almost every woman and man can achieve a highly attractive appearance. The question is, why so many people do not take advantage of these opportunities? This pilot-study investigates individual attitudes of people towards aesthetic plastic surgery. A questionnaire was developed which combined self-developed items for a measurement of attitudes towards plastic surgery. In addition, items of the "Freiburger Personality Inventory" (FPI-R) were used. The study was conducted in Hamburg/Germany. 104One hundred and four test persons participated in the survey (81 females, 23 males, age 20-30 years). Eighty six of the participants (82.7%) had an A-level as degree of education, 14.4% achieved the secondary school certificate and 2.9% had completed their bachelor on a high school. The data supported the hypothesis that people who are unsatisfied with their body appearance showed more willingness for a surgical intervention. On the other hand, fear of complications and pain as far as anxiety before an unsatisfactory result hinders them from a decision for an intervention. Significant correlations with regard to extraversion-introversion and the education level were not found. Females showed more willingness regarding an intervention than men. Gender-specific differences concerning the cost factor were not found. Interestingly more than 65% of the total sample felt dissatisfaction with a specific body part and are thus target of aesthetic surgery. The yellow press often reports about failed cosmetic surgery, especially in VIP-persons. Aesthetic surgery should keep working to reduce unwarranted fears of people toward these kinds of operations.


Importance of Pyruvate Sensing and Transport for the Resuscitation of Viable but Nonculturable Escherichia coli K-12.
Escherichia coli and many other bacterial species can enter into a viable but nonculturable (VBNC) state, which is a survival strategy adopted by cells exposed to adverse environmental conditions. Pyruvate is known to be one factor that promotes resuscitation of VBNC cells. Here we studied the role of a pyruvate-sensing network, composed of the histidine kinase-response regulator systems BtsS/BtsR and YpdA/YpdB and the target gene btsT, encoding the high-affinity pyruvate/H+ symporter BtsT, in the resuscitation of VBNC E. coli K-12 cells after exposure to cold for 120 days. Analysis of the proteome of VBNC cells revealed upregulation, relative to exponentially growing cells, of BtsT and other proteins involved in pyruvate metabolism. Provision of pyruvate stimulated protein and DNA biosynthesis, and thus resuscitation, in wild-type but not btsSR ypdAB mutant VBNC cells. This result was corroborated by time-dependent tracking of the resuscitation of individual VBNC E. coli cells observed in a microfluidic system. Finally, transport assays revealed that 14C-labeled pyruvate was rapidly taken up into VBNC cells by BtsT. These results provide the first evidence that pyruvate is taken up as a carbon source for the resuscitation of VBNC E. coli cells.IMPORTANCE Viable but nonculturable (VBNC) bacteria do not form colonies in standard medium but otherwise retain their metabolic activity and can express toxic proteins. Many bacterial genera, including Escherichia, Vibrio, and Listeria, have been shown to enter the VBNC state upon exposure to adverse conditions, such as low temperature, radiation, and starvation. Ultimately, these organisms pose a public health risk with potential implications for the pharmaceutical and food industries, as dormant organisms are especially difficult to selectively eliminate and VBNC bacteria can be resuscitated if placed in an environment with appropriate nutrition and temperature. Here we used a microfluidic system to monitor the resuscitation of single VBNC cells over time. We provide new molecular insights into the initiation of resuscitation by demonstrating that VBNC E. coli cells rapidly take up pyruvate with an inducible high-affinity transporter, whose expression is triggered by the BtsSR-YpdAB sensing network.


Excitatory amino acids stimulate aerobic glycolysis in astrocytes via an activation of the Na+/K+ ATPase.
Astrocytes appear to be ideally localized to couple neuronal activity to energy metabolism. First, specialized processes, the astrocytic end-feet surround blood vessels, the source of glucose for the brain. Second, other processes ensheath synapses and express receptors and transporters for various neurotransmitters, endowing astrocytes with the capacity to 'sense' synaptic activity. We have previously described the stimulation by L-glutamate of glucose utilization by astrocytes, monitored by 2-deoxyglucose uptake and phosphorylation. Here we have further characterized the pharmacological characteristics and molecular mechanisms of this action, which involve a massive influx of Na+ as a result of the cotransport of the amino acid with Na+, by Na(+)-dependent transporters and a subsequent activation of the Na+/K+ ATPase. To fuel the ATPase, glucose is processed glycolytically thus leading to increased lactate production. Since excitatory amino acids are released during activation by cortical afferents, these data reveal a simple mechanism for coupling neuronal activity to glucose utilization and provide further evidence for the concept of a transient stimulation of aerobic glycolysis during activation occurring preferentially in astrocytes.


Outcome of extensive descending aorta repair adopting present concepts of spinal cord preservation.
Preoperative radiological identification of the Adamkiewicz artery and intraoperative neurologic monitoring are known to be helpful for preventing paraplegia after thoracoabdominal aorta replacement. To answer whether they should be used routinely, we investigated the incidence of spinal cord ischemia after extensive descending aortic repair without using such modalities. We retrospectively reviewed the outcome of 95 patients who underwent extensive descending thoracic (DTA) or thoracoabdominal aorta (TAA) repair without the Adamkiewicz artery identification or neurologic monitoring from 2006 through 2010. Spinal cord protection strategy consisted of distal aortic perfusion, cerebrospinal fluid drainage, mild hypothermia, and maintenance of hypertension (systolic≥120mmHg) through the second postoperative day. A few segmental arteries were empirically selected for reimplantation based on the size and the amount of backbleeding; overall 1.4 per patient, 0.3 for DTA, 1.4 for type I, 2.4 for type II, 0.9 for type III, and 0 for type IV TAA. Two patients died early after surgery. All the remaining patients awoke without paraplegia or paraparesis. Delayed deficit occurred in 7 patients (7.4%) after hypotensive events caused by sedation, bleeding, respiratory distress, or cardiac dysfunction. Three patients (3.2%) became permanently paraplegic and the other four recovered completely within 48 hours after cerebrospinal fluid drainage and elevation of systemic blood pressure. Even without the Adamkiewicz artery identification and neuromonitoring, the incidence of immediate paraplegia could be kept low by applying the strategy based on the modern concept of cord perfusion. The relatively high incidence of delayed deficit suggests the importance of postoperative hemodynamic management and prevention of cardiopulmonary complications.


ACT: the Artemis Comparison Tool.
The Artemis Comparison Tool (ACT) allows an interactive visualisation of comparisons between complete genome sequences and associated annotations. The comparison data can be generated with several different programs; BLASTN, TBLASTX or Mummer comparisons between genomic DNA sequences, or orthologue tables generated by reciprocal FASTA comparison between protein sets. It is possible to identify regions of similarity, insertions and rearrangements at any level from the whole genome to base-pair differences. ACT uses Artemis components to display the sequences and so inherits powerful searching and analysis tools. ACT is part of the Artemis distribution and is similarly open source, written in Java and can run on any Java enabled platform, including UNIX, Macintosh and Windows.


N-butyl cyanoacrylate embolization using a detachable tip microcatheter: initial experience.
Endovascular embolization of intracranial vascular malformations with N-butyl cyanoacrylate (nBCA) using a detachable tip microcatheter allows prolonged injection and decreases the risk of catheter retention. Between March and December 2013, the Apollo 1.5 cm detachable tip microcatheter was used in five patients after being approved by both the Food and Drug Administration and the institutional review board as a compassionate use device. Nine pedicles were embolized and the follow-up ranged from 1 to 3 months. Five of the nine catheter tips detached. The length of reflux was not directly associated with the detachment of the distal tip. There were no cases of premature microcatheter detachment during navigation, manipulation with multiple microguidewire reintroduction and guidance. There was no leak of embolic agent at the detachment zone. Follow-up showed the detached tip to be stable without migration. A detachable tip microcatheter offers an advance in the safety and effectiveness of nBCA embolization. Catheter retrieval becomes more controlled and less traumatic. Our initial experience is encouraging, and more experience is needed to categorically ascertain its safety and efficacy.


Recombinant Mycobacterium bovis BCG as an HIV vaccine vector.
HIV-1 has resulted in a devastating AIDS pandemic. An effective HIV/AIDS vaccine that can be used to either, prevent HIV infection, control infection or prevent progression of the disease to AIDS is needed. In this review we discuss the use of Mycobacterium bovis BCG, the tuberculosis vaccine, as a vaccine vector for an HIV vaccine. Numerous features make BCG an attractive vehicle to deliver HIV antigens. It has a good safety profile, elicits long-lasting cellular immune responses and in addition manufacturing costs are affordable, a necessary consideration for developing countries. In this review we discuss the numerous factors that influence generation of a genetically stable recombinant BCG vaccine for HIV.


Clays as dietary supplements for swine: A review.
Clays are crystalline, hydrated aluminosilicate molecules composed of alkali and alkaline earth cations along with small amounts of various other elements. The best-known are montmorillonite, smectite, illite, kaolinite, biotite and clinoptilolite. The molecules in these clays are arranged in three-dimensional structures creating internal voids and channels capable of trapping a wide variety of molecules. As a result of this structure, clay minerals are regarded as a simple and effective tool for the prevention of the negative effects of many toxic compounds. Dietary supplementation with clays has been shown to improve weight gain and feed conversion in pigs. Where improvements in performance have been noted, one of the most likely explanations for the improvement is the fact clays increase nutrient digestibility. Clays reduce the speed of passage of feed along the digestive tract which allows more time for digestion. Feeding clays also causes morphological changes in the intestinal mucosa such as an increase in villus height and an increase in the villus height to crypt depth ratio. These changes increase the surface area of the gastrointestinal tract thus increasing nutrient digestibility. Several studies have indicated that feeding clay reduces the incidence, severity and duration of diarrhea in pigs. The mechanism for the reduction in diarrhea is likely due to increases in the numbers of Bifidobacteria and Lactobacillus and decreases in Clostridia and E. coli in the small intestine of pigs fed clays. In addition, the numbers of pigs born alive and weaned, birth weight and weaning weight have been shown to be higher for sows fed clays. Several studies have indicated that clays can help mitigate the effects of mycotoxins. The aim of the present review is to focus on the various clays which have been given attention in recent research and to discuss their potential to improve pig performance.


Twelve new Demospongiae (Porifera) from Chilean fjords, with remarks upon sponge-derived biogeographic compartments in the SE Pacific.
This article reports on 12 new species originating from the Chilean fjords region, namely Clathria (Microciona) mytilifila sp. nov., Haliclona (Reniera) caduca sp. nov., Latrunculia (L.) ciruela sp. nov., Latrunculia (L.) copihuensis sp. nov., Latrunculia (L.) verenae sp. nov., Latrunculia (L.) yepayek sp. nov., Myxilla (Burtonanchora) araucana sp. nov., Neopodospongia tupecomareni sp. nov., Oceanapia guaiteca sp. nov., Oceanapia spinisphaera sp. nov., Suberites cranium sp. nov. and Tethya melinka sp. nov. The material studied was collected between 5 and 30 m depth at latitudes comprised between 42º and 50ºS, and is part of a large collection of Chilean sponges gathered by an international team in a series of expeditions. Identification keys are provided for SE Pacific Suberites and Latrunculia, and the known species of Myxilla (Burtonanchora) and Neopodospongia. A trans-Pacific link to the New Zealand fauna was retrieved for the latter genus. Distribution ranges apparent from the materials studied here are judged too preliminary to allow any inference on biotic boundaries in the SE Pacific. A revision of earlier assertions about these biogeographic units and their boundaries concluded that very little support remains other than for existence of a Magellanic fauna. This is in part a consequence of revising the taxonomy of sponge species originally deemed to underpin these areas. Specifically, the former proposal of a Central to Southern Chile biogeographic unit (33-56ºS) has been markedly undone.


Should dermatologists prescribe hormonal contraceptives for acne?
ABSTRACT One of the primary factors contributing to the development of acne vulgaris is excess sebum. Sebaceous glands and sebum excretion are regulated, at least in part, by androgen hormones. Acne treatments that block this androgen effect include spironolactone and combination oral contraceptives (COC). Three COC are now FDA approved to treat moderate acne. Dermatologists must become experts at prescribing these hormonal contraceptives. Likewise, it is vital to be aware of contraindications to hormonal contraceptive therapy. Proper patient selection relies on an appropriate medical history and an assessment of blood pressure. A pelvic exam and/or Papanicolaou smear are not required prior to initiating therapy with a COC. It is important to counsel patients about potential adverse effects of COC pills and to establish appropriate expectations concerning acne improvement.


Influence of light source and extended time of curing on microhardness and degree of conversion of different regions of a nanofilled composite resin.
The aim of this study was to evaluate the effects of different light sources and curing time on the degree of conversion and microhardness of two surfaces within a nanofilled composite resin. Four experimental groups (n=10) were formed in accordance with the light source (quartz-tungsten halogen (QTH - 600mW/cm(2)), or light-emitting-diode (LED - 800mW/cm(2))) and the time of curing (20 s or 40 s). The specimens were prepared with a circular mould (5 mm ∅ and 2 mm thick), according to the respective protocol, and the Knoop microhardness and degree of conversion was measured at the top and the base of the specimens. The degree of conversion was evaluated by the Fourier transform infrared spectrometer (FTIR). The results were analyzed by ANOVA two-way repeated measures and Tukey's test (α=,05). Both the degree of conversion and microhardness were higher at the top than at the bottom of the specimens. The QTH light source presented better values on the degree of conversion evaluation, but this result was not observed in the microhardness evaluation. Although forty seconds of curing promotes an increased level of microhardness, it did not influence the degree of conversion. It could be concluded that increasing the time of curing to 40 s promotes an increase in microhardness, but it does not influence the degree of conversion of a nanofilled composite resin. QTH promote better monomeric conversion; however, the microhardness values are similar to LED curing. For all situations tested, the bottom of the specimens presented lower results than the top.


The economic consequences of practice style variation in providing medical interventions: A systematic review of the literature.
The practice style variation (PSV) incurs undesirable clinical and economic consequences for patients and the healthcare system. This review aims to analyze the economic consequences of PSV in medical interventions. A comprehensive electronic search was conducted through PubMed, Web of Sciences, EBSCO, EMBASE, and Cochrane databases to retrieve studies on economic consequences of PSV within 1975-2018. The studies were independently assessed by two reviewers. The quality of studies was assessed by Strengthening the Reporting of Observational Studies in Epidemiology checklist. No language restriction was applied. Only four studies met the eligibility criteria. These studies have been conducted retrospectively in developed countries. Most of the included studies used consumer demand theory to measure the economic consequences of PSV. Findings showed 12%-74% of all variations in healthcare services are related to PSV, thereby incurring up to 23 million dollars for the healthcare system. The PSV is related to the total expenditure, price elasticity, and coefficient of variation of healthcare services. PSV associated with huge inefficiency and inequity in access to healthcare services. To mitigate the consequences of PSV, policymakers should consider PSV in both developing the medical education plans as well as cost management. Using multilevel analysis to investigate the determinants of PSV would be beneficial.


Experimental method for the examination of systematic distortions in lidar data.
An experimental method for determining the presence and the level of systematic distortions in lidar data is considered. The method has been developed on the basis of two years of field experiments with the Fire Sciences Laboratory elastic scanning lidar. The influence of multiplicative and additive distortion components is considered using numerical experiments and is illustrated with experimental data. The examination method is most applicable for short wavelengths at which the atmospheric molecular component in clear atmospheres is large enough to stabilize the Kano-Hamilton multiangle solution, based on the assumption of horizontal atmospheric homogeneity.


Massively parallel sequencing of single cells by epicPCR links functional genes with phylogenetic markers.
Many microbial communities are characterized by high genetic diversity. 16S ribosomal RNA sequencing can determine community members, and metagenomics can determine the functional diversity, but resolving the functional role of individual cells in high throughput remains an unsolved challenge. Here, we describe epicPCR (Emulsion, Paired Isolation and Concatenation PCR), a new technique that links functional genes and phylogenetic markers in uncultured single cells, providing a throughput of hundreds of thousands of cells with costs comparable to one genomic library preparation. We demonstrate the utility of our technique in a natural environment by profiling a sulfate-reducing community in a freshwater lake, revealing both known sulfate reducers and discovering new putative sulfate reducers. Our method is adaptable to any conserved genetic trait and translates genetic associations from diverse microbial samples into a sequencing library that answers targeted ecological questions. Potential applications include identifying functional community members, tracing horizontal gene transfer networks and mapping ecological interactions between microbial cells.


Bioelectric-calcineurin signaling module regulates allometric growth and size of the zebrafish fin.
The establishment of relative size of organs and structures is paramount for attaining final form and function of an organism. Importantly, variation in the proportions of structures frequently underlies adaptive change in morphology in evolution and maybe a common mechanism underlying selection. However, the mechanism by which growth is integrated within tissues during development to achieve proper proportionality is poorly understood. We have shown that signaling by potassium channels mediates coordinated size regulation in zebrafish fins. Recently, calcineurin inhibitors were shown to elicit changes in zebrafish fin allometry as well. Here, we identify the potassium channel kcnk5b as a key player in integrating calcineurin's growth effects, in part through regulation of the cytoplasmic C-terminus of the channel. We propose that the interaction between Kcnk5b and calcineurin acts as a signaling node to regulate allometric growth. Importantly, we find that this regulation is epistatic to inherent mechanisms instructing overall size as inhibition of calcineurin is able to bypass genetic instruction of size as seen in sof and wild-type fins, however, it is not sufficient to re-specify positional memory of size of the fin. These findings integrate classic signaling mediators such as calcineurin with ion channel function in the regulation of size and proportion during growth.


NC1-peptide derived from collagen α3 (IV) chain is a blood-tissue barrier regulator: lesson from the testis.
Collagen α3 (IV) chains are one of the major constituent components of the basement membrane in the mammalian testis. Studies have shown that biologically active fragments, such as noncollagenase domain (NC1)-peptide, can be released from the C-terminal region of collagen α3 (IV) chains, possibly through the proteolytic action of metalloproteinase 9 (MMP9). NC1-peptide was shown to promote blood-testis barrier (BTB) remodeling and fully developed spermatid (e.g., sperm) release from the seminiferous epithelium because this bioactive peptide was capable of perturbing the organization of both actin- and microtubule (MT)-based cytoskeletons at the Sertoli cell-cell and also Sertoli-spermatid interface, the ultrastructure known as the basal ectoplasmic specialization (ES) and apical ES, respectively. More importantly, recent studies have shown that this NC1-peptide-induced effects on cytoskeletal organization in the testis are mediated through an activation of mammalian target of rapamycin complex 1/ribosomal protein S6/transforming retrovirus Akt1/2 protein (mTORC1/rpS6/Akt1/2) signaling cascade, involving an activation of cell division control protein 42 homolog (Cdc42) GTPase, but not Ras homolog family member A GTPase (RhoA), and the participation of end-binding protein 1 (EB1), a microtubule plus (+) end tracking protein (+TIP), downstream. Herein, we critically evaluate these findings, providing a critical discussion by which the basement membrane modulates spermatogenesis through one of its locally generated regulatory peptides in the testis.


MicroRNA-145 post-transcriptionally regulates the expression and function of P-glycoprotein in intestinal epithelial cells.
P-glycoprotein (P-gp/MDR1) is a multispecific efflux transporter regulating the pharmacokinetics of various drugs. Although P-gp expression in the small intestine is elevated after liver ischemia-reperfusion (I/R) injury, the regulatory mechanism remains to be clarified. MicroRNAs (miRNAs) play an important role in the post-transcriptional regulation of the expression of drug transporters. Here, we investigated the intestinal expression profile of miRNAs after liver I/R and the role of miRNAs in the post-transcriptional regulation of P-gp in intestinal epithelial cells. Microarray analysis showed that microRNA-145 (miR-145) level was decreased in the small intestine of I/R rats. This downregulation of miR-145 was further confirmed by real-time polymerase chain reaction. In silico analysis revealed that 3'-untranslated regions (UTRs) of rat Mdr1a, mouse Mdr1a, and human MDR1 mRNA retain binding sites for miR-145. Luciferase assays using MDR1 3'-UTR reporter plasmid in HEK293 cells showed that luciferase activity was decreased by the overexpression of miR-145, and the deletion of miR-145 binding site within MDR1 3'-UTR abolished this decreased luciferase activity. The downregulation of miR-145 in Caco-2 cells, an epithelial cell line derived from human colon, increased P-gp expression and efflux activity of rhodamine 123, but not MDR1 mRNA level. These findings demonstrated that miR-145 negatively regulates the expression and function of P-gp through the repression of mRNA by direct interaction on the 3'-UTR of MDR1 mRNA. In addition, the downregulation of miR-145 should significantly contribute to the elevated intestinal P-gp expression after liver I/R. Our results provide new insight into the post-transcriptional regulation of intestinal P-gp.


Differential activation of the frontal pole to high vs low calorie foods: The neural basis of food preference in Anorexia Nervosa?
Neuroimaging studies in anorexia nervosa (AN) suggest that altered food reward processing may result from dysfunction in both limbic reward and cortical control centers of the brain. This fMRI study aimed to index the neural correlates of food reward in a subsample of individuals with restrictive AN: twelve currently ill, fourteen recovered individuals and sixteen healthy controls. Participants were shown pictures of high and low-calorie foods and asked to evaluate how much they wanted to eat each one following a four hour fast. Whole-brain task-activated analysis was followed by psychophysiological interaction analysis (PPI) of the amygdala and caudate. In the AN group, we observed a differential pattern of activation in the lateral frontal pole: increasing following presentation of high-calorie stimuli and decreasing in during presentation of low-calorie food pictures, the opposite of which was seen in the healthy control (HC) group. In addition, decreased activation to food pictures was observed in somatosensory regions in the AN group. PPI analyses suggested hypo-connectivity in reward pathways, and between the caudate and both somatosensory and visual processing regions in the AN group. No significant between-group differences were observed between the recovered group and the currently ill and healthy controls in the PPI analysis. Taken together, these findings further our understanding of the neural processes which may underpin the avoidance of high-calorie foods in those with AN and might exacerbate the development of compulsive weight-loss behavior, despite emaciation.


MiR-30a-3p negatively regulates BAFF synthesis in systemic sclerosis and rheumatoid arthritis fibroblasts.
We evaluated micro (mi) RNA-mediated regulation of BAFF expression in fibroblasts using two concomitant models: (i) synovial fibroblasts (FLS) isolated from healthy controls (N) or Rheumatoid Arthritis (RA) patients; (ii) human dermal fibroblasts (HDF) isolated from healthy controls (N) or Systemic Sclerosis (SSc) patients. Using RT-qPCR and ELISA, we first showed that SScHDF synthesized and released BAFF in response to Poly(I:C) or IFN-γ treatment, as previously observed in RAFLS, whereas NHDF released BAFF preferentially in response to IFN-γ. Next, we demonstrated that miR-30a-3p expression was down regulated in RAFLS and SScHDF stimulated with Poly(I:C) or IFN-γ. Moreover, we demonstrated that transfecting miR-30a-3p mimic in Poly(I:C)- and IFN-γ-activated RAFLS and SScHDF showed a strong decrease on BAFF synthesis and release and thus B cells survival in our model. Interestingly, FLS and HDF isolated from healthy subjects express higher levels of miR-30a-3p and lower levels of BAFF than RAFLS and SScHDF. Transfection of miR-30a-3p antisense in Poly(I:C)- and IFN-γ-activated NFLS and NHDF upregulated BAFF secretion, confirming that this microRNA is a basal repressors of BAFF expression in cells from healthy donors. Our data suggest a critical role of miR-30a-3p in the regulation of BAFF expression, which could have a major impact in the regulation of the autoimmune responses occurring in RA and SSc.


Kinetic and thermodynamic compensation. A current and practical review for foods.
Kinetic and thermodynamic compensations have been reported in many chemical, physical, biological and food processes. Kinetic compensation can be found for any process and when it takes place, it gives information about the reaction mechanism and whether the reaction is controlled by enthalpy or entropy. It consists of the linear relationship between the logarithm of the frequency factor (lnk0) and the activation energy (Ea), both previously obtained from the Arrhenius equation for different values of an environmental variable (e.g. pH, concentration of any substance not involved in the process, pressure, water activity, etc.). A mathematical consequence of kinetic compensation is the isokinetic temperature, this being the temperature at which the kinetic constant should be the same regardless of the environmental variable. Thermodynamic compensation can be found for any process involving an equilibrium and consists of the linear relationship between the variation of enthalpy and entropy, both previously obtained from the Van't Hoff equation for different values of an environmental variable. A mathematical consequence of thermodynamic compensation is the isoequilibrium temperature, this being the temperature at which the equilibrium constant should be the same regardless of the environmental variable. According to the transition state theory, some kinetic constants can be related to the equilibrium constant of the initial equilibrium stage between the reagents and the transition state. For these cases, it can be concluded that both compensations are related mathematically and therefore not only does the existence of one kind of compensation imply the existence of the other, but the isokinetic and isoequilibrium temperatures should both be the same, or at least very close to each other. However, there is no reason that forces the linearities that cause either kind of compensation. So, some processes have shown these linear relationships while others have not. Moreover, some authors have reported that, due to the fact that the estimates of the parameters for the couples lnk0-Ea and ΔH≠-ΔS≠ being correlated with each other, there is a statistic compensation that consists of the propagation of experimental errors, and this effect has to be considered before concluding kinetic and/or thermodynamic compensations. This work reviews how to deal with kinetic and thermodynamic compensations physically, mathematically and statistically, prior to a second part that reviews the food processes for which one or both of these compensations have been studied.


The diversity of experimental organisms in biomedical research may be influenced by biomedical funding.
Contrary to concerns of some critics, we present evidence that biomedical research is not dominated by a small handful of model organisms. An exhaustive analysis of research literature suggests that the diversity of experimental organisms in biomedical research has increased substantially since 1975. There has been a longstanding worry that organism-centric funding policies can lead to biases in experimental organism choice, and thus negatively impact the direction of research and the interpretation of results. Critics have argued that a focus on model organisms has unduly constrained the diversity of experimental organisms. The availability of large electronic databases of scientific literature, combined with interest in quantitative methods among philosophers of science, presents new opportunities for data-driven investigations into organism choice in biomedical research. The diversity of organisms used in NIH-funded research may be considerably lower than in the broader biomedical sciences, and may be subject to greater constraints on organism choice.


Current Progresses of Single Cell DNA Sequencing in Breast Cancer Research.
Breast cancers display striking genetic and phenotypic diversities. To date, several hypotheses are raised to explain and understand the heterogeneity, including theories for cancer stem cell (CSC) and clonal evolution. According to the CSC theory, the most tumorigenic cells, while maintaining themselves through symmetric division, divide asymmetrically to generate non-CSCs with less tumorigenic and metastatic potential, although they can also dedifferentiate back to CSCs. Clonal evolution theory recapitulates that a tumor initially arises from a single cell, which then undergoes clonal expansion to a population of cancer cells. During tumorigenesis and evolution process, cancer cells undergo different degrees of genetic instability and consequently obtain varied genetic aberrations. Yet the heterogeneity in breast cancers is very complex, poorly understood and subjected to further investigation. In recent years, single cell sequencing (SCS) technology developed rapidly, providing a powerful new way to better understand the heterogeneity, which may lay foundations to some new strategies for breast cancer therapies. In this review, we will summarize development of SCS technologies and recent advances of SCS in breast cancer.


Testing a TheoRY-inspired MEssage ('TRY-ME'): a sub-trial within the Ontario Printed Educational Message (OPEM) trial.
A challenge for implementation researchers is to develop principles that could generate testable hypotheses that apply across a range of clinical contexts, thus leading to generalisability of findings. Such principles may be provided by systematically developed theories. The opportunity has arisen to test some of these theoretical principles in the Ontario Printed Educational Materials (OPEM) trial by conducting a sub-trial within the existing trial structure. OPEM is a large factorial cluster-randomised trial evaluating the effects of short directive and long discursive educational messages embedded into informed, an evidence-based newsletter produced in Canada by the Institute for Clinical Evaluative Sciences (ICES) and mailed to all primary care physicians in Ontario. The content of educational messages in the sub-trial will be constructed using both standard methods and methods inspired by psychological theory. The aim of this study is to test the effectiveness of the TheoRY-inspired MEssage ('TRY-ME') compared with the 'standard' message in changing prescribing behaviour. The OPEM trial participants randomised to receive the short directive message attached to the outside of informed (an 'outsert') will be sub-randomised to receive either a standard message or a message informed by the theory of planned behaviour (TPB) using a two (long insert or no insert) by three (theory-based outsert or standard outsert or no outsert) design. The messages will relate to prescription of thiazide diuretics as first line drug treatment for hypertension (described in the accompanying protocol, "The Ontario Printed Educational Materials trial"). The short messages will be developed independently by two research teams.The primary outcome is prescription of thiazide diuretics, measured by routinely collected data available within ICES. The study is designed to answer the question, is there any difference in guideline adherence (i.e., thiazide prescription rates) between physicians in the six groups? A process evaluation survey instrument based on the TPB will be administered pre- and post-intervention (described in the accompanying protocol, "Looking inside the black box"). The second research question concerns processes that may underlie observed differences in prescribing behaviour. We expect that effects of the messages on prescribing behaviour will be mediated through changes in physicians' cognitions.


The fine-scale structure of recombination rate variation in the human genome.
The nature and scale of recombination rate variation are largely unknown for most species. In humans, pedigree analysis has documented variation at the chromosomal level, and sperm studies have identified specific hotspots in which crossing-over events cluster. To address whether this picture is representative of the genome as a whole, we have developed and validated a method for estimating recombination rates from patterns of genetic variation. From extensive single-nucleotide polymorphism surveys in European and African populations, we find evidence for extreme local rate variation spanning four orders in magnitude, in which 50% of all recombination events take place in less than 10% of the sequence. We demonstrate that recombination hotspots are a ubiquitous feature of the human genome, occurring on average every 200 kilobases or less, but recombination occurs preferentially outside genes.


Secondary structure formation precedes tertiary structure in the refolding of ribonuclease A.
The kinetics of refolding of ribonuclease A were monitored by circular dichroism (CD), tyrosine fluorescence and absorbance in the -40 to -10 degrees C range using a methanol cryosolvent. The native-like far-ultraviolet CD signal returned in the dead-time of the mixing, whereas the native absorbance and fluorescence signals returned in a multiphasic process at rates several orders of magnitude more slowly. Thus the secondary structure was formed much more rapidly than the tertiary structure. In addition, the absorbance signal showed evidence of an early intermediate in which one, or more, tyrosine residues was in a transiently more polar environment. A total of four kinetic phases were observed by absorbance in refolding, the slowest two of which had energies of activation consistent with proline isomerization. A refolding scheme involving initial hydrophobic collapse, concurrent with secondary structure formation, followed by much slower rearrangement to the native tertiary structure is proposed.


Unexplained vomiting: a diagnostic challenge.
When vomiting is not related to preventing the entry of physically or chemically unsuitable substances into the absorbing gut, it may be regarded as pathologic. The commonest causes of chronic vomiting are structural lesions affecting the mucosa of the upper gastrointestinal tract (often with luminal obstruction) and psychogenic disorders. Diseases affecting extrinsic and intrinsic neural control of gut motility and visceral smooth muscle may also cause unexplained vomiting. A stratified management approach to patients with vomiting is suggested. The first assessment is aimed at exclusion of mucosal lesions of the upper gut and systemic or psychiatric disease that may affect it. Second is a therapeutic trial, usually with a prokinetic agent. The final phase, reserved for recalcitrant undiagnosed patients, is evaluation at special centers with gastric emptying studies, gastrointestinal manometry, other electrophysiologic studies, and, in a few patients, laparotomy with examination of full-thickness biopsy specimens of the small intestine.


Recognition of possible risk factors for clinically significant drug-drug interactions among Indian people living with HIV receiving highly active antiretroviral therapy and concomitant medications.
Greatest challenges for clinician is to recognize risk factors for clinically significant drug interactions (CSDIs). There is a lack of awareness about CSDIs among healthcare professionals in India. To recognize all possible risk factors for drug-drug interactions (DDIs) and to identify clinically significant drug interactions (CSDIs), the prevalence, pattern of occurrence of DDIs in People Living with HIV (PLW-HIV) receiving highly active antiretroviral therapy (HAART) and concomitant medications. A retrospective medical record review was carried out by clinical pharmacist with ethics committee approval. Case files of HIV patients receiving HAART with concomitant medications were analyzed for CSDIs using University of Liverpool drug interaction database and CSDIs were classified based on red flag indication (RFI) or contraindicated drug-drug interaction (XDDIs) and orange flag indication (OFI) or DDIs that needs close monitoring. Patients with DDIs (cases) and patients without DDIs (controls) were compared with Chi-square tests. P value <0.05 was considered as statistically significant. A total of 240 HIV patients' cases were screened. Out of which 267 DDIs were reported in 107 patients. Prevalence of DDIs was higher in male 71 (66.4%) compared to female 36 (33.6%). On zero-inflated poisson regression analysis, factors of polypharmacy, opportunistic infections, comorbid condition like Ischemic heart disease, respiratory tract infections, and psychiatric disorder were found to be predictors of high risk factors for DDIs to HAART. Fourteen XDDIs with RFI and two hundred fifty three DDIs with OFI were reported. XDDIs were atazanavir with fluconazole 4 (28.6%), ritonavir with fluconazole 4 (28.6%), nevirapine with rifampicin 2 (14.4%), ritonavir with quetiapine, atazanavir with pantoprazole. Pharmacokinetic DDIs were highest 238 (89.1%). Sixteen DDIs were reported in a single patient. The majority 97 (90.6%) patients had developed ≤5 DDIs, 8 (7.5%) developed six to eleven DDIs. The highest DDIs were reported with efavirenz 49 (18.4%) and zidovudine 44 (16.5%) based HAART regimen. In India, with the increasing access to HAART usage, Clinician must focus to pay attention to recognize possible risk factors for CSDIs associated with HAART regimen and strictly to avoid "Red Flag Indication combinations" while prescribing so as to prevent CSDIs.


Castleman disease of the hyaline-vascular type confined to the kidney.
The case is a 38-year-old man in whom a solitary subcapsular left renal cortical mass was successfully resected. Comorbidities included a benign epididymal cyst and a history of nephrolithiasis. Computed tomographic imaging demonstrated a 1.8-cm enhancing mass in the anterior midregion of the kidney. An open partial nephrectomy was performed, and histopathologic examination established a diagnosis of the hyaline-vascular type of Castleman disease (CD). The patient had an uneventful postoperative course and has experienced no local or metastatic recurrence in the 10 months since surgery. CD localized in the kidney is an exceptionally rare occurrence but should be included in the complete differential diagnosis of solitary renal cortical mass lesions.


HIV type 1 in a rural coastal town in Kenya shows multiple introductions with many subtypes and much recombination.
The extent of HIV-1 diversity was examined among patients attending a rural district hospital in a coastal area of Kenya. The pol gene was sequenced in samples from 153 patients. Subtypes were designated using the REGA, SCUEAL, and jpHMM programs. The most common subtype was A1, followed by C and D; A2 and G were also detected. However, a large proportion of the samples was found to be recombinants, which clustered within the pure subtype branches. Phylogeographic analysis of Kilifi sequences compared with those from other regions of Africa showed that while many sequences were closely related to sequences from Kenya, others were most closely related to known sequences from other parts of Africa, including West Africa. Overall, these data indicate that there have been multiple introductions of HIV-1 into this small rural town and surroundings with ongoing diversity being generated by recombination.


Targeted high-throughput sequencing identifies pathogenic mutations in KCNQ4 in two large Chinese families with autosomal dominant hearing loss.
Autosomal dominant non-syndromic hearing loss (ADNSHL) is highly heterogeneous, among them, KCNQ4 is one of the most frequent disease-causing genes. More than twenty KCNQ4 mutations have been reported, but none of them were detected in Chinese mainland families. In this study, we identified a novel KCNQ4 mutation in a five generation Chinese family with 84 members and a known KCNQ4 mutation in a six generation Chinese family with 66 members. Mutation screening of 30 genes for ADNSHL was performed in the probands from thirty large Chinese families with ADNSHL by targeted region capture and high-throughput sequencing. The candidate variants and the co-segregation of the phenotype were verified by polymerase chain reaction (PCR) amplification and Sanger sequencing in all ascertained family members. Then we identified a novel KCNQ4 mutation p.W275R in exon 5 and a known KCNQ4 mutation p.G285S in exon 6 in two large Chinese ADNSHL families segregating with post-lingual high frequency-involved and progressive sensorineural hearing loss. This is the first report of KCNQ4 mutation in Chinese mainland families. KCNQ4, a member of voltage-gated potassium channel family, is likely to be a common gene in Chinese patients with ADNSHL. The results also support that the combination of targeted enrichment and high-throughput sequencing is a valuable molecular diagnostic tool for autosomal dominant hereditary deafness.


Lipid metabolism in cancer cachexia.
Cancer cachexia, characterized by losses in muscle and adipose tissue (AT), is associated with poor quality of life and prognosis, and lacks effective therapies. Both tumor- and host- derived factors disrupt normal metabolism and are vital to the catabolic drive in cancer cachexia. While muscle loss has long dominated cachexia research, recent work conducted predominantly in rodent models has begun to recognize the significance of AT lipid metabolism alterations in the development and progression of cancer cachexia. AT losses are mainly attributed to the activation of lipolytic pathways. An important recent discovery has been in the demonstration of white AT (WAT) "browning" conferring thermogenic properties to adipocytes that results in wasteful energy expenditure. Collectively, both elevated lipolysis and WAT thermogenesis play an important role in AT depletion in cancer. The purpose of this review is to highlight current knowledge related to the regulation of AT function in cancer cachexia.


Body fluid derived exosomes as a novel template for clinical diagnostics.
Exosomes are small membrane vesicles with a size of 40-100 nm that are released by different cell types from a late endosomal cellular compartment. They can be found in various body fluids including plasma, malignant ascites, urine, amniotic fluid and saliva. Exosomes contain proteins, miRNAs and mRNAs (exosome shuttle RNA, esRNA) that could serve as novel platform for diagnosis. We isolated exosomes from amniotic fluid, saliva and urine by differential centrifugation on sucrose gradients. Marker proteins were identified by Western blot and FACS analysis after adsorption of exosomes to latex beads. We extracted esRNA from exosomes, carried out RT-PCR, and analyzed amplified products by restriction length polymorphism. Exosomes were positive for the marker proteins CD24, CD9, Annexin-1 and Hsp70 and displayed the correct buoyant density and orientation of antigens. In sucrose gradients the exosomal fractions contained esRNA that could be isolated with sufficient quantity for further analysis. EsRNAs were protected in exosomes from enzymatic degradation. Amniotic fluid esRNA served as template for the typing of the CD24 single nucleotide polymorphism (rs52812045). It also allowed sex determination of the fetus based on the detection of the male specific ZFY gene product. Our data demonstrate that exosomes from body fluids carry esRNAs which can be analyzed and offers access to the transcriptome of the host organism. The exosomal lipid bilayer protects the genetic information from degradation. As the isolation of exosomes is a minimally invasive procedure, this technique opens new possibilities for diagnostics.


Metabolic Rearrangements Causing Elevated Proline and Polyhydroxybutyrate Accumulation During the Osmotic Adaptation Response of Bacillus megaterium.
For many years now, Bacillus megaterium serves as a microbial workhorse for the high-level production of recombinant proteins in the g/L-scale. However, efficient and stable production processes require the knowledge of the molecular adaptation strategies of the host organism to establish optimal environmental conditions. Here, we interrogated the osmotic stress response of B. megaterium using transcriptome, proteome, metabolome, and fluxome analyses. An initial transient adaptation consisted of potassium import and glutamate counterion synthesis. The massive synthesis of the compatible solute proline constituted the second longterm adaptation process. Several stress response enzymes involved in iron scavenging and reactive oxygen species (ROS) fighting proteins showed higher levels under prolonged osmotic stress induced by 1.8 M NaCl. At the same time, the downregulation of the expression of genes of the upper part of glycolysis resulted in the activation of the pentose phosphate pathway (PPP), generating an oversupply of NADPH. The increased production of lactate accompanied by the reduction of acetate secretion partially compensate for the unbalanced (NADH/NAD+) ratio. Besides, the tricarboxylic acid cycle (TCA) mainly supplies the produced NADH, as indicated by the higher mRNA and protein levels of involved enzymes, and further confirmed by 13C flux analyses. As a consequence of the metabolic flux toward acetyl-CoA and the generation of an excess of NADPH, B. megaterium redirected the produced acetyl-CoA toward the polyhydroxybutyrate (PHB) biosynthetic pathway accumulating around 30% of the cell dry weight (CDW) as PHB. This direct relation between osmotic stress and intracellular PHB content has been evidenced for the first time, thus opening new avenues for synthesizing this valuable biopolymer using varying salt concentrations under non-limiting nutrient conditions.


Salt intake, blood pressure and clinical outcomes.
Salt intake has long been known to influence blood pressure among hypertensive patients, but its effect among those without overt hypertension, as well as its effects on cardiovascular disease itself, have been disputed. This report reviews the evidence for an effect on both blood pressure and cardiovascular disease, particularly among normotensive participants, including recent data from randomized trials. The Dietary Approaches to Stop Hypertension study provided clear evidence for a short-term effect of sodium on blood pressure among those with and without hypertension. Longer term trials among nonhypertensive particpants suggest more modest effects of lifestyle sodium reduction interventions on blood pressure. The recent Trials of Hypertension Prevention follow-up study found that, despite small changes in blood pressure, the risk of cardiovascular disease was reduced by 25% among those in the sodium reduction intervention. A study of potassium salt substitution among Taiwanese veterans supports this finding. Sodium and potassium may act jointly in the development of hypertension and cardiovascular disease. Average sodium consumption in the US population is excessively high, and well above recommended limits. Because most sodium derives from processed and restaurant foods, a reduction of sodium in these sources, as recently called for by the American Medical Association, is necessary to reduce exposure.


Imaging mass spectrometry: a new tool for kidney disease investigations.
Matrix-assisted laser desorption ionization (MALDI)-profiling and imaging mass spectrometry are promising technologies for measuring hundreds of different molecules directly on tissues. For instance, small molecules, drugs and their metabolites, endogenous lipids, carbohydrates and complex peptides/proteins can be measured at the same time without significant disruption of sample integrity. In this review, the potential of MALDI-profiling/imaging technologies in disease proteomics, drug action and studies of cellular processes in the context of kidney tissue is described. Spatial and sequence information obtained in tissue MALDI-profiling/imaging studies can be correlated with other mass spectrometry-based techniques, auxiliary imaging technologies and routine (immuno) histochemical staining.


DNA stickers promote polymer adsorption onto cellulose.
Adsorption of oligonucleotides onto model cellulose surfaces was investigated by comparing the Boese and Breaker's cellulose binding oligonucleotide (CBO) with a nonspecific oligonucleotide control (NSO). Measurements using the quartz crystal microbalance with dissipation technique confirmed that CBO adsorbed onto cellulose more than NSO, particularly at high ionic strengths (100 mM CaCl(2)). CBO showed a higher maximum adsorption on nanofibrillated and nanocrystalline cellulose than on regenerated cellulose, indicating a preference for the native cellulose I crystal structure under conditions that favored specific adsorption over calcium-mediated electrostatically driven adsorption. In addition, an anionic polyacrylamide (A-PAM) with grafted CBO also adsorbed onto the surface of cellulose in CaCl(2), whereas the unmodified A-PAM did not. This work shows that CBO performs as a "sticker", facilitating the adsorption of polyacrylamide onto cellulose, even under high ionic strength conditions where the adsorption of conventional polyelectrolytes is inhibited.


Structure of the prefusion-locking broadly neutralizing antibody RVC20 bound to the rabies virus glycoprotein.
Rabies virus (RABV) causes fatal encephalitis in more than 59,000 people yearly. Upon the bite of an infected animal, the development of clinical disease can be prevented with post-exposure prophylaxis (PEP), which includes the administration of Rabies immunoglobulin (RIG). However, the high cost and limited availability of serum-derived RIG severely hamper its wide use in resource-limited countries. A safe low-cost alternative is provided by using broadly neutralizing monoclonal antibodies (bnAbs). Here we report the X-ray structure of one of the most potent and most broadly reactive human bnAbs, RVC20, in complex with its target domain III of the RABV glycoprotein (G). The structure reveals that the RVC20 binding determinants reside in a highly conserved surface of G, rationalizing its broad reactivity. We further show that RVC20 blocks the acid-induced conformational change required for membrane fusion. Our results may guide the future development of direct antiviral small molecules for Rabies treatment.


Follow-up of children with celiac disease - lost in translation?
Celiac disease (CD) is a prevalent condition with a broad spectrum of presentations requiring a lifelong gluten-free diet (GFD). Our aims were to examine the presentation and adherence to a GFD as well as the adequacy of follow-up of children diagnosed with CD at a tertiary referral center. A retrospective electronic chart review of pediatric patients suspected of CD (n = 581) who were seen at our institute between January 1999 and December 2008 was performed. 387 children were diagnosed with CD (F/M ratio of 1.54, median age: 6.25 years). Presenting symptoms were iron deficiency anemia (n = 82, 34%), short stature (n = 59, 24.5%) and abdominal pain (n = 59, 24.5%). In 63 patients (16.3%) an associated autoimmune disease was recorded. Only 42.7% of the patients (165/387) had regular out-patient gastroenterologist visits; 22% (86/387) were followed by their primary care physician. Over 35% (136/387) were completely lost to follow-up. Negative serology on follow-up was present in 91% of the CD patients(150/165) followed at our center in comparison to 70% (60/86) in those followed up by their primary physician (p = 0.0002). At least in our referral center, follow-up of children diagnosed with CD is far from satisfactory. Initiatives aimed at improving adherence to regular follow-up are needed as this intervention is associated with a significant increase in patient compliance with a long-term GFD.


Cannabinoid CB2 receptors are involved in the protection of RAW264.7 macrophages against the oxidative stress: an in vitro study.
Research in the last decades has widely investigated the anti-oxidant properties of natural products as a therapeutic approach for the prevention and the treatment of oxidative-stress related disorders. In this context, several studies were aimed to evaluate the therapeutic potential of phytocannabinoids, the bioactive compounds of Cannabis sativa. Here, we examined the anti-oxidant ability of Cannabigerol (CBG), a non-psychotropic cannabinoid, still little known, into counteracting the hydrogen peroxide (H2O2)-induced oxidative stress in murine RAW264.7 macrophages. In addition, we tested selective receptor antagonists for cannabinoid receptors and specifically CB1R (SR141716A) and CB2R (AM630) in order to investigate through which CBG may exert its action. Taken together, our in vitro results showed that CBG is able to counteract oxidative stress by activation of CB2 receptors. CB2 antagonist pre-treatment indeed blocked the protective effects of CBG in H2O2 stimulated macrophages, while CB1R was not involved. Specifically, CBG exhibited a potent action in inhibiting oxidative stress, by down-regulation of the main oxidative markers (iNOS, nitrotyrosine and PARP-1), by preventing IκB-α phosphorylation and translocation of the nuclear factor-κB (NF-κB) and also via the modulation of MAP kinases pathway. On the other hand, CBG was found to increase anti-oxidant defense of cells by modulating superoxide dismutase-1 (SOD-1) expression and thus inhibiting cell death (results focused on balance between Bax and Bcl-2). Based on its antioxidant activities, CBG may hold great promise as an anti-oxidant agent and therefore used in clinical practice as a new approach in oxidative-stress related disorders.


Evaluation of aviation-based safety team training in a hospital in The Netherlands.
The purpose of this paper is to evaluate the implementation of a broad-scale team resource management (TRM) program on safety culture in a Dutch eye hospital, detailing the program's content and procedures. Aviation-based TRM training is recognized as a useful approach to increase patient safety, but little is known about how it affects safety culture. Pre- and post-assessments of the hospitals' safety culture was based on interviews with ophthalmologists, anesthesiologists, residents, nurses, and support staff. Interim observations were made at training sessions and in daily hospital practice. The program consisted of safety audits of processes and (team) activities, interactive classroom training sessions by aviation experts, a flight simulator session, and video recording of team activities with subsequent feedback. Medical professionals considered aviation experts inspiring role models and respected their non-hierarchical external perspective and focus on medical-technical issues. The post-assessment showed that ophthalmologists and other hospital staff had become increasingly aware of safety issues. The multidisciplinary approach promoted social (team) orientation that replaced the former functionally-oriented culture. The number of reported near-incidents greatly increased; the number of wrong-side surgeries stabilized to a minimum after an initial substantial reduction. The study was observational and the hospital's variety of efforts to improve safety culture prevented us from establishing a causal relation between improvement and any one specific intervention. Aviation-based TRM training can be a useful to stimulate safety culture in hospitals. Safety and quality improvements are not single treatment interventions but complex socio-technical interventions. A multidisciplinary system approach and focus on "team" instead of "profession" seems both necessary and difficult in hospital care.


Transcellular passage of Neisseria meningitidis across a polarized respiratory epithelium.
Neisseria meningitidis is a major cause of sepsis and meningitis but is also a common commensal, present in the nasopharynx of between 8 and 20% of healthy individuals. During carriage, the bacterium is found on the surface of the nasopharyngeal epithelium and in deeper tissues, while to develop disease the meningococcus must spread across the respiratory epithelium and enter the systemic circulation. Therefore, investigating the pathways by which N. meningitidis crosses the epithelial barrier is relevant for understanding carriage and disease but has been hindered by the lack of appropriate models. Here, we have established a physiologically relevant model of the upper respiratory epithelial cell barrier to investigate the mechanisms responsible for traversal of N. meningitidis. Calu-3 human respiratory epithelial cells were grown on permeable cell culture membranes to form polarized monolayers of cells joined by tight junctions. We show that the meningococcus crosses the epithelial cell barrier by a transcellular route; traversal of the layer did not disrupt its integrity, and bacteria were detected within the cells of the monolayer. We demonstrate that successful traversal of the epithelial cell barrier by N. meningitidis requires expression of its type 4 pili (Tfp) and capsule and is dependent on the host cell microtubule network. The Calu-3 model should be suitable for dissecting the pathogenesis of infections caused by other respiratory pathogens, as well as the meningococcus.


Metazoan Parasite Vaccines: Present Status and Future Prospects.
Eukaryotic parasites and pathogens continue to cause some of the most detrimental and difficult to treat diseases (or disease states) in both humans and animals, while also continuously expanding into non-endemic countries. Combined with the ever growing number of reports on drug-resistance and the lack of effective treatment programs for many metazoan diseases, the impact that these organisms will have on quality of life remain a global challenge. Vaccination as an effective prophylactic treatment has been demonstrated for well over 200 years for bacterial and viral diseases. From the earliest variolation procedures to the cutting edge technologies employed today, many protective preparations have been successfully developed for use in both medical and veterinary applications. In spite of the successes of these applications in the discovery of subunit vaccines against prokaryotic pathogens, not many targets have been successfully developed into vaccines directed against metazoan parasites. With the current increase in -omics technologies and metadata for eukaryotic parasites, target discovery for vaccine development can be expedited. However, a good understanding of the host/vector/pathogen interface is needed to understand the underlying biological, biochemical and immunological components that will confer a protective response in the host animal. Therefore, systems biology is rapidly coming of age in the pursuit of effective parasite vaccines. Despite the difficulties, a number of approaches have been developed and applied to parasitic helminths and arthropods. This review will focus on key aspects of vaccine development that require attention in the battle against these metazoan parasites, as well as successes in the field of vaccine development for helminthiases and ectoparasites. Lastly, we propose future direction of applying successes in pursuit of next generation vaccines.


Position paper: the science of deep specification.
We introduce our efforts within the project 'The science of deep specification' to work out the key formal underpinnings of industrial-scale formal specifications of software and hardware components, anticipating a world where large verified systems are routinely built out of smaller verified components that are also used by many other projects. We identify an important class of specification that has already been used in a few experiments that connect strong component-correctness theorems across the work of different teams. To help popularize the unique advantages of that style, we dub it deep specification, and we say that it encompasses specifications that are rich, two-sided, formal and live (terms that we define in the article). Our core team is developing a proof-of-concept system (based on the Coq proof assistant) whose specification and verification work is divided across largely decoupled subteams at our four institutions, encompassing hardware microarchitecture, compilers, operating systems and applications, along with cross-cutting principles and tools for effective specification. We also aim to catalyse interest in the approach, not just by basic researchers but also by users in industry.This article is part of the themed issue 'Verified trustworthy software systems'.


Self-rated pain and perceived health in relation to stress and physical activity among school-students: a 3-year follow-up.
The aim of this longitudinal study was to assess changes with age regarding prevalence of pain and perceived health in a student population, as well as change over time at grade level. Pain included frequency of headache, abdominal, and musculoskeletal pain and perceived health included problems sleeping and/or if they often felt tired, lonely, and sad. If gender, age (grade level), stress, physically activity were related to pain and health complaints were tested with multivariate logistic regression analysis. The students (n=1908) came from randomly selected schools throughout Sweden and attended grades 3, 6 and 9 (ages 9, 12 and 15 at the onset of the year) in 2001. Three years later, 67% (n=1276) of the same students answered a questionnaire that was constructed for the purpose of the studies. The responses given by the same students showed that girls' complaints of pain and perceived health increased with age and boys decreased. Over half (56%) of the girls and two-thirds (67%) of the boys reported no frequent complaints either year. At grade level most variables were rated the same as three years earlier by the same age group. Stress was significantly related to pain and health complaints for girls and the risk of complaints, as calculated with odds ratio, was most evident for students who were characterized as being physically inactive in 2001 and remained inactive three years later. Jointly, significant predictors, such as stress, being physically inactive, gender and grade level, explained 8-20% of the frequent complaints.


Adenovirus-associated antibodies in UK cohort of hemophilia patients: A seroprevalence study of the presence of adenovirus-associated virus vector-serotypes AAV5 and AAV8 neutralizing activity and antibodies in patients with hemophilia A.
Current treatment for severe hemophilia A is replacement of deficient factor. Although replacement therapy has improved life expectancy and quality, limitations include frequent infusions and high costs. Gene therapy is a potential alternative that utilizes an adeno-associated virus (AAV) vector containing the human genetic code for factor 8 (FVIII) that transduces the liver, enabling endogenous production of FVIII. Individuals with preexisting immunity to AAV serotypes may be less likely to benefit from this treatment. This study measured seroprevalence of antibodies to AAV5 and 8 in an UK adult hemophilia A cohort. Patients were recruited from seven hemophilia centres in the UK. Citrated plasma samples from 100 patients were tested for preexisting activities against AAV5 and 8 using AAV transduction inhibition and total antibodies assays. Twent-one percent of patients had antibodies against AAV5 and 23% had antibodies against AAV8. Twenty-five percent and 38% of patients exhibited inhibitors of AAV5 or AAV8 cellular transduction respectively. Overall seroprevalence using either assay against AAV5 was 30% and against AAV8 was 40% in this cohort of hemophilia A patients. Seropositivity for both AAV5 and AAV8 was seen in 24% of participants. Screening for preexisting immunity may be important in identifying patients most likely to benefit from gene therapy. Clinical studies may be needed to evaluate the impact of preexisting immunity on the safety and efficacy of AAV mediated gene therapy.


Pediatric nurses' perceptions of obstacles and supportive behaviors in end-of-life care.
Each year 55 000 children die in the United States, and most of these deaths occur in hospitals. The barriers and supportive behaviors in providing end-of-life care to children should be determined. To determine pediatric intensive care unit nurses' perceptions of sizes, frequencies, and magnitudes of selected obstacles and helpful behaviors in providing end-of-life care to children. A national sample of 1047 pediatric intensive care unit nurses who were members of the American Association of Critical-Care Nurses were surveyed. A 76-item questionnaire adapted from 3 similar surveys with critical care, emergency, and oncology nurses was mailed to possible participants. Nurses who did not respond to the first mailing were sent a second mailing. Nurses were asked to rate the size and frequency of listed obstacles and supportive behaviors in caring for children at the end of life. A total of 474 usable questionnaires were received from 985 eligible respondents (return rate, 48%). The 2 items with the highest perceived obstacle magnitude scores for size and frequency means were language barriers and parental discomfort in withholding and/or withdrawing mechanical ventilation. The highest supportive behavior item was allowing time alone with the child when he or she has died. Pediatric intensive care unit nurses play a vital role in caring for dying children and the children's families. Overcoming language and communication barriers with children's families and between interdisciplinary team members could greatly improve the end-of-life experience for dying children.


Luteinizing hormone causes MAP kinase-dependent phosphorylation and closure of connexin 43 gap junctions in mouse ovarian follicles: one of two paths to meiotic resumption.
Luteinizing hormone (LH) acts on ovarian follicles to reinitiate meiosis in prophase-arrested mammalian oocytes, and this has been proposed to occur by interruption of a meioisis-inhibitory signal that is transmitted through gap junctions into the oocyte from the somatic cells that surround it. To investigate this idea, we microinjected fluorescent tracers into live antral follicle-enclosed mouse oocytes, and we demonstrate for the first time that LH causes a decrease in the gap junction permeability between the somatic cells, prior to nuclear envelope breakdown (NEBD). The decreased permeability results from the MAP kinase-dependent phosphorylation of connexin 43 on serines 255, 262 and 279/282. We then tested whether the inhibition of gap junction communication was sufficient and necessary for the reinitiation of meiosis. Inhibitors that reduced gap junction permeability caused NEBD, but an inhibitor of MAP kinase activation that blocked gap junction closure in response to LH did not prevent NEBD. Thus, both MAP kinase-dependent gap junction closure and another redundant pathway function in parallel to ensure that meiosis resumes in response to LH.


What are the differences among occupational groups related to their palliative care-specific educational needs and intensity of interprofessional collaboration in long-term care homes?
The purpose of this study was to compare the differences across occupational groups related to their end-of-life care-specific educational needs and reported intensity of interprofessional collaboration in long-term care (LTC) homes. A cross-sectional survey, based on two questionnaires, was administered at four LTC homes in Ontario, Canada using a modified Dilman's approach. The first questionnaire, End of Life Professional Caregiver Survey, included three domains: patients and family-centered communication, cultural and ethical values, effective care delivery. The Intensity of Interprofessional Collaboration Scale included two subscales: care sharing activities, and interprofessional coordination. In total, 697 LTC staff were given surveys, including personal support workers, support staff (housekeeping, kitchen, recreation, laundry, dietician aids, office staff), and registered staff (licensed nurses, physiotherapists, social workers, pharmacists, physicians). A total of 317 participants completed the survey (126 personal support workers, 109 support staff, 82 registered staff) for a response rate of 45%. Significant differences emerged among occupational groups across all scales and subscales. Specifically, support staff rated their comfort of working with dying patients significantly lower than both nurses and PSWs. Support staff also reported significantly lower ratings of care sharing activities and interprofessional coordination compared to both registered staff and personal support workers. These study findings suggest there are differing educational needs and sense of interprofessional collaboration among LTC staff, specific to discipline group. Both the personal support workers and support staff groups appeared to have higher needs for education; support staff also reported higher needs related to integration on the interdisciplinary team. Efforts to build capacity within support staff related to working with dying residents and their families are needed. Optimal palliative care may require resources to increase the availability of support for all staff involved in the care of patients.


Employment advice in primary care: a realistic evaluation.
Every organisation in the UK is affected by mental distress and ill-health in the workforce. The first point of contact for most people with common mental health problems, such as mild to moderate anxiety or depression, is their general practitioner. The location of specialist employment advisers in GP surgeries is therefore a logical attempt to address the issue of people falling out of the workplace, through the provision of early intervention and combined vocational and psychological treatment packages. In 2007 the Richmond Fellowship, a national mental health charity, received a grant to provide four employment advisers to work with GP surgeries in Eastern England. The aim was to help people with mental health problems gain work (Regain clients) or retain their current employment (Retain clients). In this study a realistic evaluation framework was applied to address the question of what works, for whom and in which contexts through interviews with key stakeholders including 22 clients of the project, five primary health care staff and the four employment advisers. The interventions that Retain clients found most helpful were careers guidance (including psychological profiling) and developing strategies to negotiate and communicate with employers. These appeared to help individuals to take control, broaden their horizons and move forward. In many cases this was supported by assistance in helping clients think through whether they wanted to consider a career change. For Regain clients the most important interventions were help with interview skills, CV writing and assertiveness training. Employment outcomes were considerably higher for the Retain clients than for the Regain clients. The study indicates that it could be more effective for Retain and Regain services to be delivered through different care pathways to avoid diluting the services offered and consequently reducing their effectiveness.


Irregular Sleep/Wake Patterns Are Associated With Reduced Quality of Life in Post-treatment Cancer Patients: A Study Across Three Cancer Cohorts.
Background: Cancer patients often describe poor sleep quality and sleep disruption as contributors to poor quality of life (QoL). In a cross-sectional study of post-treatment breast, endometrial, and melanoma cancer patients, we used actigraphy to quantify sleep regularity using the sleep regularity index (SRI), and examined relationships with reported sleep symptoms and QoL. Methods: Participants were recruited post-primary treatment (35 diagnosed with breast cancer, 24 endometrial cancer, and 29 melanoma) and wore an actigraphy device for up to 2 weeks and SRI was calculated. Self-report questionnaires for cancer-related QoL [European Organization for Research and Treatment of Cancer EORTC (QLQ-C30)] were completed. Data were compared using analysis of variance (ANOVA) or Chi-Square tests. Multivariate linear regression analysis was used to determine independent variable predictors for questionnaire-derived data. Results: Age distribution was similar between cohorts. Endometrial and breast cancer cohorts were predominantly female, as expected, and body mass index (BMI) was higher in the endometrial cancer cohort, followed by breast and melanoma. There were no differences between tumor groups in: total sleep time, sleep onset latency, bedtime, and SRI (breast 80.9 ± 8.0, endometrial 80.3 ± 12.2, and melanoma 81.4 ± 7.0) (all p > 0.05). A higher SRI was associated with both better functional and symptom scores, including increased global QoL, better physical functioning, less sleepiness and fatigue, better sleep quality, and associated with less nausea/vomiting, dyspnea, and diarrhea (all p < 0.05). Conclusion: In cancer patients post-treatment, greater sleep regularity is associated with increased global QoL, as well as better physical functioning and fewer cancer related symptoms. Improving sleep regularity may improve QoL for cancer patients.


Change in gene abundance in the nitrogen biogeochemical cycle with temperature and nitrogen addition in Antarctic soils.
The microbial community (bacterial, archaeal, and fungi) and eight genes involved in the nitrogen biogeochemical cycle (nifH, nitrogen fixation; bacterial and archaeal amoA, ammonia oxidation; narG, nitrate reduction; nirS, nirK, nitrite reduction; norB, nitric oxide reduction; and nosZ, nitrous oxide reduction) were quantitatively assessed in this study, via real-time PCR with DNA extracted from three Antarctic soils. Interestingly, AOB amoA was found to be more abundant than AOA amoA in Antarctic soils. The results of microcosm studies revealed that the fungal and archaeal communities were diminished in response to warming temperatures (10 °C) and that the archaeal community was less sensitive to nitrogen addition, which suggests that those two communities are well-adapted to colder temperatures. AOA amoA and norB genes were reduced with warming temperatures. The abundance of only the nifH and nirK genes increased with both warming and the addition of nitrogen. NirS-type denitrifying bacteria outnumbered NirK-type denitrifiers regardless of the treatment used. Interestingly, dramatic increases in both NirS and NirK-types denitrifiers were observed with nitrogen addition. NirK types increase with warming, but NirS-type denitrifiers tend to be less sensitive to warming. Our findings indicated that the Antarctic microbial nitrogen cycle could be dramatically altered by temperature and nitrogen, and that warming may be detrimental to the ammonia-oxidizing archaeal community. To the best of our knowledge, this is the first report to investigate genes associated with each process of the nitrogen biogeochemical cycle in an Antarctic terrestrial soil environment.