Limbic versus cognitive target for deep brain stimulation in treatment-resistant depression: accumbens more promising than caudate.
High-frequency deep brain stimulation (DBS) represents a major stake for treatment for treatment-resistant depression (TRD). We describe a preliminary trial of DBS of two potential brain targets in chronic TRD: the nucleus accumbens (Acb) and, in the event of failure, the caudate nucleus. Patients were followed for 6 months before surgery (M0). From M1 to M5, they underwent stimulation of the Acb target. PET scans allowed us to track metabolic modifications resulting from this stimulation. The caudate target of nonresponders was stimulated between M5 and M9. Patients then entered an extension phase, in which it was possible to adapt stimulation parameters and treatments. Six patients were included and four were operated on. At M5, none of the patients were either responders or remitters, but we did observe a decrease in Hamilton Depression Rating Scale (HDRS) scores. Three patients were switched to caudate stimulation, but no improvement was observed. During the extension phase, the Acb target was stimulated for all patients, three of whom exhibited a significant response. A decrease in glucose metabolism was observed after Acb stimulation, in the posterior cingulate gyrus, left frontal lobe, superior and medial gyrus, and bilateral cerebellum. An increase in metabolism was observed in the bilateral frontal lobe (superior gyrus), left frontal lobe (medial gyrus), and right limbic lobe (anterior cingulate gyrus). The results of this trial suggest that Acb is a more promising target than the caudate. NCT01569711.


Unmet refractive need and its determinants in Shahroud, Iran.
Uncorrected refractive error plays a significant role in poor vision and blindness, and its correction is the most cost-effective intervention in eye care. In this study, we report the status of the unmet refractive need and the role of economic inequality in determining the level of this need in Shahroud, Iran. This cross-sectional nested case-control study was performed on 5,190 individuals aged 40-64 years. Cases and controls were individuals with uncorrected visual acuity worse than 0.3 LogMAR in the better eye who showed at least 0.2 LogMAR improvement after correction. Cases were individuals whose presenting vision was worse than 0.3 in the better eye but improved by at least 0.2 LogMAR after correction. Controls were individuals in whom the difference between the presenting and corrected vision was less than 0.2 LogMAR. The prevalence of the unmet need was 5.7 % and it was more prevalent in women (6.5 %) than in men (4.6 %) (p = 0.003). There was a gap of 19.6 % between the two groups of high and low economic status. The Oaxaca-Blinder decomposition method revealed that differences in the education level of the two groups accounted for half of this gap. Spectacle usage is better in Iran than in some other developing countries; however, in this study, about 40 % of those who required spectacles did not have them.


An Osteopathic Modular Approach to Asthma: A Narrative Review.
Asthma is among of the first ailments documented in the existing academic literature as being successfully managed with osteopathic manipulative treatment (OMT) techniques. Time-efficient and well-tolerated OMT techniques have been gradually added to the literature to manage this increasingly prevalent disease. In this narrative review, the authors discuss previously-published literature describing the history, diagnosis, and management of asthma related to osteopathic principles and practices and OMT application. They also present current and newly-approved medical managements, including biologics and inhaled corticosteroids. This article also includes supplemental videos showcasing OMT techniques for asthma management, which were developed by the authors based on recommendations indicated in the literature.


Transcranial Doppler detection of vertebrobasilar vasospasm following subarachnoid hemorrhage.
Transcranial Doppler sonography is of established value in the detection and monitoring of middle cerebral artery vasospasm. Little information exists on the utility of transcranial Doppler for detection of posterior circulation vasospasm. Cerebral angiography and conventional hand-held transcranial Doppler sonography were compared to determine sensitivity and specificity of transcranial Doppler for detection of vertebral and basilar artery vasospasm. Of 59 consecutive subarachnoid hemorrhage patients with transcranial Doppler angiogram correlations, 42 underwent posterior circulation angiography to evaluate 64 vertebral arteries and 42 basilar arteries during the period of risk for vasospasm and had technically adequate transcranial Doppler examinations within 24 hours of the angiogram. A mean flow velocity of 60 cm/s and above was indicative of both vertebral and basilar artery vasospasm. For the vertebral artery, there were 7 true-positive test results, 42 true-negatives, 6 false-positives (unknown cause in 3, increased collateral flow in 1, adjacent vessel vasospasm in 1, hyperperfusion in 1), and 9 false-negatives (anatomic in 7, operator error in 2). Sensitivity was 44% and specificity was 87.5%. For the basilar artery, there were 10 true-positives, 23 true-negatives, 6 false-positives (unknown cause in 4, hyperemia/hyperperfusion in 1, increased collateral flow in 1), and 3 false-negatives (operator error in 2, tortuous vessel course in 1). Sensitivity was 76.9% and specificity was 79.3%. When the diagnostic criterion was changed to > or = 80 cm/s (vertebral artery) and > or = 95 cm/s (basilar artery), all false-positive results were eliminated (specificity and positive predictive value, 100%). Our data suggest that transcranial Doppler has good specificity for the detection of vertebral artery vasospasm and good sensitivity and specificity for the detection of basilar artery vasospasm. Transcranial Doppler is highly specific (100%) for vertebral and basilar artery vasospasm when flow velocities are > or = 80 and > or = 95 cm/s, respectively.


Structure and morphogenesis of Dugbe virus (Bunyaviridae, Nairovirus) studied by immunogold electron microscopy of ultrathin cryosections.
We have studied the structure and morphogenesis of Dugbe (DUG) virus (Bunyaviridae, Nairovirus) in cultured porcine kidney (PS) cells and a tick cell line (Ra 243) using immunogold electron microscopy. DUG virus is a tickborne arbovirus, considered to be a low health hazard, that is antigenically and genetically related to Crimean Congo haemorrhagic fever (CCHF) virus (Marriott et al., 1990). We have investigated the maturation and intracellular transport of DUG virus particles as a model for other more pathogenic nairoviruses using monoclonal antibodies for immunogold labelling of ultrathin cryosections and immunofluorescence techniques. The spherical DUG virus particle measures about 90 nm in diameter, with a 5 nm thick membrane covered by 5-7 nm long projections or "spikes". These projections form hollow cylindrical morphological units, about 5 nm in diameter. DUG virus infection caused only a slight cytopathogenic effect in mammalian cells and none in tick cells. DUG virus particles assembled by budding from the Golgi complex, where the DUG virus glycoprotein G1 accumulated in vesicles originating from Golgi cisternae. The nucleocapsid protein N accumulated in scattered foci throughout the cytoplasm, and this appears to be related to the limited maturation of DUG virus particles that occurred. The reduced number of budding virus particles observed in tick cells was correlated with the reduced cytopathology observed.


Finite-element modeling of intrastromal ring segment implantation into a hyperelastic cornea.
Intrastromal corneal-ring segments (ICRSs) are applied to improve highly distorted vision in keratoconic, myopic, and astigmatic patients. Selections of ICRS geometry and position are primarily based on empirical nomograms. We developed a finite-element model (FEM) predicting the corneal response to different ICRS geometries in normal and keratoconic corneas. A two-dimensional FEM was built in proprietary software (ANSYS-APDL), consisting of hyperelastic ocular tissues (cornea, limbus, sclera) and a triangular/hexagonal ICRS of poly(methyl methacrylate). An incrustation model was developed considering the local material addition and rigidity increase at the ICRS position and also for the triangular ICRS the geometric difference between its base (plane) and corneal tunnel (parallel to corneal surface). Different ICRS heights (150-350 μm) and optical zones (4.4-6.6 mm) were simulated. An axis-symmetric model of keratoconus was studied, where corneal elasticity was decreased locally. ICRS GEOMETRY (HEIGHT AND OPTICAL ZONE) HAD A SIGNIFICANT INFLUENCE ON CORNEAL POWER: changes from 4.08 to -17.7 diopters (D) (healthy)/3.31 to -20.5 D (keratoconic) were observed. Central corneal thickness was predicted to increase by up to 38.5 μm (healthy)/97.9 μm (keratoconic). Spherical aberration also changed upon ICRS implantation. The protrusion of the posterior cornea behind the rings was well predicted. The model confirmed the clinically reported trends on the effect of ring geometry. FEM is a powerful tool to study the corneal response to ICRS implantation. The combination of FEM with individual biomechanical properties and geometry of patients holds promise to increase the predictability of ICRS surgery.


Mycobacterium ulcerans infection (Buruli ulcer): first reported case in a traveler.
A chronic, painless sore developed over a 2-month period on the left calf of a Canadian man traveling for 8 months in Africa. A presumptive diagnosis of a Mycobacterium spp. infection was made despite initially negative biopsy and culture results, after failure of several courses of anti-bacterial antibiotics. Mycobacterium ulcerans was eventually isolated and the lesion progressed despite treatment with multiple anti-mycobacterial agents. The lesion finally responded to wide and repeated excision, aggressive treatment with anti-mycobacterial antibiotics, and split-thickness skin grafting. The isolation and treatment of this unusual organism are discussed.


Effects of fat on glucose uptake and utilization in patients with non-insulin-dependent diabetes.
It was the aim of this study to determine whether FFA inhibit insulin-stimulated whole body glucose uptake and utilization in patients with non-insulin-dependent diabetes. We performed five types of isoglycemic (approximately 11mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin; (c) with insulin plus glycerol; (d) with saline; (e) with saline plus fat/heparin and two types of euglycemic (approximately 5mM) clamps: (a) with insulin; (b) with insulin plus fat/heparin. During these studies, we determined rates of glucose uptake, glycolysis (both with 3[3H] glucose), glycogen synthesis (determined as glucose uptake minus glycolysis), carbohydrate oxidation (by indirect calorimetry) and nonoxidative glycolysis (determined as glycolysis minus carbohydrate oxidation). Fat/heparin infusion did not affect basal glucose uptake, but inhibited total stimulated (insulin stimulated plus basal) glucose uptake by 40-50% in isoglycemic and in euglycemic patients at plasma FFA concentration of approximately 950 and approximately 550 microM, respectively. In isoglycemic patients, the 40-50% inhibition of total stimulated glucose uptake was due to near complete inhibition of the insulin-stimulated part of glucose uptake. Proportional inhibition of glucose uptake, glycogen synthesis, and glycolysis suggested a major FFA-mediated defect involving glucose transport and/or phosphorylation. In summary, fat produced proportional inhibitions of insulin-stimulated glucose uptake and of intracellular glucose utilization. We conclude, that physiologically elevated levels of FFa could potentially be responsible for a large part of the peripheral insulin resistance in patients with non-insulin-dependent diabetes mellitus.


Honokiol suppresses pancreatic tumor growth, metastasis and desmoplasia by interfering with tumor-stromal cross-talk.
The poor clinical outcome of pancreatic cancer (PC) is largely attributed to its aggressive nature and refractoriness to currently available therapeutic modalities. We previously reported antitumor efficacy of honokiol (HNK), a phytochemical isolated from various parts of Magnolia plant, against PC cells in short-term in vitro growth assays. Here, we report that HNK reduces plating efficiency and anchorage-independent growth of PC cells and suppresses their migration and invasiveness. Furthermore, significant inhibition of pancreatic tumor growth by HNK is observed in orthotopic mouse model along with complete-blockage of distant metastases. Histological examination suggests reduced desmoplasia in tumors from HNK-treated mice, later confirmed by immunohistochemical analyses of myofibroblast and extracellular matrix marker proteins (α-SMA and collagen I, respectively). At the molecular level, HNK treatment leads to decreased expression of sonic hedgehog (SHH) and CXCR4, two established mediators of bidirectional tumor-stromal cross-talk, both in vitro and in vivo . We also show that the conditioned media (CM) from HNK-treated PC cells have little growth-inducing effect on pancreatic stellate cells (PSCs) that could be regained by the addition of exogenous recombinant SHH. Moreover, pretreatment of CM of vehicle-treated PC cells with SHH-neutralizing antibody abolishes their growth-inducing potential on PSCs. Likewise, HNK-treated PC cells respond poorly to CM from PSCs due to decreased CXCR4 expression. Lastly, we show that the transfection of PC cells with constitutively active IKKβ mutant reverses the suppressive effect of HNK on nuclear factor-kappaB activation and partially restores CXCR4 and SHH expression. Taken together, these findings suggest that HNK interferes with tumor-stromal cross-talk via downregulation of CXCR4 and SHH and decreases pancreatic tumor growth and metastasis.


Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis.
Previous studies, such as the Women's Health Initiative, have shown that a low dose of vitamin D did not protect against colorectal cancer, yet a meta-analysis indicates that a higher dose may reduce its incidence. Five studies of serum 25(OH)D in association with colorectal cancer risk were identified using PubMed. The results of all five serum studies were combined using standard methods for pooled analysis. The pooled results were divided into quintiles with median 25(OH)D values of 6, 16, 22, 27, and 37 ng/mL. Odds ratios were calculated by quintile of the pooled data using Peto's Assumption-Free Method, with the lowest quintile of 25(OH)D as the reference group. A dose-response curve was plotted based on the odds for each quintile of the pooled data. Data were abstracted and analyzed in 2006. Odds ratios for the combined serum 25(OH)D studies, from lowest to highest quintile, were 1.00, 0.82, 0.66, 0.59, and 0.46 (p(trend)<0.0001) for colorectal cancer. According to the DerSimonian-Laird test for homogeneity of pooled data, the studies were homogeneous (chi(2)=1.09, df=4, p=0.90. The pooled odds ratio for the highest quintile versus the lowest was 0.49 (p<0.0001, 95% confidence interval, 0.35-0.68). A 50% lower risk of colorectal cancer was associated with a serum 25(OH)D level > or =33 ng/mL, compared to < or =12 ng/mL. The evidence to date suggests that daily intake of 1000-2000 IU/day of vitamin D(3) could reduce the incidence of colorectal with minimal risk.


White Matter Microstructure Predicts Focal and Broad Functional Brain Dedifferentiation in Normal Aging.
Ventral visual cortex exhibits highly organized and selective patterns of functional activity associated with visual processing. However, this specialization decreases in normal aging, with functional responses to different visual stimuli becoming more similar with age, a phenomenon termed "dedifferentiation." The current study tested the hypothesis that age-related degradation of the inferior longitudinal fasciculus (ILF), a white matter pathway involved in visual perception, could account for dedifferentiation of both localized and distributed brain activity in ventral visual cortex. Participants included 281 adults, ages 20-89 years, from the Dallas Lifespan Brain Study who underwent diffusion-weighted imaging to measure white matter diffusivity, as well as fMRI to measure functional selectivity to viewing photographs from different categories (e.g., faces, houses). In general, decreased ILF anisotropy significantly predicted both focal and broad functional dedifferentiation. Specifically, there was a localized effect of structure on function, such that decreased anisotropy in a smaller mid-fusiform region of ILF predicted less selective (i.e., more dedifferentiated) response to viewing faces in a proximal face-responsive region of fusiform. On the other hand, the whole ILF predicted less selective response across broader ventral visual cortex for viewing animate (e.g., human faces, animals) versus inanimate (e.g., houses, chairs) images. This structure-function relationship became weaker with age and was no longer significant after the age of 70 years. These findings indicate that decreased white matter anisotropy is associated with maladaptive differences in proximal brain function and is an important variable to consider when interpreting age differences in functional selectivity.


Hypothyroidism in children: diagnosis and treatment.
To present relevant and updated information on the status of hypothyroidism in the pediatric population (newborn infants to adolescents). Original and review articles and books containing relevant updated data. This review addressed data on the etiopathogeny of hypothyroidism and on the importance of screening for congenital hypothyroidism to assure early diagnosis and treatment of the newborn. We point out the difficulties experienced in the handling of subclinical hypothyroidism; we also address the importance of diagnosing autoimmune Hashimoto's thyroiditis, the high incidence of the disease among adolescents, mainly females, and the occurrence of a severe neurological condition, Hashimoto's encephalopathy. We indicate situations in which severe hypothyroidism may lead to puberty disorders (precocious or delayed puberty) and describe the importance of transcription factors in thyroid embryogenesis. Diagnostic and therapeutic criteria are also addressed. Thyroid hormones are necessary for normal growth and development since fetal life. Insufficient production or inadequate activity on the cellular or molecular level lead to hypothyroidism. These hormones are necessary for the development of the brain in the fetus and in the newborn infant. Neonatologists and pediatricians deal with child development issues in their practice, and many of these issues start during intrauterine life. Currently, with neonatal screening, neonatologists and pediatricians can prevent irreversible damage through early treatment. They should also be alert for dysfunctions such as subclinical hypothyroidism and Hashimoto's thyroiditis, which may provoke damage not only to growth, but also to the neurological and psychological development of these children and adolescents.


Myocardial perfusion following acute subarachnoid hemorrhage in patients with an abnormal electrocardiogram.
To test the hypothesis that acute subarachnoid hemorrhage is associated with abnormal myocardial perfusion, we assessed myocardial blood flow with thallium scintigraphy in 19 patients with a confirmed subarachnoid hemorrhage and an abnormal electrocardiogram. A thallium scan was performed at the bedside of each patient 3 +/- 2 days (mean +/- SD) after subarachnoid hemorrhage and subsequently was analyzed both qualitatively and quantitatively. Patients averaged 58 +/- 13 yr of age and 68% had one or more cardiac risk factors. The neurologic condition of patients on the day of the scan was II (median; range I-V) on the standard 5-point scale of Botterell. Abnormalities on a standard 12-lead electrocardiogram obtained on the same day as the scan consisted of repolarization changes in most patients; 10 had T wave inversions and 8 had nonspecific ST segment changes. Thirty-two percent (n = 6) of patients had an abnormal thallium scan. There were, however, no features of the clinical history, electrocardiogram pattern, or neurologic condition that were associated with a positive scan. For instance, 2 of 4 patients with diffuse deeply inverted T waves had a normal thallium scan, whereas the scan was abnormal in 2 of 8 patients with minor nonspecific electrocardiographic abnormalities. The thallium scan was also positive in neurologically intact (grade I) as well as severely injured (grade V) patients. Thus, abnormal myocardial perfusion and possibly myocardial ischemia occur frequently following subarachnoid hemorrhage, but no specific electrocardiographic characteristic identifies patients with a perfusion abnormality.


Melatonin effects on bone: experimental facts and clinical perspectives.
Bone formation proceeds through a remodeling process that runs continuously, involving the resorption of old bone by osteoclasts, and the subsequent formation of new bone by osteoblasts. This is controlled by growth factors and cytokines produced in bone marrow microenvironment and by the action of systemic hormones, like parathyroid hormone, estradiol or growth hormone (GH). One candidate for hormonal modulation of osteoblast and osteoclast formation is melatonin. Because circulating melatonin declines with age, its possible involvement in post-menopausal and senescence osteoporosis is considered. This review article discusses early studies on melatonin-bone relationships and recent data that suggest a direct effect of melatonin on bone. Melatonin could act as an autacoid in bone cells as it is present in high quantities in bone marrow, where precursors of bone cells are located. Melatonin dose-dependently augmented proteins that are incorporated into the bone matrix, like procollagen type I c-peptide. Osteoprotegerin, an osteoblastic protein that inhibits the differentiation of osteoclasts is also augmented by melatonin in vitro. Another possible target cell for melatonin is the osteoclast, which degrades bone partly by generating free radicals. Melatonin through its free radical scavenger and antioxidant properties may impair osteoclast activity and bone resorption. At least in one study melatonin was both inhibitory to osteoclastic and osteoblastic cells. Therefore, the documented bone-protecting effect of melatonin in ovariectomized rats can depend in part on the free radical scavenging properties of melatonin. Additionally, melatonin may impair development of osteopenia associated with senescence by improving non-rapid eye movement sleep and restoring GH secretion. Whether melatonin can be used as a novel mode of therapy for augmenting bone mass in diseases deserves to be studied.


Syringe exchange: HIV prevention, key findings, and future directions.
HIV among injecting drug users (IDUs) has now been documented in over 60 countries in the world, and there are an additional 40 countries where injecting drug use has been reported including widespread epidemics in Southeast and southern Asia and in Latin America. At present HIV infection is almost always fatal, and there is no promise that a preventive vaccine will become available soon. Given the enormity of the HIV epidemic among IDUs and the critical need to reduce the spread of HIV transmission to and from IDUs, prevention efforts are essential. Syringe-exchange programs have become a major component of HIV prevention strategies in most developed countries and work within the philosophy of harm reduction. Increasing access to sterile syringes has been met with considerable controversy. Opponents of syringe exchange have generally argued that increasing access to sterile syringes would simultaneously increase the number of injecting drug users, increase the frequency of injection for already active IDUs, and appear to "condone" an illegal behavior. To date many research studies and four major reviews of syringe exchange literature have been conducted. All studies thus far have shown no increase in illicit drug injection associated with syringe exchanges, and significant decrease in drug risk behaviors.


Human alveolar macrophages predominately express combined classical M1 and M2 surface markers in steady state.
Alveolar macrophages (AM) are critical to the homeostasis of the inflammatory environment in the lung. Differential expression of surface markers classifies macrophages to either classically (M1) or alternatively activated (M2). We investigated the phenotype of human alveolar macrophages (AM) in adults living in two different geographical locations: UK and Malawi. We show that the majority of AM express high levels of M1 and M2 markers simultaneously, with the M1/M2 phenotype being stable in individuals from different geographical locations. The combined M1/M2 features confer to AM a hybrid phenotype, which does not fit the classic macrophage classification. This hybrid phenotype may confer to alveolar macrophages an ability to quickly switch between M1 or M2 associated functions allowing for appropriate responses to stimuli and tissue environment.


A Bayesian spatio-temporal model for forecasting the prevalence of antibodies to Ehrlichia species in domestic dogs within the contiguous United States.
Dogs in the United States are hosts to a diverse range of vector-borne pathogens, several of which are important zoonoses. This paper describes factors deemed to be significantly related to the prevalence of antibodies to Ehrlichia spp. in domestic dogs, including climatic conditions, geographical factors, and societal factors. These factors are used in concert with a spatio-temporal model to construct an annual seroprevalence forecast. The proposed method of forecasting and an assessment of its fidelity are described. Approximately twelve million serological test results for canine exposure to Ehrlichia spp. were used in the development of a Bayesian approach to forecast canine infection. Data used were collected on the county level across the contiguous United States from routine veterinary diagnostic tests between 2011-2015. Maps depicting the spatial baseline Ehrlichia spp. prevalence were constructed using Kriging and head-banging smoothing methods. Data were statistically analyzed to identify factors related to antibody prevalence via a Bayesian spatio-temporal conditional autoregressive (CAR) model. Finally, a forecast of future Ehrlichia seroprevalence was constructed based on the proposed model using county-level data on five predictive factors identified at a workshop hosted by the Companion Animal Parasite Council and published in 2014: annual temperature, percentage forest coverage, percentage surface water coverage, population density and median household income. Data were statistically analyzed to identify factors related to disease prevalence via a Bayesian spatio-temporal model. The fitted model and factor extrapolations were then used to forecast the regional seroprevalence for 2016. The correlation between the observed and model-estimated county-by-county Ehrlichia seroprevalence for the five-year period 2011-2015 is 0.842, demonstrating reasonable model accuracy. The weighted correlation (acknowledging unequal sample sizes) between 2015 observed and forecasted county-by-county Ehrlichia seroprevalence is 0.970, demonstrating that Ehrlichia seroprevalence can be forecasted accurately. The forecast presented herein can be an a priori alert to veterinarians regarding areas expected to see expansion of Ehrlichia beyond the accepted endemic range, or in some regions a dynamic change from historical average prevalence. Moreover, this forecast could potentially serve as a surveillance tool for human health and prove useful for forecasting other vector-borne diseases.


A label-free microfluidic assay to quantitatively study antibiotic diffusion through lipid membranes.
With the rise in antibiotic resistance amongst pathogenic bacteria, the study of antibiotic activity and transport across cell membranes is gaining widespread importance. We present a novel, label-free microfluidic assay that quantifies the permeability coefficient of a broad spectrum fluoroquinolone antibiotic, norfloxacin, across lipid membranes using the UV autofluorescence of the drug. We use giant lipid vesicles as highly controlled model systems to study the diffusion through lipid membranes. Our technique directly determines the permeability coefficient without requiring the measurement of the partition coefficient of the antibiotic.


Retraction of publications in nursing and midwifery research: A systematic review.
Rates of manuscript retraction in academic journals are increasing. Papers are retracted because of scientific misconduct or serious error. To date there have been no studies that have examined rates of retraction in nursing and midwifery journals. A systematic review of Journal Citation Report listed nursing science journals. The Medline database was searched systematically from January 1980 through July 2017, and www.retractionwatch.com was manually searched for relevant studies that met the inclusion criteria. Two researchers undertook title and abstract and full text screening. Data were extracted on the country of the corresponding author, journal title, impact factor, study design, year of retraction, number of citations after retraction, and reason for retraction. Journals retraction index was also calculated. Twenty-nine retracted papers published in nursing science journals were identified, the first in 2007. This represents 0.029% of all papers published in these journals since 2007. We observed a significant increase in the retraction rate of 0.44 per 10,000 publications per year (95% CI; 0.03-0.84, p = .037). There was a negative association between a journal's retraction index and impact factor with a significant reduction in retraction index of -0.57 for a one-point increase in impact factor (95% CI; -1.05 to -0.09, p = .022). Duplicate publication was the most common reason for retraction (n = 18, 58%). The mean number of citations manuscripts received after retraction was seven, the highest was 52. Most (n = 27, 93.1%) of the retracted papers are still available online (with a watermark indicating they are retracted). Compared to more established academic disciplines, rates of retraction in nursing and midwifery are low. Findings suggest that unsound research is not being identified and that the checks and balances incumbent in the scientific method are not working. In a clinical discipline, this is concerning and may indicate that research that should have been removed from the evidence base continues to influence nursing and midwifery care.


Identifying Shared Brain Networks in Individuals by Decoupling Functional and Anatomical Variability.
The connectivity architecture of the human brain varies across individuals. Mapping functional anatomy at the individual level is challenging, but critical for basic neuroscience research and clinical intervention. Using resting-state functional connectivity, we parcellated functional systems in an "embedding space" based on functional characteristics common across the population, while simultaneously accounting for individual variability in the cortical distribution of functional units. The functional connectivity patterns observed in resting-state data were mapped in the embedding space and the maps were aligned across individuals. A clustering algorithm was performed on the aligned embedding maps and the resulting clusters were transformed back to the unique anatomical space of each individual. This novel approach identified functional systems that were reproducible within subjects, but were distributed across different anatomical locations in different subjects. Using this approach for intersubject alignment improved the predictability of individual differences in language laterality when compared with anatomical alignment alone. Our results further revealed that the strength of association between function and macroanatomy varied across the cortex, which was strong in unimodal sensorimotor networks, but weak in association networks.


Biofilm: A dental microbial infection.
Recent advances in research technology have allowed researchers to study bacteria in their natural environment. Dental biofilm forms via an ordered sequence of events, resulting in structured and functionally organized species rich microbial community and modern molecular biological techniques have identified about 1000 different bacterial species in the dental biofilm, twice as many as can be cultured. Sites for biofilm formation include all kinds of surfaces: natural materials above and below ground, metals, plastics, medical implant materials-even plant and body tissue. Wherever you find a combination of moisture, nutrients and a surface, you are likely to find biofilm. The biofilm is used to describe the communities of micro-organisms attached to a surface; such microbes are usually spatially organized into three-dimension structure and are enclosed in matrix of extracellular material derived both from the cells themselves and from the environment. Dental biofilm pathogenicity in the oral cavity is magnified by specific biofilm characteristics and modern molecular biological techniques have identified about 1000 different bacterial species in the dental biofilm, twice as many as can be cultured. Adaptation to a biofilm lifestyle involves regulation of a vast set of genes, and the micro-organisms are thus able to optimize phenotypic properties for the particular environment.


Performance and health of weanling bulls after butorphanol and xylazine administration at castration.
A total of 268 crossbred, 6- to 9-mo-old, bull calves (214 +/- 19 kg) were used in two separate 27-d experiments to assess the effects of butorphanol and xylazine administration (BXA) on the subsequent performance and health of beef calves. In each experiment, calves were randomly allotted to four treatment groups: 1) castration with BXA, 2) castration without BXA, 3) no castration with BXA, and 4) no castration without BXA. There were two replicates within each experiment. The intravenous administration of .07 mg/kg of butorphanol and .02 mg/kg of xylazine occurred 90 s before tail hold and castration procedures. Calves were placed in a squeeze chute and manually restrained by tail elevation. In Exp. 2, the cattle also were scored for chute activity (on a 1 to 5 scale with 5 being the most active). Cattle were weighed at the beginning and end of the experiment, feed intake was recorded daily, and cattle were monitored daily for respiratory disease. There were no castration x BXA interactions (P greater than .51). Castration reduced (P less than .01) daily gain and gain/feed and tended (P = .13) to reduce feed intake. The administration of BXA had no effect (P greater than .05) on gain or gain/feed but did tend (P = .13) to reduce feed intake. No differences (P greater than .45) were observed in morbidity or mortality due to either BXA or castration. Castration and BXA increased (P less than .01) blood cortisol levels on d 3, whereas control animals had reduced cortisol levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Reflections on a field across time and space: the emergent medical and health humanities in South Africa.
In this paper, we draw on our own cross-cultural experience of engaging with different incarnations of the medical and health humanities (MHH) in the UK and South Africa to reflect on what is distinct and the same about MHH in these locations. MHH spaces, whether departments, programmes or networks, have espoused a common critique of biomedical dualism and reductionism, a celebration of qualitative evidence and the value of visual and performative arts for their research, therapeutic and transformative social potential. However, there have also been differences, and importantly a different 'identity' among some leading South African scholars and practitioners, who have felt that if MHH were to speak from the South as opposed to the North, they would say something quite different. We seek to contextualise our personal reflections on the development of the field in South Africa over recent years within wider debates about MHH in the context of South African academia and practice, drawing in part on interviews conducted by one of the authors with South African researchers and practitioners and our own reflections as 'Northerners' in the 'South'.


The effect of different antimicrobial treatment regimens on the faecal shedding of ESBL-producing Escherichia coli in horses.
Fourth-generation cephalosporins can select for extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae in horses, but it is unknown to what extent this occurs compared to penicillin/gentamicin combination treatment. The objective was to evaluate the effect of different antimicrobial treatments on faecal shedding and diversity of ESBL-producing Escherichia coli (ESBL-EC) in horses. Upon hospital admission, 86 horses in need of antimicrobial treatment or prophylaxis were randomly allocated to receive penicillin and gentamicin (PG) or cefquinome (CEF). Untreated horses were included as controls (NOAMD, n = 33). Faecal samples from admission (T1), 3 days after admission (T2), and faecal swabs 28 days after discharge (T3) were cultured selectively. Differences in prevalence (T1, T2, T3) and counts (T1, T2) of ESBL-EC between groups and over time were analysed. On a subset of ESBL-EC isolates, antimicrobial susceptibility testing (n = 45) and whole-genome sequencing followed by SNP-analysis (n = 46) were performed. The prevalence of ESBL-EC at T1 was 12 % with no significant difference between groups. In all groups, significantly higher carriage rates were observed at T2 and T3 compared to T1. Carriage and counts of ESBL-EC at T2 were significantly higher in treated compared to untreated horses. There was no significant difference between PG and CEF at any time points. Despite a large genetic diversity, indistinguishable ESBL clones were observed in different horses over time. In conclusion, antimicrobial treatment and hospitalization increased prevalence and counts of ESBL-EC, and transmission of ESBL-EC in the hospital was suspected. These findings highlight the importance of antimicrobial stewardship and infection control practices in equine medicine.


A new class of bioactive and biodegradable soybean-based bone fillers.
The reconstruction of large bone defects in periodontal, maxillofacial, and orthopedic surgery relies on the implantation of biomaterials able to support the growth of new tissue. None of the materials currently available is able to combine all the properties required, which are (i) easy handling, (ii) biodegradation, (iii) low immunogenicity, and more importantly, (iv) induction of tissue regeneration. A new class of biodegradable biomaterials has been obtained by simple thermosetting of defatted soybean curd. The final material can be processed into films, porous scaffolds, and granules for different surgical needs. When incubated in physiological solutions the material shows water uptake of 80%, elongation at break of 0.9 mm/mm, and 25% (w/w) degradation in 7 days. Soybean-based biomaterial granules are shown to reduce the activity of the monocytes/macrophages and of the osteoclasts and to induce osteoblast differentiation in vitro, thus demonstrating a bone regeneration potential suitable for many clinical applications.


HDAC signaling in neuronal development and axon regeneration.
The development and repair of the nervous system requires the coordinated expression of a large number of specific genes. Epigenetic modifications of histones represent an essential principle by which neurons regulate transcriptional responses and adapt to environmental cues. The post-translational modification of histones by chromatin-modifying enzymes histone acetyltransferases (HATs) and histone deacetylases (HDACs) shapes chromatin to adjust transcriptional profiles during neuronal development. Recent observations also point to a critical role for histone acetylation and deacetylation in the response of neurons to injury. While HDACs are mostly known to attenuate transcription through their deacetylase activity and their interaction with co-repressors, these enzymes are also found in the cytoplasm where they display transcription-independent activities by regulating the function of diverse proteins. Here we discuss recent studies that go beyond the traditional use of HDAC inhibitors and have begun to dissect the roles of individual HDAC isoforms in neuronal development and repair after injury.


A thermosensitive carrageenan-based polymer: synthesis, characterization and interactions with a cationic surfactant.
Novel polyelectrolytes were obtained by grafting N-isopropylacrylamide (NIPAM) on the ι-carrageenan (CAR) chain. Two polymers with different grafting degrees were synthesized. The polymers were found to show the lower critical solution temperature (LCST) close to that of PNIPAM. The LCST values were dependent on the concentration of salt and cationic surfactant. The interactions of CAR-graft-PNIPAM with a model cationic surfactant-dodecyltrimethyl ammonium chloride (DTAC) in water and 0.15M NaCl were studied. It was found that both ι-carrageenan and CAR-graft-PNIPAM polymers interact with DTAC. The presence of CAR-graft-PNIPAM in the solution of DTAC induces formation of surfactant aggregates at the critical aggregation concentration much lower than the cmc of the surfactant. Cac increased with ionic strength. The values of cac for CAR-graft-PNIPAM - DTAC system and standard free enthalpy changes attributed to the complexation process were determined. The results obtained for CAR-graft-PNIPAM were compared with these for the non-modified ι-carrageenan. The surfactant interactions with non-modified and grafted polymers were found to be different in nature.


Homologies between enzymes involved in steroid and xenobiotic carbonyl reduction in vertebrates, invertebrates and procaryonts.
Evidence is reported for the existence of a structurally and functionally related and probably evolutionarily conserved class of membrane-bound liver carbonyl reductases/hydroxysteroid dehydrogenases involved in steroid and xenobiotic carbonyl metabolism. Carbonyl reduction was investigated in liver microsomes of 8 vertebrate species, as well as in insect larvae total homogenate and in purified 3 alpha-hydroxysteroid dehydrogenase preparations of the procaryont Pseudomonas testosteroni, using the ketone compound 2-methyl-1,2 di-(3-pyridyl)-1-propanone (metyrapone) as substrate. The enzyme activities involved in the metyrapone metabolism were screened for their sensitivity to several steroids as inhibitors. In all fractions tested, steroids of the adrostane or pregnane class strongly inhibited xenobiotic carbonyl reduction, whereas only in the insect and procaryotic species could ecdysteroids inhibit this reaction. Immunoblot analysis with antibodies against the respective microsomal mouse liver metyrapone reductase revealed strong crossrections in all fractions tested, even in those of the insect and the procaryont. A similar crossreaction pattern was achieved when the same fractions were incubated with antibodies against 3 alpha-hydroxysteroid dehydrogenase from Pseudomonas testosteroni. The mutual immunoreactivity of the antibody species against proteins from vertebrate liver microsomes, insects and procaryonts suggests the existence of structural homologies within these carbonyl reducing enzymes. This is further confirmed by limited proteolysis of purified microsomal mouse liver carbonyl reductase and subsequent analysis of the peptide fragments with antibodies specifically purified by immunoreactivity against this respective crossreactive antigen. These immunoblot experiments revealed a 22 kDa peptide fragment which was commonly recognized by all antibodies and which might represent a conserved domain of the enzyme.


Species composition of the international shark fin trade assessed through a retail-market survey in Hong Kong.
The shark fin trade is a major driver of shark exploitation in fisheries all over the world, most of which are not managed on a species-specific basis. Species-specific trade information highlights taxa of particular concern and can be used to assess the efficacy of management measures and anticipate emerging threats. The species composition of the Hong Kong Special Administrative Region of China, one of the world's largest fin trading hubs, was partially assessed in 1999-2001. We randomly selected and genetically identified fin trimmings (n = 4800), produced during fin processing, from the retail market of Hong Kong in 2014-2015 to assess contemporary species composition of the fin trade. We used nonparametric species estimators to determine that at least 76 species of sharks, batoids, and chimaeras supplied the fin trade and a Bayesian model to determine their relative proportion in the market. The diversity of traded species suggests species substitution could mask depletion of vulnerable species; one-third of identified species are threatened with extinction. The Bayesian model suggested that 8 species each comprised >1% of the fin trimmings (34.1-64.2% for blue [Prionace glauca], 0.2-1.2% for bull [Carcharhinus leucas] and shortfin mako [Isurus oxyrinchus]); thus, trade was skewed to a few globally distributed species. Several other coastal sharks, batoids, and chimaeras are in the trade but poorly managed. Fewer than 10 of the species we modeled have sustainably managed fisheries anywhere in their range, and the most common species in trade, the blue shark, was not among them. Our study and approach serve as a baseline to track changes in composition of species in the fin trade over time to better understand patterns of exploitation and assess the effects of emerging management actions for these animals.


Relative importance of intracellular glutathione peroxidase and catalase in vivo for prevention of peroxidation to the heart.
The relative importance in vivo of catalase and the selenoenzyme glutathione peroxidase for protection against peroxidation was assessed in the rat heart. Each of these enzymes was modulated by feeding animals a low selenium diet either unsupplemented or supplemented with 0.5 parts per million of selenium, with or without the catalase inhibitor, 3-amino-1,2,4-triazole, in their drinking water. After 8 weeks, selenium deficient rats had 88% reductions in cytosolic and mitochondrial glutathione peroxidase activities. These reductions were accompanied by increased peroxidation in heart homogenates and mitochondrial suspensions. Since increased mitochondrial peroxidation only occurred when both the cytosolic and mitochondrial glutathione peroxidase activities were compromised, these selenoenzymes appear to work in tandem and reductions in both are a prerequisite for increased peroxidation in this organ. Peroxidation did not occur in aminotriazole treated animals even though cytosolic catalase activity was inhibited by 65-80%. Moreover, inhibition of catalase activity did not exacerbate the level of peroxidation in selenium deficient animals depleted of glutathione peroxidase activity. Because increased peroxidation was only associated with reductions in glutathione peroxidase activity irrespective of catalase activity, the selenoenzyme appears to be more important for detoxification of hydrogen peroxide in the heart.


Pollution pathways of pharmaceutical residues in the aquatic environment on the island of Mallorca, Spain.
This work determines the principal environmental pollution pathways of pharmaceuticals on the island of Mallorca (Spain). The evaluation was made on the basis of the quantification of pharmaceutical residues by liquid chromatography-tandem mass spectrometry in several environmental water samples, including wastewater-treatment plant effluents, municipal solid waste landfill leachates, groundwater (GW), and marine water. An overall set of 19 pharmaceuticals has been identified in the environment of the 27 human pharmaceuticals investigated in this study. WWTP effluents are the main source of discharge of the pharmaceuticals into the aquatic environment. The data indicate that reuse of treated domestic wastewater for irrigation (which supplies some 30 % of the total water demand in Mallorca) contributes to the contamination of GW. In addition, leaching from landfills is identified as another, but minor, possible source of introduction of pharmaceuticals to GW aquifers. Finally, WWTP effluents ending in the Mediterranean Sea, primarily highly urbanized coastal areas, cause pharmaceutical residues to occur in marine water bodies.


Older people receiving family-based support in the community: a survey of quality of life among users of 'Shared Lives' in England.
Shared Lives (adult placement) is a model of community-based support where an adult who needs support and/or accommodation moves into or regularly visits the home of an approved Shared Lives carer, after they have been matched for compatibility. It is an established but small service which has been used mainly by people with learning disabilities but which has the potential to offer an alternative to traditional services for some older people. However, there is little research on the outcomes for older users of Shared Lives. This paper presents findings from a survey of 150 older people using Shared Lives support across 10 Shared Lives schemes in England, which took place between June 2013 and January 2014. The aim was to identify outcomes for older users of Shared Lives and compare these to outcomes for older users of other social care services. In the absence of an ideal study design involving randomised allocation, statistical matching was used to generate a comparison group from the Adult Social Care Survey from 2011/12, with 121 cases matched to 121 Shared Lives cases. The main outcome measures were Social Care-Related Quality of Life (measured by the ASCOT) and overall quality of life. Findings indicated that Shared Lives can deliver good outcomes for older people, particularly for overall quality of life. In comparison to the matched group of older people using other forms of support, there was some evidence that Shared Lives may deliver better outcomes in some aspects of quality of life. Limitations to the research mean, however, that more work is needed to fully understand the role Shared Lives could play in supporting older people.


Targeting the Warburg effect with a novel glucose transporter inhibitor to overcome gemcitabine resistance in pancreatic cancer cells.
Gemcitabine resistance remains a significant clinical challenge. Here, we used a novel glucose transporter (Glut) inhibitor, CG-5, as a proof-of-concept compound to investigate the therapeutic utility of targeting the Warburg effect to overcome gemcitabine resistance in pancreatic cancer. The effects of gemcitabine and/or CG-5 on viability, survival, glucose uptake and DNA damage were evaluated in gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cell lines. Mechanistic studies were conducted to determine the molecular basis of gemcitabine resistance and the mechanism of CG-5-induced sensitization to gemcitabine. The effects of CG-5 on gemcitabine sensitivity were investigated in a xenograft tumor model of gemcitabine-resistant pancreatic cancer. In contrast to gemcitabine-sensitive pancreatic cancer cells, the resistant Panc-1 and Panc-1(GemR) cells responded to gemcitabine by increasing the expression of ribonucleotide reductase M2 catalytic subunit (RRM2) through E2F1-mediated transcriptional activation. Acting as a pan-Glut inhibitor, CG-5 abrogated this gemcitabine-induced upregulation of RRM2 through decreased E2F1 expression, thereby enhancing gemcitabine-induced DNA damage and inhibition of cell survival. This CG-5-induced inhibition of E2F1 expression was mediated by the induction of a previously unreported E2F1-targeted microRNA, miR-520f. The addition of oral CG-5 to gemcitabine therapy caused greater suppression of Panc-1(GemR) xenograft tumor growth in vivo than either drug alone. Glut inhibition may be an effective strategy to enhance gemcitabine activity for the treatment of pancreatic cancer.


Poly (3, 4-ethylenedioxythiophene)-ionic liquid coating improves neural recording and stimulation functionality of MEAs.
In vivo multi-electrode arrays (MEAs) can sense electrical signals from a small set of neurons or modulate neural activity through micro-stimulation. Electrode's geometric surface area (GSA) and impedance are important for both unit recording and neural stimulation. Smaller GSA is preferred due to enhanced selectivity of neural signal, but it tends to increase electrode impedance. Higher impedance leads to increased electrical noise and signal loss in single unit neural recording. It also yields a smaller charge injection window for safe neural stimulation. To address these issues, poly (3, 4-ethylenedioxythiophene) - ionic liquid (PEDOT-IL) conducting polymers were electrochemically polymerized on the surface of the microelectrodes. The PEDOT-IL coating reduced the electrode impedance modulus by over 35 times at 1 kHz. It also exhibited compelling nanostructure in surface morphology and significant impedance reduction in other physiologically relevant range (100Hz-1000Hz). PEDOT-IL coated electrodes exhibited a Charge Storage Capacity (CSC) that was about 20 times larger than that of bare electrodes. The neural recording performance of PEDOT-IL coated electrodes was also compared with uncoated electrodes and PEDOT-poly (styrenesulfonate) (PSS) coated electrodes in rat barrel cortex (SI). Spontaneous neural activity and sensory evoked neural response were utilized for characterizing the electrode performance. The PEDOT-IL electrodes exhibited a higher unit yield and signal-to-noise ratio (SNR) in vivo. The local field potential recording was benefited from the low impedance PEDOT-IL coating in noise and artifact reduction as well. Moreover, cell culture on PEDOT-IL coating demonstrated that the material is safe for neural tissue and reduces astrocyte fouling. Taken together, PEDOT-IL coating has the potential to benefit neural recording and stimulation electrodes, especially when integrated with novel small GSA electrode arrays designed for high recording density, minimal insertion damage and alleviated tissue reaction.


Single-subject classification of presymptomatic frontotemporal dementia mutation carriers using multimodal MRI.
Classification models based on magnetic resonance imaging (MRI) may aid early diagnosis of frontotemporal dementia (FTD) but have only been applied in established FTD cases. Detection of FTD patients in earlier disease stages, such as presymptomatic mutation carriers, may further advance early diagnosis and treatment. In this study, we aim to distinguish presymptomatic FTD mutation carriers from controls on an individual level using multimodal MRI-based classification. Anatomical MRI, diffusion tensor imaging (DTI) and resting-state functional MRI data were collected in 55 presymptomatic FTD mutation carriers (8 microtubule-associated protein Tau, 35 progranulin, and 12 chromosome 9 open reading frame 72) and 48 familial controls. We calculated grey and white matter density features from anatomical MRI scans, diffusivity features from DTI, and functional connectivity features from resting-state functional MRI. These features were applied in a recently introduced multimodal behavioural variant FTD (bvFTD) classification model, and were subsequently used to train and test unimodal and multimodal carrier-control models. Classification performance was quantified using area under the receiver operator characteristic curves (AUC). The bvFTD model was not able to separate presymptomatic carriers from controls beyond chance level (AUC = 0.570, p = 0.11). In contrast, one unimodal and several multimodal carrier-control models performed significantly better than chance level. The unimodal model included the radial diffusivity feature and had an AUC of 0.646 (p = 0.021). The best multimodal model combined radial diffusivity and white matter density features (AUC = 0.680, p = 0.005). FTD mutation carriers can be separated from controls with a modest AUC even before symptom-onset, using a newly created carrier-control classification model, while this was not possible using a recent bvFTD classification model. A multimodal MRI-based classification score may therefore be a useful biomarker to aid earlier FTD diagnosis. The exclusive selection of white matter features in the best performing model suggests that the earliest FTD-related pathological processes occur in white matter.


Cadence, peak vertical acceleration, and peak loading rate during ambulatory activities: implications for activity prescription for bone health.
Previous research has reported peak vertical acceleration and peak loading rate thresholds beneficial to bone mineral density (BMD). Such thresholds are difficult to translate into meaningful recommendations for physical activity. Cadence (steps/min) is a more readily interpretable measure of ambulatory activity. To examine relationships between cadence, peak vertical acceleration and peak loading rate during ambulation and identify the cadence associated with previously reported bone-beneficial thresholds for peak vertical acceleration (4.9 g) and peak loading rate (43 BW/s). Ten participants completed 8 trials each of: slow walking, brisk walking, slow running, and fast running. Acceleration data were captured using a GT3×+ accelerometer worn at the hip. Peak loading rate was collected via a force plate. Strong relationships were identified between cadence and peak vertical acceleration (r = .96, P < .05) and peak loading rate (r = .98, P < .05). Regression analyses indicated cadences of 157 ± 12 steps/min (2.6 ± 0.2 steps/s) and 122 ± 10 steps/min (2.0 ± 0.2 steps/s) corresponded with the 4.9 g peak vertical acceleration and 43 BW/s peak loading rate thresholds, respectively. Cadences ≥ 2.0 to 2.6 steps/s equate to acceleration and loading rate thresholds related to bone health. Further research is needed to investigate whether the frequency of daily occurrences of this cadence is associated with BMD.


Health, employment, and financial outcomes in workers with occupational asthma.
To study the health, employment, and financial outcome of occupational asthma. A follow study of workers with confirmed occupational asthma. A specialist occupational lung disease clinic. All workers had a diagnosis of occupational asthma made at least one year earlier. Diagnosis was confirmed by serial peak expiratory flow measurement, specific bronchial provocation testing, or specific immunology. Respiratory symptoms, medication, pulmonary function, employment state, and financial position. 112 of a total of 140 eligible workers were followed up. 32% of patients remained exposed to the causative agent. These workers had more symptoms at follow up than those removed and a greater number were taking inhaled steroids. Continued exposure was also associated with a fall in % predicted forced expiratory volume in one second (FEV1) of 3% compared with that at presentation. Their median loss of annual income due to occupational asthma was 35%. Those removed from exposure were worse off financially (median loss 54% of annual income), had fewer respiratory symptoms than the group who remained exposed, and their % predicted FEV1 had improved by 4.6%. Statutory compensation and that obtained by common law suits did not match the loss of earnings due to the development of occupational asthma. Of the workers removed from exposure, those who no longer complained of breathlessness had been diagnosed significantly earlier after the onset of their first symptom (48 v 66 months, p = 0.001) and had a significantly higher FEV1 at presentation (90% v 73% predicted, p = 0.008) compared with those who were still breathless. They had developed symptoms earlier after first exposure (48 v 66 months, p > 0.05) and had been removed from exposure sooner (eight v 12 months, p > 0.05). Removal from exposure after diagnosis of occupational asthma is beneficial in terms of symptoms and lung function, but is associated with a loss of income. Early diagnosis is important for symptomatic improvement after removal from exposure. Inadequate compensation may contribute to the workers' decision to remain exposed after diagnosis.


Prevalence and molecular profiling of Epstein Barr virus (EBV) among healthy blood donors from different nationalities in Qatar.
The Epstein-Barr virus (EBV) is the causative agent of infectious mononucleosis. EBV is highly prevalent lymphotropic herpesvirus and has been linked to several malignancies. Transmission is generally by oral secretions, but can be through blood transfusions and organ transplantations. This study aimed to determine the seroprevalence, viremia rates, and circulating genotypes of EBV in healthy blood donors in Qatar. Blood samples from 673 blood donors of different nationalities residing in Qatar (mainly Qatar, Egypt, Syria, Jordan, Pakistan, and India) were collected and tested for anti-EBV capsid (VCA; IgG & IgM), nuclear (EBNA; IgG), and early (EA-D; IgG) antigens. Avidity testing was determined when active infection was suspected. DNA was extracted from the buffy coat and subjected to EBV-DNA quantification using qRT-PCR. Genotyping was performed using nested-PCR targeting EBV-EBNA2 gene, and phylogeny by sequence analysis of the LMP-1 gene. 97.9% (673/659) of the samples were seropositive as indicated by the presence VCA-IgG, while 52.6% (354/673) had detectible EBV-DNA. EBV seroprevalence and viremia rates increased significantly with age. Genotyping of 51 randomly selected samples showed predominance of Genotype 1 (72.5%, 37/51) as compared to genotype 2 (3.5%), and mixed infections were detected in 4% of the samples. Sub-genotyping for these samples revealed that the Mediterranean strain was predominant (65.3%), followed by B95.8 prototype and North Carolina strains (12.2% each), and China1 strain (6%). As a first study to evaluate EBV infection in highly diverse population in Qatar, where expatriates represent more than 85% of the population, our results indicated high seroprevalence and viremia rate of EBV in different nationalities, with genotype 1 and Mediterranean strain being predominant. Clinical significance of these finding have not been investigated and shall be evaluated in future studies.


Artificial Intelligence-Based Breast Cancer Nodal Metastasis Detection: Insights Into the Black Box for Pathologists.
Nodal metastasis of a primary tumor influences therapy decisions for a variety of cancers. Histologic identification of tumor cells in lymph nodes can be laborious and error-prone, especially for small tumor foci. To evaluate the application and clinical implementation of a state-of-the-art deep learning-based artificial intelligence algorithm (LYmph Node Assistant or LYNA) for detection of metastatic breast cancer in sentinel lymph node biopsies. Whole slide images were obtained from hematoxylin-eosin-stained lymph nodes from 399 patients (publicly available Camelyon16 challenge dataset). LYNA was developed by using 270 slides and evaluated on the remaining 129 slides. We compared the findings to those obtained from an independent laboratory (108 slides from 20 patients/86 blocks) using a different scanner to measure reproducibility. LYNA achieved a slide-level area under the receiver operating characteristic (AUC) of 99% and a tumor-level sensitivity of 91% at 1 false positive per patient on the Camelyon16 evaluation dataset. We also identified 2 "normal" slides that contained micrometastases. When applied to our second dataset, LYNA achieved an AUC of 99.6%. LYNA was not affected by common histology artifacts such as overfixation, poor staining, and air bubbles. Artificial intelligence algorithms can exhaustively evaluate every tissue patch on a slide, achieving higher tumor-level sensitivity than, and comparable slide-level performance to, pathologists. These techniques may improve the pathologist's productivity and reduce the number of false negatives associated with morphologic detection of tumor cells. We provide a framework to aid practicing pathologists in assessing such algorithms for adoption into their workflow (akin to how a pathologist assesses immunohistochemistry results).


Identification of volatile/semivolatile products derived from chemical remediation of cis-1,3-dichloropropene by thiosulfate.
The prevalent use of soil fumigants has resulted in air pollution in some agricultural regions. Our previous research showed that application of thiosulfate fertilizers at the soil surface may offer an effective and economical approach to reduce the emission of halogenated fumigants via a chemical remediation process. In this fumigant emission-reduction strategy, volatile 1,3-dichloropropene (1,3-D) reacts with thiosulfate to generate a nonvolatile Bunte salt (thiosulfate derivative of 1,3-D). However, the decomposition of the Bunte salt may be associated with the production of perceptible odors. This study investigated the stability of this reaction product in different environmental media. Hydrolysis experiments demonstrated that the thiosulfate derivative was relatively stable in neutral and moderately acidic aqueous solutions. In contrast, the thiosulfate derivative was readily converted to a dialkyl disulfide via a base hydrolysis process in pH 10 buffer solution. In a strongly acidic solution, a mercaptan and a dialkyl disulfide compound were detected as two primary hydrolysis products. In soil, this initial reaction product underwent a series of biotic conversions to generate several volatile or semivolatile organic sulfur compounds. The formation and distribution of four volatile/semivolatile products in the air and soil were detected in different soils treated with the thiosulfate derivative of 1,3-D. This study indicated that odors occurring in soil treated with halogenated fumigants and thiosulfate fertilizers might arise from the generation and release of these and other volatile/semivolatile organic sulfur products. The environmental fate and effects of such volatile/semivolatile sulfur compounds should be considered in the application of sulfur-containing fertilizers in fumigated fields.


A microsurgical study of the anatomy and course of the ophthalmic artery and its possibly dangerous anastomoses.
The authors studied the microsurgical anatomy of the ophthalmic artery (OphA), paying particular attention to its possibly dangerous anastomoses with the middle meningeal artery (MMA). The microsurgical anatomy of the OphA and its anastomoses with the MMA were studied in 14 vessels from seven adult cadaveric heads. The origination order of the OphA branches varies in relation to whether the artery, along its intraorbital course, crosses above or below the optic nerve (ON). The central retinal artery is the first branch to course from the OphA when it crosses over the ON, and it is the second branch to course from the OphA when the artery crosses under the ON. Anastomoses between branches of the MMA and the OphA were present in the majority of the specimens examined. Detailed knowledge of the microanatomy of the OphA and recognition of anastomoses between the external carotid artery and the OphA are critically important in avoiding disastrous complications during endovascular procedures.


[Liver apudoma simulating cystic liver].
A 36-year-old man in otherwise good general condition and with completely normal laboratory results suffered from right upper abdominal pain. Hepatomegaly was diagnosed as due to cystic liver disease after ultrasound, computed tomography and magnetic resonance imaging. Recurrent abdominal pain continued over several months. Open liver biopsy eventually revealed trabecular-tubular carcinoma (APUDoma). Silver reaction was positive in many tumour cells. Electronmicroscopy demonstrated membrane-bound granules typical for endocrine cells. Immunohistological examinations of various hormones and of neurone-specific enolase were negative, but repeatedly measured high serum levels of pancreatic polypeptide and of beta-HCG nonetheless suggested an endocrine tumour. This case demonstrates that nonparasitic cystic changes in the liver, especially multiple ones, should have a firm diagnosis established by invasive means. Endocrine tumours can be mistaken for polycystic liver disease.


Economic causes and consequences of obesity.
Obesity is not only a health but also an economic phenomenon. This chapter (a) examines underlying economic causes, such as technological advancements, behind the obesity epidemic; (b) describes economic consequences of obesity, including increasing obesity-related medical expenditures; and (c) discusses the role of government in combating the obesity epidemic. Because of the high costs of obesity, and the fact that the majority of these costs are financed by taxpayers, there is a clear motivation for government to try to reduce these costs. However, because obesity may result from poor information and addictive behavior and/or as a result of living in an increasingly obesogenic environment, interventions will need to be multifaceted to ensure the best chance of success.


Deep brain stimulation modulates directional limbic connectivity in obsessive-compulsive disorder.
Deep brain stimulation is effective for patients with treatment-refractory obsessive-compulsive disorder. Deep brain stimulation of the ventral anterior limb of the internal capsule rapidly improves mood and anxiety with optimal stimulation parameters. To understand these rapid effects, we studied functional interactions within the affective amygdala circuit. We compared resting state functional MRI data during chronic stimulation versus 1 week of stimulation discontinuation in patients, and obtained two resting state scans from matched healthy volunteers to account for test-retest effects. Imaging data were analysed using functional connectivity analysis and dynamic causal modelling. Improvement in mood and anxiety following deep brain stimulation was associated with reduced amygdala-insula functional connectivity. Directional connectivity analysis revealed that deep brain stimulation increased the impact of the ventromedial prefrontal cortex on the amygdala, and decreased the impact of the amygdala on the insula. These results highlight the importance of the amygdala circuit in the pathophysiology of obsessive-compulsive disorder, and suggest a neural systems model through which negative mood and anxiety are modulated by stimulation of the ventral anterior limb of the internal capsule for obsessive-compulsive disorder and possibly other psychiatric disorders.


Independent and joint effects of family history and lifestyle on colorectal cancer risk: implications for prevention.
It has been suggested that, for a substantial proportion of "sporadic" colorectal cancers (CRCs), inheritance determines individual susceptibility and that lifestyle determines which susceptible individuals express cancer. Because the genetic basis of this inherited susceptibility remains undefined, we used family history of the disease as a proxy for a genetic predisposition to examine its interactions with a variety of lifestyle factors in a large population-based case-control study of CRC. The subjects were 698 male and 494 female Japanese, Caucasian, Filipino, Hawaiian, and Chinese patients diagnosed with CRC in Hawaii during 1987-1991 and 1192 population controls matched to cases on age, sex, and ethnicity. Fourteen percent of the cases and 6% of the controls reported a family history of CRC among parents or siblings. After adjusting for other covariates, significant interactions with family history were found for beef and ethanol intakes in males (P = 0.03). Relative to men without a family history and whose intake fell in the lower third, odds ratios (ORs) for CRC for men with a family history and in the upper tertile of intake were 10.8 [95% confidence interval (CI), 4.2-27.6] and 7.5 (CI, 3.1-18.2) for beef and ethanol, respectively. The corresponding ORs for men without a family history and in the upper tertile were 1.5 (CI, 1.0-2.3) and 1.4 (CI, 1.0-1.9), respectively. No interactions were detected in women. Using a summary measure of lifestyle, we found that family history was not associated with CRC among men who were at the lower-risk tertile for all of the lifestyle risk factors. In contrast, the OR for men with a family history and at the higher-risk tertile for all of the lifestyle variables was 11.7 (CI, 5.8-23.9). In the absence of a family history, this OR was 4.8 (CI, 3.2-7.2). These data suggest that family history increases the risk of sporadic CRC in men mainly through its interaction with lifestyle exposures, primarily a high beef and ethanol intake, and are consistent with recent reports of effect modifications of dietary associations by metabolic genes. Computation of population attributable risks also suggested that a comprehensive reduction in exposure to lifestyle risk factors--and more specifically to ethanol and beef for individuals with a familial predisposition for the disease--may have a large beneficial effect on CRC incidence.


Nonequilibrium thermodynamics in sheared hard-sphere materials.
We combine the shear-transformation-zone (STZ) theory of amorphous plasticity with Edwards' statistical theory of granular materials to describe shear flow in a disordered system of thermalized hard spheres. The equations of motion for this system are developed within a statistical thermodynamic framework analogous to that which has been used in the analysis of molecular glasses. For hard spheres, the system volume V replaces the internal energy U as a function of entropy S in conventional statistical mechanics. In place of the effective temperature, the compactivity X=∂V/∂S characterizes the internal state of disorder. We derive the STZ equations of motion for a granular material accordingly, and predict the strain rate as a function of the ratio of the shear stress to the pressure for different values of a dimensionless, temperature-like variable near a jamming transition. We use a simplified version of our theory to interpret numerical simulations by Haxton, Schmiedeberg, and Liu, and in this way are able to obtain useful insights about internal rate factors and relations between jamming and glass transitions.


Competent immune responses to SARS-CoV-2 variants in older adults following two doses of mRNA vaccination.
Aging is associated with a reduced magnitude of primary immune responses to vaccination. mRNA-based SARS-CoV-2 vaccines have shown efficacy in older adults but virus variant escape is still unclear. Here we analyze humoral and cellular immunity against an early-pandemic viral isolate and compare that to the P.1 (Gamma) and B.1.617.2 (Delta) variants in two cohorts (<50 and >55 age) of mRNA vaccine recipients. We further measure neutralizing antibody titers for B.1.617.1 (Kappa) and B.1.595, with the latter SARS-CoV-2 isolate bearing the spike mutation E484Q. Robust humoral immunity is measured following second vaccination, and older vaccinees manifest cellular immunity comparable to the adult group against early-pandemic SARS-CoV-2 and more recent variants. More specifically, the older cohort has lower neutralizing capacity at 7-14 days following the second dose but equilibrates with the younger cohort after 2-3 months. While long-term vaccination responses remain to be determined, our results implicate vaccine-induced protection in older adults against SARS-CoV-2 variants and inform thinking about boost vaccination.


Gender inequalities, intimate partner violence and HIV preventive practices: findings of a South African cross-sectional study.
The aim of the paper is to investigate associations between a range of markers of gender inequity, including financial, psychological and physical violence, and two proximal practices in HIV prevention, namely discussion of HIV between partners and the woman suggesting condom use. The paper presents an analysis of data from a cross-sectional study of a representative sample of women from three South African Provinces which was primarily undertaken as an epidemiological study of gender-based violence. A multi-stage sampling design was used with clusters sampled with probability proportional to number of households. Households were randomly selected from within clusters. One randomly selected woman aged 18-49 years was interviewed in each selected home. One thousand three hundred and six women were interviewed (90.3% of eligible women). One thousand one hundred sixty four women had a partner in the previous year and were asked questions related to HIV prevention and gender inequalities in the relationship. The results indicate that discussion of HIV was significantly positively associated with education, living in Mpumalanga Province, the man being a migrant, the woman having multiple partners in the past year and having no confidante. It was significantly negatively associated with living in the Northern Province, the relationship being poor and there being a substantial age difference between partners. The woman suggesting condom use was significantly positively associated with her education, her having multiple partners, domestic violence prior to the past year and financial abuse. It was negatively associated with the relationship being poor. We conclude that this suggests that some indicators of gender inequalities are significantly associated with discussion of HIV and condom use but the direction of association found was both positive and negative. This highlights the need for a more nuanced understanding of gender inequalities and their relationship to HIV risk. Suggestions for key research questions are made.


Improving the capacity of lithium-sulfur batteries by tailoring the polysulfide adsorption efficiency of hierarchical oxygen/nitrogen-functionalized carbon host materials.
The use of monolithic carbons with structural hierarchy and varying amounts of nitrogen and oxygen functionalities as sulfur host materials in high-loading lithium-sulfur cells is reported. The primary focus is on the strength of the polysulfide/carbon interaction with the goal of assessing the effect of (surface) dopant concentration on cathode performance. The adsorption capacity - which is a measure of the interaction strength between the intermediate lithium polysulfide species and the carbon - was found to scale almost linearly with the nitrogen level. Likewise, the discharge capacity of lithium-sulfur cells increased linearly. This positive correlation can be explained by the favorable effect of nitrogen on both the chemical and electronic properties of the carbon host. The incorporation of additional oxygen-containing surface groups into highly nitrogen-functionalized carbon helped to further enhance the polysulfide adsorption efficiency, and therefore the reversible cell capacity. Overall, the areal capacity could be increased by almost 70% to around 3 mA h cm-2. We believe that the design parameters described here provide a blueprint for future carbon-based nanocomposites for high-performance lithium-sulfur cells.


High proportion of false-positive Clostridium difficile enzyme immunoassays for toxin A and B in pediatric patients.
To determine the frequency of false-positive Clostridium difficile toxin enzyme immunoassay (EIA) results in hospitalized children and to examine potential reasons for this false positivity. Nested case-control. Two tertiary care pediatric hospitals. As part of a natural history study, prospectively collected EIA-positive stools were cultured for toxigenic C. difficile, and characteristics of children with false-positive and true-positive EIA results were compared. EIA-positive/culture-negative samples were recultured after dilution and enrichment steps, were evaluated for presence of the tcdB gene by polymerase chain reaction (PCR), and were further cultured for Clostridium sordellii, a cause of false-positive EIA toxin assays. Of 112 EIA-positive stools cultured, 72 grew toxigenic C. difficile and 40 did not, indicating a positive predictive value of 64% in this population. The estimated prevalence of C. difficile infection (CDI) in the study sites among children tested for this pathogen was 5%-7%. Children with false-positive EIA results were significantly younger than those with true-positive tests but did not differ in other characteristics. No false-positive specimens yielded C. difficile when cultured after enrichment or serial dilution, 1 specimen was positive for tcdB by PCR, and none grew C. sordellii. Approximately one-third of EIA tests used to evaluate pediatric inpatients for CDI were falsely positive. This finding was likely due to the low prevalence of CDI in pediatric hospitals, which diminishes the test's positive predictive value. These data raise concerns about the use of EIA assays to diagnosis CDI in children.


Primary care provider turnover and quality in managed care organizations.
To examine the association between primary care provider turnover in managed care organizations and measures of member satisfaction and preventive care. Retrospective cohort study of a national sample of 615 managed care organizations that reported HEDIS data to the National Committee for Quality Assurance from 1999 through 2001. Multivariable hierarchical regression modeling was used to evaluate the association between health plan primary care provider turnover rate and member satisfaction and preventive care measures, including childhood immunization, well-child visits, cholesterol, diabetes management, and breast and cervical cancer screening, adjusting for patient and organizational characteristics, time, and repeated measures. The median primary care provider turnover rate was 7.1% (range, 0%-53.3%). After adjustment for plan characteristics, health plans with higher primary care provider turnover rates had significantly lower measures of member satisfaction, including overall rating of healthcare (P < .01). A 10% higher primary care provider turnover rate was associated with 0.9% fewer members rating high overall satisfaction with healthcare. Health plans with higher provider turnover rates also had lower rates of preventive care, including childhood immunization (P = .045), well-child visits (P = .002), cholesterol screening after cardiac event (P = .042), and cervical cancer screening (P = .024). For example, a 10% higher primary care provider turnover was associated with a 2.7% lower rate of child-members receiving well-child visits in the first 15 months of life. Primary care provider turnover is associated with several measures of care quality, including aspects of member satisfaction and preventive care. Future studies should evaluate whether interventions to reduce primary care provider turnover can improve quality of care and patient outcomes.


Who made the Aurignacian and other early Upper Paleolithic industries?
The Aurignacian is typically taken as a marker of the spread of anatomically modern humans into Europe. However, human remains associated with this industry are frustratingly sparse and often limited to teeth. Some have suggested that Neandertals may, in fact, be responsible for the Aurignacian and the earliest Upper Paleolithic industries. Although dental remains are frequently considered to be taxonomically undiagnostic in this context, recent research shows that Neandertals possess a distinct dental pattern relative to anatomically modern humans. Even so, it is rare to find mandibles or maxillae that preserve all or most of their teeth; and, the probability of correctly identifying individuals represented by only a few teeth or a single tooth is unknown. We present a Bayesian statistical approach to classifying individuals represented exclusively by teeth into two possible groups. The classification is based on dental trait frequencies and sample sizes for 'known' samples of 95 Neandertals and 63 Upper Paleolithic modern humans. In a cross validation test of the known samples, 89% of the Neandertals and 89% of the Upper Paleolithic modern humans were classified correctly. We then classified an 'unknown' sample of 52 individuals: 34 associated with Aurignacian or other (non-Châtelperronian) early Upper Paleolithic industries, 15 associated with the Châtelperronian, and three unassociated. Of the 34 early Upper Paleolithic-associated individuals, 29 were assigned to modern humans, which is well within the range expected (95% of the time 26-33) with an 11% misclassification rate for an entirely modern human sample. These results provide some of the strongest evidence that anatomically modern humans made the Aurignacian and other (non-Châtelperronian) early Upper Paleolithic industries.


Activation of SRC kinase and phosphorylation of signal transducer and activator of transcription-5 are required for decidual transformation of human endometrial stromal cells.
Progesterone induces decidual transformation of estrogen-primed human endometrial stromal cells (hESCs), critical for implantation and maintenance of pregnancy, through activation of many signaling pathways involving protein kinase A and signal transducer and activator of transcription (STAT)-5. We have previously shown that kinase activation of v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC) kinase is closely associated with decidualization and that SRC is indispensable for maximal decidualization in mice. To address whether SRC kinase activity is essential for decidualization in humans, hESCs were infected with adenoviruses carrying enhanced green fluorescent protein alone (Ad-EGFP), a kinase-inactive dominant-negative mutant (Ad-SRC/K295R), or an inactive autophosphorylation site mutant (Ad-SRC/Y416F). The cells were cultured in the presence of estradiol and progesterone (EP) to induce decidualization and subjected to RT-PCR, immunoblot, and ELISA analyses. Ad-EGFP-infected hESCs exhibited decidual transformation and up-regulation of decidualization markers including IGF binding protein 1 and prolactin in response to 12-d treatment with EP. In contrast, hESCs infected with Ad-SRC/K295R remained morphologically fibroblastoid without production of IGF binding protein 1 and prolactin even after EP treatment. Ad-SRC/Y416F displayed similar but less inhibitory effects on decidualization, compared with Ad-SRC/K295R. During decidualization, STAT5 was phosphorylated on tyrosine 694, a well-known SRC phosphorylation site. Phosphorylation was markedly attenuated by Ad-SRC/K295R but not Ad-EGFP. These results indicate that the SRC-STAT5 pathway is essential for decidualization of hESCs.


Altered fluid transport across airway epithelium in cystic fibrosis.
In cystic fibrosis (CF), absence or dysfunction of a phosphorylation-regulated chloride channel [CF transmembrane conductance regulator (CFTR)] leads to the loss or reduction of chloride secretion into the airways. Active sodium absorption is also increased in CF, and both of these ion transport changes could alter fluid transport across the airways. Under baseline conditions, cultured human airway epithelia from normal individuals absorbed fluid, and this absorption was increased in epithelia from patients with CF. In normal and CF epithelial cultures fluid absorption was inhibited by amiloride. Adenosine 3',5'-monophosphate stimulated fluid secretion in normal epithelial cultures but not in cultures from individuals with CF. In contrast, fluid secretion induced by nucleotide triphosphates (uridine triphosphate or adenosine triphosphate) was unaltered in cultures of epithelia from patients with CF, suggesting an approach to the treatment of CF.


The extraordinary impact of Michael Faraday on chemistry and related subjects.
Biographers of Michael Faraday, as well as many dictionaries of science, often describe him as a physicist, which he certainly was. But he was also an astonishingly effective chemist: in fact, he was the Fullerian Professor of Chemistry (at the Royal Institution, RI) from 1834 until the time of his death in August, 1867. To mark the sesquicentenary of his passing, this editorial, by one of his distant successors as Director and Fullerian Professor at the RI, focuses on Faraday's output and influence as a scientist.


The development of optimal pathological assessment of sentinel lymph nodes for melanoma.
1158 sentinel lymph nodes (SLNs), excised from patients with primary cutaneous melanoma, were assessed pathologically using histology with immunohistochemistry (IHC) on all nodes, and RT-PCR for Mart-1 and tyrosinase on 55 nodes. RT-PCR was compared with the histology and IHC assessed on the same nodes. The evaluation of progressively more detailed protocols for histology and IHC modulated by the RT-PCR results led to a procedure that consistently detects metastases in 34% of patients submitted to SLN biopsy for cutaneous melanomas with a vertical growth phase and a mean thickness of 2.02 mm (range 0.25, with regression, to 19 mm). As this technique is virtually free of false positives and produces only a marginally lower detection rate than RT-PCR, which was subject to false positives of 7% in our study, it is suggested that this extended protocol should be the basis on which further evaluation of the place of RT-PCR in SLN assessment takes place. The evolved protocol described here has been adopted by the EORTC as the standard procedure for pathological handling of sentinel lymph nodes for melanoma when SLN status is a criterion in their clinical trials or studies.


Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.
The GH Research Society held a Consensus Workshop in Sydney, Australia, 2007 to incorporate the important advances in the management of GH deficiency (GHD) in adults, which have taken place since the inaugural 1997 Consensus Workshop. Two commissioned review papers, previously published Consensus Statements of the Society and key questions were circulated before the Workshop, which comprised a rigorous structure of review with breakout discussion groups. A writing group transcribed the summary group reports for drafting in a plenary forum on the last day. All participants were sent a polished draft for additional comments and gave signed approval to the final revision. Testing for GHD should be extended from hypothalamic-pituitary disease and cranial irradiation to include traumatic brain injury. Testing may indicate isolated GHD; however, idiopathic isolated GHD occurring de novo in the adult is not a recognized entity. The insulin tolerance test, combined administration of GHRH with arginine or growth hormone-releasing peptide, and glucagon are validated GH stimulation tests in the adult. A low IGF-I is a reliable diagnostic indicator of GHD in the presence of hypopituitarism, but a normal IGF-I does not rule out GHD. GH status should be reevaluated in the transition age for continued treatment to complete somatic development. Interaction of GH with other axes may influence thyroid, glucocorticoid, and sex hormone requirements. Response should be assessed clinically by monitoring biochemistry, body composition, and quality of life. There is no evidence that GH replacement increases the risk of tumor recurrence or de novo malignancy.


Trends in net survival from colon cancer in six European Latin countries: results from the SUDCAN population-based study.
Colon cancer represents a major public health issue. The aim of the SUDCAN collaborative study was to compare the net survival from colon cancer between six European Latin countries (Belgium, France, Italy, Portugal, Spain, and Switzerland) and provide trends in net survival and dynamics of the excess mortality rates up to 5 years after diagnosis. The data were extracted from the EUROCARE-5 database. First, net survival was studied over the 2000-2004 period using the Pohar-Perme estimator. For trend analyses, the study period was specific to each country. Results were reported from 1992 to 2004 in France, Italy, Spain, and Switzerland and from 2000 to 2004 in Belgium and Portugal. These analyses were carried out using a flexible excess rate modeling strategy. There were few differences between countries in age-standardized net survivals (2000-2004). During the 2000-2004 period, the 5-year net survival ranged between 57 (Spain and Portugal) and 61% (Belgium and Switzerland). The age-standardized survival at 1 and 5 years after diagnosis increased between 1992 and 2004. This increase was observed at ages 60 and 70, but was less marked at 80. This increase was linked to a marked decrease in the excess mortality rate between 1992 and 2004 until 18 months after diagnosis. Beyond this period, the decrease in the excess mortality rates among countries was modest and nearly the same whatever the year of diagnosis. There were minor differences in survival after colon cancer between European Latin countries. A considerable improvement in the 5-year net survival was observed in all countries, but the gain was mainly limited to the first 18 months after diagnosis. Further improvements are expected through the implementation of mass screening programs.


Late effects of treatment in survivors of childhood acute myeloid leukemia.
To investigate the incidence of and risk factors for late sequelae of treatment in patients who survived for more than 10 years after the diagnosis of childhood acute myeloid leukemia (AML). Of 77 survivors (median follow-up duration, 16. 7 years), 44 (group A) had received chemotherapy, 18 (group B) had received chemotherapy and cranial irradiation, and 15 (group C) had received chemotherapy, total-body irradiation, and allogeneic bone marrow transplantation. Late complications, tobacco use, and health insurance status were assessed. Growth abnormalities were found in 51% of survivors, neurocognitive abnormalities in 30%, transfusion-acquired hepatitis in 28%, endocrine abnormalities in 16%, cataracts in 12%, and cardiac abnormalities in 8%. Younger age at the time of diagnosis or initiation of radiation therapy, higher dose of radiation, and treatment in groups B and C were risk factors for the development of academic difficulties and greater decrease in height Z: score. In addition, treatment in group C was a risk factor for a greater decrease in weight Z: score and the development of growth-hormone deficiency, hypothyroidism, hypogonadism, infertility, and cataracts. The estimated cumulative risk of a second malignancy at 20 years after diagnosis was 1.8% (95% confidence interval, 0.3% to 11.8%). Twenty-two patients (29%) were smokers, and 11 (14%) had no medical insurance at the time of last follow-up. Late sequelae are common in long-term survivors of childhood AML. Our findings should be useful in defining areas for surveillance of and intervention for late sequelae and in assessing the risk of individual late effects on the basis of age and history of treatment.


Drosophila lamin mutations cause melanotic mass formation and lamellocyte differentiation.
The fruit fly immune system is a valuable model for invertebrate and innate immunity. Cellular immune reactions in Drosophila are of great interest, especially the molecular genetic mechanisms of hemocyte differentiation and the encapsulation of foreign bodies. Here we report that changes in the lamin gene cause melanotic masses. These darkened clusters of cells result from autoimmune-like encapsulation of self-tissue, as shown by the presence in lam larvae of lamellocytes, effector hemocytes that appear in larvae following wounding or parasitization. Lamins thus affect immunity in Drosophila, and lam mutations can serve as genetic tools to dissect cellular immune signaling and effector pathways.


Is economic valuation of ecosystem services useful to decision-makers? Lessons learned from Australian coastal and marine management.
Economic valuation of ecosystem services is widely advocated as being useful to support ecosystem management decision-making. However, the extent to which it is actually used or considered useful in decision-making is poorly documented. This literature blindspot is explored with an application to coastal and marine ecosystems management in Australia. Based on a nation-wide survey of eighty-eight decision-makers representing a diversity of management organizations, the perceived usefulness and level of use of economic valuation of ecosystem services, in support of coastal and marine management, are examined. A large majority of decision-makers are found to be familiar with economic valuation and consider it useful - even necessary - in decision-making, although this varies across groups of decision-makers. However, most decision-makers never or rarely use economic valuation. The perceived level of importance and trust in estimated dollar values differ across ecosystem services, and are especially high for values that relate to commercial activities. A number of factors are also found to influence respondent's use of economic valuation. Such findings concur with conclusions from other studies on the usefulness and use of ESV in environmental management decision-making. They also demonstrate the strength of the survey-based approach developed in this application to examine this issue in a variety of contexts.