Completion total thyroidectomy in children with thyroid cancer secondary to the Chernobyl accident.
To evaluate the usefulness of submitting children with thyroid cancer secondary to nuclear accidents to a completion total thyroidectomy. A case series consisting of patients living and operated on in Belarus whose parents had asked for a clinical evaluation in a western European center. A tertiary care referral center. The conditions of 47 children from Gomel, Belarus, with differentiated thyroid carcinoma following the nuclear accident at Chernobyl, Ukraine, were evaluated at the University of Pisa, Pisa, Italy. In approximately half of the cases, the treatment in Belarus consisted of a hemithyroidectomy. After a complete evaluation, the decision was made to reoperate on 19 of them by performing a completion total thyroidectomy. The preoperative evaluation revealed that 5 (26%) of the 19 patients who had undergone a hemithyroidectomy had unilateral recurrent nerve palsy and that 2 (10.5%) had hypoparathyroidism. Neck ultrasonography was used for the preoperative localization of thyroid residuals, thyroid nodules, suspicious lymph nodes, and a guided fine-needle aspiration biopsy specimen. The circulating thyroglobulin measurement was obtained before reoperation. An iodine 131 whole-body scan (WBS) was performed and circulating thyroglobulin levels were obtained after completion of the thyroidectomy during withdrawal of levothyroxine sodium therapy. The number of patients with a recurrence of thyroid cancer and lung or lymph node metastases after the completion total thyroidectomy. The results of the histologic examination were positive for papillary thyroid cancer in 6 (28.6%) of 21 patients, 3 with residual cancer in the remaining thyroid lobe and 3 with metastatic lymph node disease. A posttherapy WBS demonstrated lung metastases in 5 (28%) of 18 patients and lymph node metastases in 6 (33%) of 18 patients; the results of a posttherapy WBS were negative for metastases in 7 (39%) of 18 patients. Hypoparathyroidism developed in 4 (21%) of 19 patients who underwent a completion total thyroidectomy; unilateral laryngeal nerve palsy developed in 1 (5.2%) of these 19 patients. Among 22 children who previously underwent total thyroidectomy in Belarus, a diagnostic WBS showed lung metastases in 10 (45%) of the children and lymph node metastases alone in 3 (14%) of the children; the results of a diagnostic WBS were negative for metastases in 9 (41%) of the children. Statistical analysis showed a nonsignificant (P>.05) difference in the prevalence of lung and lymph node metastases in patients who previously underwent total thyroidectomy compared with patients who underwent completion total thyroidectomy. Completion total thyroidectomy allowed for the diagnosis and treatment of recurrent thyroid cancer and lung or lymph node metastases in 61% (11/18) of the patients in whom residual differentiated thyroid carcinoma was not previously recognized.


Placebo-controlled trial of fluoxetine and phenelzine for obsessive-compulsive disorder.
It is now well documented that fluoxetine is a viable treatment option for patients with obsessive-compulsive disorder (OCD), and there is a small body of evidence indicating that monoamine oxidase inhibitors may be effective in at least a subset of patients. The authors conducted a 10-week placebo-controlled trial of these two agents in patients who met DSM-III-R criteria for OCD. Sixty-four subjects were randomly assigned to receive placebo, phenelzine (60 mg/day), or fluoxetine (80 mg/day). These doses were achieved by the end of week 3 of the active phase of the study. Outcomes were assessed with standardized instruments to measure OCD, mood, and anxiety. Fifty-four patients completed the study. There was a significant difference among the three treatments on one OCD scale, with fluoxetine-treated patients improving significantly more than those in the placebo or phenelzine group. A subgroup of OCD patients with symmetry obsessions did respond to phenelzine. This study provides no evidence to support the use of phenelzine in OCD except possibly for those patients with symmetry or other atypical obsessions. There was also no support for the hypothesis that patients with high levels of anxiety would respond preferentially to phenelzine.


The mechanism of hologram formation in dichromated gelatin.
Experiments have been performed which lead to the conclusion that dichromated gelatin holograms arise as a result of the formation of an air-gelatin interface, with the observed high diffraction efficiencies resulting from the air-gelatin refractive index differential of 0.52 found at the interface. It is postulated that rapid removal of water by isopropanol in the development process creates strains in the gelatin film which are relieved by splitting. The resultant cracks in the hologram manifest themselves in an obvious location, between the highly exposed planes of cross-linked gelatin. Photomicrographic evidence on Bragg-Lippmann and on plane gratings, liquid gate data, lack of thickness reciprocity for the gratings, and observations of grating thickness employing bandpass measurements comprise the bulk of the experimental work. From these data, a model is proposed that is consistent with all the experimental results for both Bragg-Lippmann and plane gratings.


Thermo-elastic multiple scattering in random dispersions of spherical scatterers.
Ultrasonic monitoring of concentrated suspensions and emulsions is limited in concentration range due to the inaccuracy of the multiple scattering models currently used to interpret measurements. This paper presents the development of a model for the additional multiple scattering caused by mode conversion to/from thermal waves. These effects are believed to cause significant deviation from established models for emulsions at high concentration, or small particle size, at low frequency. The relevant additional scattering coefficients (transition factors) are developed, in numerical and analytical form, together with the modification to the effective wavenumber. Calculations have been carried out for a bromohexadecane-in-water emulsion to demonstrate the frequency-dependence of the scattering coefficients, and the effective speed and attenuation.


New insights into the role of PPARs.
Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors belonging to the nuclear hormone receptor family. While PPARs are best known as regulators of energy homeostasis, evidence also has accumulated recently for their involvement in basic cellular functions. We review novel insights into PPAR functions in skin wound healing and liver, with emphasis on PPARβ/δ and PPARα, respectively. Activation of PPARβ/δ expression in response to injury promotes keratinocyte survival, directional sensing, and migration over the wound bed. In addition, interleukin (IL)-1 produced by the keratinocytes activates PPARβ/δ expression in the underlying fibroblasts, which hinders the mitotic activity of keratinocytes via inhibition of IL-1 signaling. Initially, roles were identified for PPARα in fatty acid catabolism. However, PPARα is also involved in downregulating many genes in female mammals. We have elucidated the mechanism of this repression, which requires sumoylation of PPARα. Physiologically, this control confers protection against estrogen-induced intrahepatic cholestasis.


Light sheet theta microscopy for rapid high-resolution imaging of large biological samples.
Advances in tissue clearing and molecular labeling methods are enabling unprecedented optical access to large intact biological systems. These developments fuel the need for high-speed microscopy approaches to image large samples quantitatively and at high resolution. While light sheet microscopy (LSM), with its high planar imaging speed and low photo-bleaching, can be effective, scaling up to larger imaging volumes has been hindered by the use of orthogonal light sheet illumination. To address this fundamental limitation, we have developed light sheet theta microscopy (LSTM), which uniformly illuminates samples from the same side as the detection objective, thereby eliminating limits on lateral dimensions without sacrificing the imaging resolution, depth, and speed. We present a detailed characterization of LSTM, and demonstrate its complementary advantages over LSM for rapid high-resolution quantitative imaging of large intact samples with high uniform quality. The reported LSTM approach is a significant step for the rapid high-resolution quantitative mapping of the structure and function of very large biological systems, such as a clarified thick coronal slab of human brain and uniformly expanded tissues, and also for rapid volumetric calcium imaging of highly motile animals, such as Hydra, undergoing non-isomorphic body shape changes.


Collaborative, Multidisciplinary Evaluation of Cancer Variants Through Virtual Molecular Tumor Boards Informs Local Clinical Practices.
The cancer research community is constantly evolving to better understand tumor biology, disease etiology, risk stratification, and pathways to novel treatments. Yet the clinical cancer genomics field has been hindered by redundant efforts to meaningfully collect and interpret disparate data types from multiple high-throughput modalities and integrate into clinical care processes. Bespoke data models, knowledgebases, and one-off customized resources for data analysis often lack adequate governance and quality control needed for these resources to be clinical grade. Many informatics efforts focused on genomic interpretation resources for neoplasms are underway to support data collection, deposition, curation, harmonization, integration, and analytics to support case review and treatment planning. In this review, we evaluate and summarize the landscape of available tools, resources, and evidence used in the evaluation of somatic and germline tumor variants within the context of molecular tumor boards. Molecular tumor boards (MTBs) are collaborative efforts of multidisciplinary cancer experts equipped with genomic interpretation resources to aid in the delivery of accurate and timely clinical interpretations of complex genomic results for each patient, within an institution or hospital network. Virtual MTBs (VMTBs) provide an online forum for collaborative governance, provenance, and information sharing between experts outside a given hospital network with the potential to enhance MTB discussions. Knowledge sharing in VMTBs and communication with guideline-developing organizations can lead to progress evidenced by data harmonization across resources, crowd-sourced and expert-curated genomic assertions, and a more informed and explainable usage of artificial intelligence. Advances in cancer genomics interpretation aid in better patient and disease classification, more streamlined identification of relevant literature, and a more thorough review of available treatments and predicted patient outcomes.


Recent advances in immunomodulation in the treatment of inflammatory bowel disease.
This review in depth considers the thiopurines azathioprine, 6-mercaptopurine and 6-thioguanine, methotrexate, ciclosporin, infliximab and less well-established immunomodulators (including thalidomide, mycophenolate, tacrolimus and natalizumab among others) in their role of modifying the course of ulcerative colitis and Crohn's disease. The five papers are preceded by an overview on the therapeutic order of precedence, the indications and duration of therapy, as well as future concepts.


Effects on thermal stress and exercise on blood volume in humans.
The opening remarks of this review emphasize, somewhat pessimistically, the serious disagreements, going back over a hundred years, between different investigators regarding effects of exercise and thermal stress on intravascular volume. However, the concluding remarks may legitimately assume a more optimistic, positive aspect, and a certain degree of order and sense may be brought to what had superficially appeared to be the chaos and confusion of conflicting observations and conclusions. Krebs and Meyer's (162) "marked differences in findings between one investigator and another," and Senay's (245) comment 77 years later that "disagreements abound" can now be seen as an inevitable consequence of the widely differing experimental protocols and procedures that have been adopted. Of particular importance in this respect is the failure to standardize conditions before subjects are exposed to thermal stress or begin to exercise--notably in terms of posture and environmental temperature; both may profoundly influence blood volume responses, quantitatively and qualitatively. Then there is subject status; physical fitness, heat acclimatization, and dehydration are important factors contributing to the variability of individual responses to thermal stress and exercise. With the causes of disagreement at least identified, it is now possible to answer the question posed in section I: Is thermal- and exercise-induced hemoconcentration fact or fantasy? Undeniably it is fact, but only under certain circumstances. For example, in resting subjects reduction in blood volume is associated only with high environmental temperatures above the upper limit of the prescriptive zone; within the upper part of the zone, blood volume commonly increases. If heat exposure is preceded by a control period in a cool environment, transient hemodilution is generally observed, followed by hemoconcentration after entry into the heat as skin temperature rises, cutaneous blood flow increases, and sweating begins. Exercise too causes hemoconcentration, but only if the exercise is performed in a supine or seated, not in an upright (standing), position. Hence cycling is almost always associated with a reduction in plasma volume, as is arm exercise and swimming. Bench stepping, walking, and running, on the other hand, are associated with an extremely variable intravascular volume response. If allowance is made for the reduction in plasma volume that occurs when moving to an upright position from a supine or seated position, the initial rapid hemoconcentration seen at the onset of cycling exercise is absent with bench stepping, walking, and running.(ABSTRACT TRUNCATED AT 400 WORDS)


Measuring the quantitative performance of surgical operating lists: theoretical modelling of 'productive potential' and 'efficiency'.
We previously defined surgical list 'efficiency' as: maximising theatre utilisation, minimising over-running, and minimising cancellations. 'Efficiency' maximises output for input; 'productivity' emphasises total output. We define six criteria that any measure of productivity (better termed 'quantitative performance') needs to satisfy. We then present a theoretical analysis that fulfils these by incorporating: 'speed' of surgery (with reference to average speeds), 'patient contact' (synonymous with minimising gaps between cases), and 'efficiency' (as previously defined). 'Speed' and 'patient contact' together constitute a 'productive potential'. Our formula satisfies the pre-set criteria and yields plausible results in both hypothetical and real data sets, To be productive in these quantitative terms, teams in any specialty need to achieve minimum quality standards defined by their sub-specialty; to plan their lists to utilise the time available with no cancellations or over-runs and to work at least as fast as average with minimal gaps between cases. 'Productive potential' combined with 'efficiency' yielding 'actual productivity' in our theoretical analysis more completely describes quantitative surgical list performance than any other single measure.


Genome sequence of Synechococcus CC9311: Insights into adaptation to a coastal environment.
Coastal aquatic environments are typically more highly productive and dynamic than open ocean ones. Despite these differences, cyanobacteria from the genus Synechococcus are important primary producers in both types of ecosystems. We have found that the genome of a coastal cyanobacterium, Synechococcus sp. strain CC9311, has significant differences from an open ocean strain, Synechococcus sp. strain WH8102, and these are consistent with the differences between their respective environments. CC9311 has a greater capacity to sense and respond to changes in its (coastal) environment. It has a much larger capacity to transport, store, use, or export metals, especially iron and copper. In contrast, phosphate acquisition seems less important, consistent with the higher concentration of phosphate in coastal environments. CC9311 is predicted to have differences in its outer membrane lipopolysaccharide, and this may be characteristic of the speciation of some cyanobacterial groups. In addition, the types of potentially horizontally transferred genes are markedly different between the coastal and open ocean genomes and suggest a more prominent role for phages in horizontal gene transfer in oligotrophic environments.


Galanin-like peptide (GALP) is a target for regulation by leptin in the hypothalamus of the rat.
Galanin-like peptide (GALP), which was recently isolated from the porcine hypothalamus, shares sequence homology with galanin and binds with high affinity to galanin receptors. To study the distribution and regulation of GALP-expressing cells in the brain, we cloned a 120 base-pair cDNA fragment of rat GALP and produced an antisense riboprobe. In situ hybridization for GALP mRNA was then performed on tissue sections throughout the forebrain of adult ovariectomized female rats. We found GALP mRNA-containing cells in the arcuate nucleus (Arc), caudal dorsomedial nucleus, median eminence and the pituitary. Because GALP mRNA in the Arc appeared to overlap with the known distribution of leptin receptor mRNA, we tested the hypothesis that GALP expression is regulated by leptin. Using in situ hybridization, we compared the number of GALP mRNA-containing cells among groups of rats that were fed ad lib or fasted for 48 h and treated with either leptin or vehicle. Fasting reduced the number of identifiable cells containing GALP mRNA in the Arc, whereas the treatment of fasted animals with leptin produced a 4-fold increase in the number of cells expressing GALP message. The presence of GALP mRNA in the hypothalamus and pituitary and its regulation by leptin suggests that GALP may have important neuroendocrine functions, including the physiological regulation of feeding, metabolism, and reproduction.


Early endotoxic shock results in enhanced vasodilator responses to nitroglycerin but unaltered responses to neuropeptides calcitonin gene-related peptide and substance P.
To determine the role that vasoactive neuropeptides, calcitonin gene-related peptide, and substance P play in tissue-blood flow regulation during early septic shock, we examined the responsiveness of arteries removed from pigs 3 h after administration of Escherichia coli lipopolysaccharide or saline vehicle. The carotid, cranial mesenteric, and left anterior descending coronary arteries were excised, and rings were cut from each vessel. Constrictor responses were obtained to cumulative doses of norepinephrine or potassium chloride. Rings were reconstricted and challenged with acetylcholine, substance P, calcitonin gene-related peptide, and nitroglycerin. Lipopolysaccharide significantly increased the cranial mesenteric artery's response to high concentrations of norepinephrine and the response to nitroglycerin in all vessels. This enhancement of responses to nitroglycerin suggests augmented smooth-muscle responsiveness to an exogenous source of nitric oxide, possibly associated with early depression of basal endothelial function. Depression of agonist-induced nitric oxide release may mask such enhancement with endothelial-dependent dilators and may enhance the response to adrenergic constrictors in some vascular beds.


The pandemic of physical inactivity: global action for public health.
Physical inactivity is the fourth leading cause of death worldwide. We summarise present global efforts to counteract this problem and point the way forward to address the pandemic of physical inactivity. Although evidence for the benefits of physical activity for health has been available since the 1950s, promotion to improve the health of populations has lagged in relation to the available evidence and has only recently developed an identifiable infrastructure, including efforts in planning, policy, leadership and advocacy, workforce training and development, and monitoring and surveillance. The reasons for this late start are myriad, multifactorial, and complex. This infrastructure should continue to be formed, intersectoral approaches are essential to advance, and advocacy remains a key pillar. Although there is a need to build global capacity based on the present foundations, a systems approach that focuses on populations and the complex interactions among the correlates of physical inactivity, rather than solely a behavioural science approach focusing on individuals, is the way forward to increase physical activity worldwide.


A Twin Study of Genetic Influences on Nephrolithiasis in Women and Men.
Nephrolithiasis is a complex phenotype influenced by both genetic and environmental factors. Previously we found a genetic component to stone disease using a sample of male twin pairs. We now report on the genetic contribution to stones in a sample of female and male twin pairs. We conducted a classic twin study of kidney stones using the Washington State Twin Registry. Data were collected by questionnaire to obtain self-reported history of kidney stones. Univariate structural equation modeling was used to determine the relative contributions of additive genetics, common environment, and unique environment. There were 7053 same-sex pairs with kidney stone data. The mean age of the sample was 39 years, similar in women and men. The prevalence of stones was 4.9% of women and 6.2% of men. We found significant contributions from genetics and the unique environment (P < 0.05 for both) for the risk for stone disease in women and men. There was no significant contribution of the common environment for either sex. After adjusting for age, heritability was 46% (95% confidence interval 0.36-0.56) in women and 57% (0.46-0.68) in men, which was significantly different (P < 0.05). Nephrolithiasis in women has a heritable component less than that we again demonstrate in men. This finding may in part explain why more stone formers are men than women. Women twins demonstrated a greater effect of the unique environment on stone prevalence. The specific environmental risk factors that account for this effect are not currently known.


G-protein-independent signaling mediated by metabotropic glutamate receptors.
Synaptically released glutamate activates ionotropic and metabotropic receptors at central synapses. Metabotropic glutamate receptors (mGluRs) are thought to modulate membrane conductances through transduction cascades involving G proteins. Here we show, in CA3 pyramidal cells from rat hippocampus, that synaptic activation of type 1 mGluRs by mossy fiber stimulation evokes an excitatory postsynaptic response independent of G-protein function, while inhibiting an afterhyperpolarization current through a G-protein-coupled mechanism. Experiments using peptide activators and specific inhibitors identified a Src-family protein tyrosine kinase as a component of the G-protein-independent transduction pathway. These results represent the first functional evidence for a dual signaling mechanism associated with a heptahelical receptor such as mGluR1, in which intracellular transduction involves activation of either G proteins or tyrosine kinases.


Burns in Sweden: an analysis of 24,538 cases during the period 1987-2004.
Burn care is always progressing, but there is little epidemiological information giving a clear picture of the current number of treated burns in Sweden. This study was conducted to provide an update of patients admitted to hospital with burns in Sweden. Data were obtained for all patients who were admitted to hospitals with a primary or secondary diagnosis of burns (ICD-9/10 codes) from 1 January 1987 to 31 December 2004; 24,538 patients were found. Most of the patients were male (69%), giving a male:female ratio of 2.23:1. Children in the age-group 0-4 years old predominated, and accounted for 27% of the study material. The median length of stay was 3 days. Throughout the period 740 patients (3%) died of their burns. Significant reductions in mortality, incidence, and length of stay were seen during the study, which correlates well with other studies. However, most of the reductions were in the younger age-groups. Men accounted for the improved mortality, as female mortality did not change significantly. We think that the improvement in results among patients admitted to hospital after burns is a combination of preventive measures, improved treatment protocols, and an expanding strategy by which burned patients are treated as outpatients.


Clinical implementation of MR-guided vaginal cylinder brachytherapy.
We present an institutional experience on the clinical implementation of magnetic resonance (MR)-guided vaginal brachytherapy using commercially available solid applicator models. To test the fidelity of solid applicator models to digitize vaginal cylinder applicators, three datasets were evaluated. The first included 15 patients who were simulated with CT alone. Next, a water phantom was used to evaluate vaginal cylinders ranging from 20 to 35 mm in diameter with CT and MR. Finally, three patients undergoing HDR brachytherapy with vaginal cylinders that were simulated with both CT and MR were evaluated. In these assessments, the solid applicator models were aligned based on the outline of the applicators on the corresponding volumetric image, and deviations between the central source positions defined based on X-ray markers (on CT) and solid applicator models (on CT and MR), and the percent dose difference between select reference points were calculated. The mean central source deviation defined based on X-ray markers (on CT) and solid applicator models (on CT and MR) for the 15-patient cohort, the phantom, and the 3-patient cohort is 0.6 mm, 0.6 mm, and 1.2 mm, respectively. The average absolute percent dose difference for the bladder, rectum, prescription, and inferior reference points were 2.2%, 2.3%, 2.2%, and 2.4%, respectively, for the 15 patient cohort. For the phantom study, the average, absolute percent dose difference for the prescription and inferior reference points are 2.0% and 2.1% for the CT, 2.3% and 2.2% for the T1W, and 2.8% and 3.0% for the T2W images. For the three patient cohort, the average absolute percent dose difference for the bladder, rectum, prescription, and inferior reference points are 2.9%, 2.6%, 3.0%, and 4.2% for the CT, 6.5%, 1.6%, 2.5%, and 4.7% for the T1W, and 6.0%, 7.4%, 2.6, and 2.0% for the T2W images. Based on the current study, aligning the applicator model to MR images provides a practical, efficient approach to perform MR-based brachytherapy planning.


Depression, antidepressants, and neurogenesis: a critical reappraisal.
The neurogenesis hypothesis of depression posits (1) that neurogenesis in the subgranular zone of the dentate gyrus is regulated negatively by stressful experiences and positively by treatment with antidepressant drugs and (2) that alterations in the rate of neurogenesis play a fundamental role in the pathology and treatment of major depression. This hypothesis is supported by important experimental observations, but is challenged by equally compelling contradictory reports. This review summarizes the phenomenon of adult hippocampal neurogenesis, the initial and continued evidence leading to the development of the neurogenesis hypothesis of depression, and the recent studies that have disputed and/or qualified those findings, to conclude that it can be affected by stress and antidepressants under certain conditions, but that these effects do not appear in all cases of psychological stress, depression, and antidepressant treatment.


Comparative evaluation of two commercial multiplex panels for detection of gastrointestinal pathogens by use of clinical stool specimens.
The detection of pathogens associated with gastrointestinal disease may be important in certain patient populations, such as immunocompromised hosts, the critically ill, or individuals with prolonged disease that is refractory to treatment. In this study, we evaluated two commercially available multiplex panels (the FilmArray gastrointestinal [GI] panel [BioFire Diagnostics, Salt Lake City, UT] and the Luminex xTag gastrointestinal pathogen panel [GPP] [Luminex Corporation, Toronto, Canada]) using Cary-Blair stool samples (n = 500) submitted to our laboratory for routine GI testing (e.g., culture, antigen testing, microscopy, and individual real-time PCR). At the time of this study, the prototype (non-FDA-cleared) FilmArray GI panel targeted 23 pathogens (14 bacterial, 5 viral, and 4 parasitic), and testing of 200 μl of Cary-Blair stool was recommended. In contrast, the Luminex GPP assay was FDA cleared for the detection of 11 pathogens (7 bacterial, 2 viral, and 2 parasitic), but had the capacity to identify 4 additional pathogens using a research-use-only protocol. Importantly, the Luminex assay was FDA cleared for 100 μl raw stool; however, 100 μl Cary-Blair stool was tested by the Luminex assay in this study. Among 230 prospectively collected samples, routine testing was positive for one or more GI pathogens in 19 (8.3%) samples, compared to 76 (33.0%) by the FilmArray and 69 (30.3%) by the Luminex assay. Clostridium difficile (12.6 to 13.9% prevalence) and norovirus genogroup I (GI)/GII (5.7 to 13.9% prevalence) were two of the pathogens most commonly detected by both assays among prospective samples. Sapovirus was also commonly detected (5.7% positive rate) by the FilmArray assay. Among 270 additional previously characterized samples, both multiplex panels demonstrated high sensitivity (>90%) for the majority of targets, with the exception of several pathogens, notably Aeromonas sp. (23.8%) by FilmArray and Yersinia enterocolitica (48.1%) by the Luminex assay. Interestingly, the FilmArray and Luminex panels identified mixed infections in 21.1% and 13.0% of positive prospective samples, respectively, compared to only 8.3% by routine methods.


Identification of the hair cell soma-1 antigen, HCS-1, as otoferlin.
Hair cells, the mechanosensitive receptor cells of the inner ear, are critical for our senses of hearing and balance. The small number of these receptor cells in the inner ear has impeded the identification and characterization of proteins important for hair cell function. The binding specificity of monoclonal antibodies provides a means for identifying hair cell-specific proteins and isolating them for further study. We have generated a monoclonal antibody, termed hair cell soma-1 (HCS-1), which specifically immunolabels hair cells in at least five vertebrate classes, including sharks and rays, bony fish, amphibians, birds, and mammals. We used HCS-1 to immunoprecipitate the cognate antigen and identified it as otoferlin, a member of the ferlin protein family. Mutations in otoferlin underlie DFNB9, a recessive, nonsyndromic form of prelingual deafness characterized as an auditory neuropathy. Using immunocytochemistry, we find that otoferlin is associated with the entire basolateral membrane of the hair cells and with vesicular structures distributed throughout most of the hair cell cytoplasm. Biochemical assays indicate that otoferlin is tightly associated with membranes, as it is not solubilized by alterations in calcium or salt concentrations. HCS-1 immunolabeling does not co-localize with ribeye, a constituent of synaptic ribbons, suggesting that otoferlin may, in addition to its proposed function in synaptic vesicle release, play additional roles in hair cells.


A randomized controlled trial comparing the Thompson hemiarthroplasty with the Exeter polished tapered stem and Unitrax modular head in the treatment of displaced intracapsular fractures of the hip: the WHiTE 3: HEMI Trial.
This study aimed to compare the change in health-related quality of life of patients receiving a traditional cemented monoblock Thompson hemiarthroplasty compared with a modern cemented modular polished-taper stemmed hemiarthroplasty for displaced intracapsular hip fractures. This was a pragmatic, multicentre, multisurgeon, two-arm, parallel group, randomized standard-of-care controlled trial. It was embedded within the WHiTE Comprehensive Cohort Study. The sample size was 964 patients. The setting was five National Health Service Trauma Hospitals in England. A total of 964 patients over 60 years of age who required hemiarthroplasty of the hip between February 2015 and March 2016 were included. A standardized measure of health outcome, the EuroQol (EQ-5D-5L) questionnaire, was carried out on admission and at four months following the operation. Of the 964 patients enrolled, 482 died or were lost to follow-up (50%). No significant differences were noted in EQ-5D between groups, with a mean difference at four months of 0.037 in favour of the Exeter/Unitrax implant (95% confidence interval (CI) 0.014 to 0.087, p = 0.156), rising to 0.045 (95% CI 0.007 to 0.098, p = 0.09) when patients who died were excluded. The minimum clinically important difference for EQ-5D-5L used in this study is 0.08, therefore any benefit between implants is unlikely to be noticeable to the patient. There was no difference in mortality or mobility score. Allowing for the high rate of loss to follow-up, the use of the traditional Thompson hemiarthroplasty in the treatment of the displaced intracapsular hip fracture shows no difference in health outcome when compared with a modern cemented hemiarthroplasty. Cite this article: Bone Joint J 2018;100-B:352-60.


Dispersion control with reflection grisms of an ultra-broadband spectrum approaching a full octave.
We report the design, implementation, and characterization of a grism-pair stretcher in a near-infrared noncollinear optical parametric chirped-pulse amplifier (OPCPA) that is capable of controlling a bandwidth of 440 nm. Our dynamic dispersion control scheme relies on the grism stretcher working in conjunction with an acousto-optic programmable dispersive filter (Dazzler) to jointly compensate large amount of material dispersion. A spectral interference technique is used to characterize the spectral phase of the grism stretcher. This ultra-broadband device opens up the way to generate sub-2-cycle laser pulses.


Cell proliferation is not required for productive HIV-1 infection of macrophages.
Lentiviruses, including HIV-1, are considered a rare example of retroviruses which do not require cell proliferation for their replication. However, this notion was questioned in several publications where productive HIV-1 infection was found to be restricted to a small fraction of macrophages with proliferative capacity. Since the mode of HIV-1 replication in macrophages is of great clinical relevance, we performed a single-cell analysis of HIV-1 replication and [3H]thymidine incorporation. Our results indicate that while 17% macrophages were detected as HIV-1 DNA-positive 12 hr after infection, only 2% of those cells had incorporated tritium, about the same percentage as in the uninfected cell population. Forty-eight hours after infection, 38% macrophages were HIV-1 DNA-positive and 47% of those had incorporated tritium, while the percentage of tritium-positive uninfected cells did not change (1%). These results demonstrate directly that HIV-1 DNA does not colocalize with [3H]thymidine and support the notion that cell proliferation is not required for HIV-1 infection of macrophages.


Signal tracking approach for phase estimation in digital holographic interferometry.
In this research work, we introduce a novel approach for phase estimation from noisy reconstructed interference fields in digital holographic interferometry using an unscented Kalman filter. Unlike conventionally used unwrapping algorithms and piecewise polynomial approximation approaches, this paper proposes, for the first time to the best of our knowledge, a signal tracking approach for phase estimation. The state space model derived in this approach is inspired from the Taylor series expansion of the phase function as the process model, and polar to Cartesian conversion as the measurement model. We have characterized our approach by simulations and validated the performance on experimental data (holograms) recorded under various practical conditions. Our study reveals that the proposed approach, when compared with various phase estimation methods available in the literature, outperforms at lower SNR values (i.e., especially in the range 0-20 dB). It is demonstrated with experimental data as well that the proposed approach is a better choice for estimating rapidly varying phase with high dynamic range and noise.


Prognostic factors for abatacept retention in patients who received at least one prior biologic agent: an interim analysis from the observational, prospective ACTION study.
The emergence of new therapies for the treatment of rheumatoid arthritis (RA), the paucity of head-to-head studies, and the heterogeneous nature of responses to current biologics highlight the need for the identification of prognostic factors for treatment response and retention in clinical practice. Prognostic factors for patient retention have not been explored thoroughly despite data for abatacept and other biologics being available from national registries. Real-world data from the ACTION study may supplement the findings of randomized controlled trials and show how abatacept is used in clinical practice. The aim of this interim analysis was to identify prognostic factors for abatacept retention in patients with RA who received at least one prior biologic agent. A large, international, non-interventional cohort of patients with moderate-to-severe RA who initiated intravenous abatacept in Canada and Europe (May 2008-January 2011) enrolled in the ACTION study. Potential prognostic factors for retention in this interim analysis (data cut-off February 2012; including patients from Canada, Germany, Greece, and Italy) were baseline demographics and disease characteristics, medical history, and previous and concomitant medication. Clinically relevant variables with p ≤ 0.20 in univariate analysis and no collinearity were entered into a Cox proportional hazards regression model, adjusted for clustered data. Variables with p ≤ 0.10 were retained in the final model (backward selection). The multivariate model included 834 patients. Anti-cyclic citrullinated peptide (CCP) antibody positivity (hazard ratio [95% confidence interval]: 0.55 [0.40, 0.75], p < 0.001), failure of <2 prior anti-tumor necrosis factors (TNFs) (0.71 [0.56, 0.90], p = 0.005 versus ≥2 prior anti-TNFs), and cardiovascular comorbidity at abatacept initiation (0.48 [0.28, 0.83], p = 0.009) were associated with lower risk of abatacept discontinuation. Patients in Greece and Italy were less likely to discontinue abatacept than patients in Germany and Canada (Greece: 0.30 [0.16, 0.58]; Italy: 0.50 [0.33, 0.76]; Canada: 1.04 [0.78, 1.40], p < 0.001 versus Germany). Real-world prognostic factors for abatacept retention include anti-CCP positivity and fewer prior anti-TNF failures. Differences in retention rates between countries may reflect differences in healthcare systems. The finding that abatacept has potential advantages in patients with cardiovascular comorbidities needs to be confirmed in further research.


Altered resting-state FMRI signals in acute stroke patients with ischemic penumbra.
Identifying the ischemic penumbra in acute stroke subjects is important for the clinical decision making process. The aim of this study was to use resting-state functional magnetic resonance singal (fMRI) to investigate the change in the amplitude of low-frequency fluctuations (ALFF) of these subjects in three different subsections of acute stroke regions: the infarct core tissue, the penumbra tissue, and the normal brain tissue. Another aim of this study was to test the feasilbility of consistently detecting the penumbra region of the brain through ALFF analysis. Sixteen subjects with first-ever acute ischemic stroke were scanned within 27 hours of the onset of stroke using magnetic resonance imaging. The core of infarct regions and penumbra regions were determined by diffusion and perfusion-weighted imaging respectively. The ALFF were measured from resting-state blood oxygen level dependent (BOLD) fMRI scans. The averaged relative ALFF value of each regions were correlated with the time after the onset of stroke. Relative ALFF values were significantly different in the infarct core tissue, penumbra tissue and normal brain tissue. The locations of lesions in the ALFF maps did not match perfectly with diffusion and perfusion-weighted imagings; however, these maps provide a contrast that can be used to differentiate between penumbra brain tissue and normal brain tissue. Significant correlations between time after stroke onset and the relative ALFF values were present in the penumbra tissue but not in the infarct core and normal brain tissue. Preliminary results from this study suggest that the ALFF reflects the underlying neurovascular activity and has a great potential to estimate the brain tissue viability after ischemia. Results also show that the ALFF may contribute to acute stroke imaging for thrombolytic or neuroprotective therapies.


National trends in resection of the distal pancreas.
To investigate national trends in distal pancreatectomy (DP) through query of three national patient care databases. From the Nationwide Inpatient Sample (NIS, 2003-2009), the National Surgical Quality Improvement Project (NSQIP, 2005-2010), and the Surveillance Epidemiology and End Results (SEER, 2003-2009) databases using appropriate diagnostic and procedural codes we identified all patients with a diagnosis of a benign or malignant lesion of the body and/or tail of the pancreas that had undergone a partial or distal pancreatectomy. Utilization of laparoscopy was defined in NIS by the International Classification of Diseases, Ninth Revision correspondent procedure code; and in NSQIP by the exploratory laparoscopy or unlisted procedure current procedural terminology codes. In SEER, patients were identified by the International Classification of Diseases for Oncology, Third Edition diagnosis codes and the SEER Program Code Manual, third edition procedure codes. We analyzed the databases with respect to trends of inpatient outcome metrics, oncologic outcomes, and hospital volumes in patients with lesions of the neck and body of the pancreas that underwent operative resection. NIS, NSQIP and SEER identified 4242, 2681 and 11,082 DP resections, respectively. Overall, laparoscopy was utilized in 15% (NIS) and 27% (NSQIP). No significant increase was seen over the course of the study. Resection was performed for malignancy in 59% (NIS) and 66% (NSQIP). Neither patient Body mass index nor comorbidities were associated with operative approach (P = 0.95 and P = 0.96, respectively). Mortality (3% vs 2%, P = 0.05) and reoperation (4% vs 4%, P = 1.0) was not different between laparoscopy and open groups. Overall complications (10% vs 15%, P < 0.001), hospital costs [44,741 dollars, interquartile range (IQR) 28 347-74 114 dollars vs 49 792 dollars, IQR 13 299-73 463, P = 0.02] and hospital length of stay (7 d, IQR 4-11 d vs 7 d, IQR 6-10, P < 0.001) were less when laparoscopy was utilized. One and two year survival after resection for malignancy were unchanged over the course of the study (ductal adenocarinoma 1-year 63.6% and 2-year 35.1%, P = 0.53; intraductal papillary mucinous neoplasm and nueroendocrine 1-year 90% and 2-year 84%, P = 0.25). The majority of resections were performed in teaching hospitals (77% NIS and 85% NSQIP), but minimally invasive surgery (MIS) was not more likely to be used in teaching hospitals (15% vs 14%, P = 0.26). Hospitals in the top decile for volume were more likely to be teaching hospitals than lower volume deciles (88% vs 43%, P < 0.001), but were no more likely to utilize MIS at resection. Complication rate in teaching and the top decile hospitals was not significantly decreased when compared to non-teaching (15% vs 14%, P = 0.72) and lower volume hospitals (14% vs 15%, P = 0.99). No difference was seen in the median number of lymph nodes and lymph node ratio in N1 disease when compared by year (P = 0.17 and P = 0.96, respectively). There appears to be an overall underutilization of laparoscopy for DP. Centralization does not appear to be occurring. Survival and lymph node harvest have not changed.


Development of a Novel CD4+ TCR Transgenic Line That Reveals a Dominant Role for CD8+ Dendritic Cells and CD40 Signaling in the Generation of Helper and CTL Responses to Blood-Stage Malaria.
We describe an MHC class II (I-Ab)-restricted TCR transgenic mouse line that produces CD4+ T cells specific for Plasmodium species. This line, termed PbT-II, was derived from a CD4+ T cell hybridoma generated to blood-stage Plasmodium berghei ANKA (PbA). PbT-II cells responded to all Plasmodium species and stages tested so far, including rodent (PbA, P. berghei NK65, Plasmodium chabaudi AS, and Plasmodium yoelii 17XNL) and human (Plasmodium falciparum) blood-stage parasites as well as irradiated PbA sporozoites. PbT-II cells can provide help for generation of Ab to P. chabaudi infection and can control this otherwise lethal infection in CD40L-deficient mice. PbT-II cells can also provide help for development of CD8+ T cell-mediated experimental cerebral malaria (ECM) during PbA infection. Using PbT-II CD4+ T cells and the previously described PbT-I CD8+ T cells, we determined the dendritic cell (DC) subsets responsible for immunity to PbA blood-stage infection. CD8+ DC (a subset of XCR1+ DC) were the major APC responsible for activation of both T cell subsets, although other DC also contributed to CD4+ T cell responses. Depletion of CD8+ DC at the beginning of infection prevented ECM development and impaired both Th1 and follicular Th cell responses; in contrast, late depletion did not affect ECM. This study describes a novel and versatile tool for examining CD4+ T cell immunity during malaria and provides evidence that CD4+ T cell help, acting via CD40L signaling, can promote immunity or pathology to blood-stage malaria largely through Ag presentation by CD8+ DC.


Neuronal intranuclear inclusion disease presenting with resting tremor.
Neuronal intranuclear inclusion disease (NIID) is a rare neurodegenerative disease with various neurological symptoms. A 73-year-old woman presented with slowly progressive tremor in both hands. The resting tremor was enhanced by cognitive activity and walking. However, there were no other signs of parkinsonism. Levodopa and trihexyphenidyl were ineffective against the tremor. A diagnosis of NIID was made based on skin biopsy findings. The tremor in this case was very similar to that seen in Parkinson's disease (PD). Previous reports and the present case indicate that NIID patients can develop tremor that is similar in character to that seen in PD. NIID should be considered in the differential diagnosis of resting tremor similar to PD.


Postsynthetic functionalization of mesoporous silica.
Functionalized mesoporous silica offers promising possibilities for numerous applications, including drug delivery, catalysis, and adsorption. This minireview focuses on recent developments related to the postsynthetic positioning of functional groups on mesoporous silica. After briefly introducing the reagents that are commonly used for this purpose, methods to control and to analyze the distribution of the grafted functional groups are discussed, with particular emphasis on concepts that allow the placement of the groups at specific distances from each other, as well as on approaches towards the selective functionalization of the external particle surface.


Thyroid function as assessed by routine laboratory tests of workers with long-term lead exposure.
Thyroid function was studied in 176 male workers occupationally exposed to lead. The mean blood lead concentration of the workers was 2.70 (SD 1.15, range 0.70-6.45) mumol/l. The mean duration of lead exposure was 7.6 (range 0.1-20) years. The total thyroxine (T4), free thyroxine (FT4), total triiodothyronine (T3), and thyrotropin concentrations in serum were similar in the workers in the low and high blood lead categories. In regression equations the duration of lead exposure had a weak but significant negative association with T4 and FT4, and this association was particularly pronounced when the analyses were restricted to workers with the most intense lead exposure over time. Thus, the results suggest that thyroid function might be depressed as a result of intense long-term lead exposure.


Regulation of notch1 signaling by nrf2: implications for tissue regeneration.
The Keap1-Nrf2-ARE signaling pathway elicits an adaptive response for cell survival after endogenous and exogenous stresses, such as inflammation and carcinogens, respectively. Keap1 inhibits the transcriptional activation activity of Nrf2 (p45 nuclear factor erythroid-derived 2-related factor 2) in unstressed cells by facilitating its degradation. Through transcriptional analyses in Keap1- or Nrf2-disrupted mice, we identified interactions between the Keap1-Nrf2-ARE and the Notch1 signaling pathways. We found that Nrf2 recognized a functional antioxidant response element (ARE) in the promoter of Notch1. Notch1 regulates processes such as proliferation and cell fate decisions. We report a functional role for this cross talk between the two pathways and show that disruption of Nrf2 impeded liver regeneration after partial hepatectomy and was rescued by reestablishment of Notch1 signaling.


Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity.
Promising results have emerged from a phase II clinical trial testing methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg-AD) that develops age-dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg-AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin- and trypsin-like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD-like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action.


New methods to identify and rank high pedestrian crash zones: an illustration.
Identifying and ranking high pedestrian crash zones plays a key role in developing efficient and effective strategies to enhance pedestrian safety. This paper presents (1) a Geographical Information Systems (GIS) methodology to study the spatial patterns of pedestrian crashes in order to identify high pedestrian crash zones, and (2) an evaluation of methods to rank these high pedestrian crash zones. The GIS based methodology to identify high pedestrian crash zones includes geocoding crash data, creating crash concentration maps, and then identifying high pedestrian crash zones. Two methods generally used to create crash concentration maps based on density values are the Simple Method and the Kernel Method. Ranking methods such as crash frequency, crash density, and crash rate, as well as composite methods such as the sum-of-the-ranks and the crash score methods are used to rank the selected high pedestrian crash zones. The use of this methodology and ranking methods for high pedestrian crash zones are illustrated using the Las Vegas metropolitan area as the study area. Crash data collected for a 5-year period (1998-2002) were address matched using the street name/reference street name intersection location reference system. A crash concentration map was then created using the Kernel Method as it facilitates the creation of a smooth density surface when compared to the Simple Method. Twenty-two linear high crash zones and seven circular high crash zones were then identified. The GIS based methodology reduced the subjectivity in the analysis process. Results obtained from the evaluation of methods to rank high pedestrian crash zones show a significant variation in ranking when individual methods were considered. However, rankings of high pedestrian crash zones were relatively consistent with little to no variation when the sum-of-the-ranks method and the crash score method were used. Thus, these composite methods are recommended for use in ranking high pedestrian crash zones instead of individual methods.


Analysis of 10 km swimming performance of elite male and female open-water swimmers.
This study investigated trends in performance and sex difference in swimming speed of elite open-water swimmers at FINA 10 km competitions (i.e. World Cup races, European Championships, World Championships and Olympic Games). Swimming speed and sex difference in swimming speed of the fastest and the top ten women and men per event competing at 10 km open-water races between 2008 and 2012 were analysed using single and multi-level regression analyses. A total of 2,591 swimmers (i.e. 1,120 women and 1,471 men) finished 47 races. Swimming speed of the fastest women (1.35 ± 0.9 m/s) and men (1.45 ± 0.10 m/s) showed no changes across years. The mean sex difference in swimming speed for the fastest swimmers was 6.8 ± 2.5%. Swimming speed of the top ten female swimmers per event was 1.34 ± 0.09 m/s and remained stable across the years. The top ten male swimmers per event showed a significant decrease in swimming speed over time, even though swimming speed in the first race (i.e. January 2008, 1.40 ± 0.0 m/s) was slower than the swimming speed in the last race (i.e. October 2012, 1.50 ± 0.0 m/s) (P < 0.05). To summarize, swimming performances remained stable for the fastest elite open-water swimmers at 10 km FINA competitions between 2008 and 2012, while performances of the top ten men tended to decrease. The sex difference in swimming speed in elite ultra-swimmers (~7%) appeared smaller compared to other ultra-distance disciplines such as running. Further studies should examine how body shape and physiology of elite open-water ultra-distance swimmers influence performances.


Enhanced ex situ bioremediation of crude oil contaminated beach sand by supplementation with nutrients and rhamnolipids.
Mediterranean coastal regions are particularly exposed to oil pollution due to extensive industrialization, urbanization and transport of crude and refined oil to and from refineries. Bioremediation of contaminated beach sand through landfarming is both simple and cost-effective to implement compared to other treatment technologies. The purpose of the present study was to investigate the effect of alternative nutrients on biodegradation of crude oil contaminated beach sand in an effort to reduce the time required for bioremediation employing only indigenous hydrocarbon degraders. A natural sandy soil was collected from Agios Onoufrios beach (Chania, Greece) and was contaminated with weathered crude oil. The indigenous microbial population in the contaminated sand was tested alone (control treatment) or in combination with inorganic nutrients (KNO3 and K2HPO4) to investigate their effects on oil biodegradation rates. In addition, the ability of biosurfactants (rhamnolipids), in the presence of organic nutrients (uric acid and lecithin), to further stimulate biodegradation was investigated in laboratory microcosms over a 45-day period. Biodegradation was tracked by GC/MS analysis of aliphatic and polycyclic aromatic hydrocarbons components and the measured concentrations were corrected for abiotic removal by hopane normalizations. It was found that the saturated fraction of the residual oil is degraded more extensively than the aromatic fraction and the bacterial growth after an incubation period of approximately 3 weeks was much greater from the bacterial growth in the control. The results show that the treatments with inorganic or organic nutrients are equally effective over almost 30 days where C12-C35n-alkanes were degraded more than 97% and polyaromatic hydrocarbons with two or three rings were degraded more than 95% within 45 days. The results clearly show that the addition of nutrients to contaminated beach sand significantly enhanced the activity of indigenous microorganisms, as well as the removal of total recoverable petroleum hydrocarbons (TRPH) over a 45-day study period.


Tackling non-muscle invasive bladder cancer in the clinic.
Non-muscle invasive bladder cancer (NMIBC) is a common disease process with a high propensity for recurrence and risk of progression to muscle-invasive or systemic disease. Optimal management of NMIBC depends on appropriate resection and staging, risk-based use of intravesical therapy and tailored surveillance. Current challenges include compliance with guideline recommendations and cancers which are refractory to standard therapies. Areas covered: This review summarizes the conventional management of NMIBC - which relies on strict cystoscopic surveillance and intravesical therapies with chemotherapy and/or immunotherapy in the form of bacillus Calmette-Guerin (BCG). As many patients will be resistant to conventional treatment, investigational therapies and novel prognostic models will also be discussed. Expert commentary: For decades, the management of NMIBC has been predicated on intravesical therapies, most often through the instillation of BCG which has proven clinical efficacy over transurethral resection alone. Despite this, many patients will recur or progress after BCG therapy. While radical cystectomy remains the standard for such patients, suitable alternatives are being actively investigated. An increased interest in immunotherapy for malignancy has reinvigorated this field and on-going advances in disease prognostication are likely to improve upon the existing treatment paradigms for NMIBC.


Gastric cancer in the era of molecularly targeted agents: current drug development strategies.
Gastric cancer is the second most common cause of cancer death worldwide with approximately one million cases diagnosed annually. Despite considerable improvements in surgical techniques, innovations in clinical diagnostics and the development of new chemotherapy regimens, the clinical outcome for patients with advanced gastric cancer and cancer of the GEJ is generally poor with 5-year survival rates ranging between 5 and 15%. The understanding of cancer relevant events has resulted in new therapeutic strategies, particularly in developing of new molecular targeted agents. These agents have the ability to target a variety of cancer relevant receptors and downstream pathways including the epidermal growth factor receptor (EGFR), the vascular endothelial growth factor receptor (VEGFR), the insulin-like growth factor receptor (IGFR), the c-Met pathway, cell-cycle pathways, and down-stream signalling pathways such as the Akt-PI3k-mTOR pathway. In the era of new molecularly targeted agents this review focuses on recent developments of targeting relevant pathways involved in gastric cancer and cancer of the GEJ.


Role of type I & type II reactions in DNA damage and activation of caspase 3 via mitochondrial pathway induced by photosensitized benzophenone.
Sunscreen users have been increased, since excessive sun exposure increased the risk of skin diseases. Benzophenone (BP) and its derivatives are commonly used in sunscreens as UV blocker. Its photosafety is concern for human health. Our study showed the role of type-I and type-II radicals in activation of caspase 3 and phototoxicity of BP under sunlight/UV radiation. BP photodegraded and formed two photoproducts. BP generates reactive oxygen species (ROS) singlet oxygen ((1)O2), superoxide anion (O2˙(-)) and hydroxyl radical (˙OH) through type-I and type-II photodynamic mechanisms. Photocytotoxicity significantly reduced cell viability under sunlight, UVB and UVA. DCF fluorescence confirmed intracellular ROS generation. BP showed single strand DNA breakage, further proved by cyclobutane pyrimidine dimmers (CPDs) formation. Lipid peroxidation and LDH leakage were enhanced by BP. P21 dependent cell cycle study showed sub G1 population which advocates apoptotic cell death, confirmed through AO/EB and annexin V/PI staining. BP decreased mitochondrial membrane potential, death protein released and activated caspase. We proposed cytochrome c regulated caspase 3 dependent apoptosis in HaCaT cell line through down regulation of Bcl2/Bax ratio. Phototoxicity potential of its photoproducts is essential to understand its total environmental fate. Hence, we conclude that BP may replace from cosmetics preparation of topical application.


Centromeres of Cucumis melo L. comprise Cmcent and two novel repeats, CmSat162 and CmSat189.
Centromeres are prerequisite for accurate segregation and are landmarks of primary constrictions of metaphase chromosomes in eukaryotes. In melon, high-copy-number satellite DNAs (SatDNAs) were found at various chromosomal locations such as centromeric, pericentromeric, and subtelomeric regions. In the present study, utilizing the published draft genome sequence of melon, two new SatDNAs (CmSat162 and CmSat189) of melon were identified and their chromosomal distributions were confirmed using fluorescence in situ hybridization. DNA probes prepared from these SatDNAs were successfully hybridized to melon somatic and meiotic chromosomes. CmSat162 was located on 12 pairs of melon chromosomes and co-localized with the centromeric repeat, Cmcent, at the centromeric regions. In contrast, CmSat189 was found to be located not only on centromeric regions but also on specific regions of the chromosomes, allowing the characterization of individual chromosomes of melon. It was also shown that these SatDNAs were transcribed in melon. These results suggest that CmSat162 and CmSat189 might have some functions at the centromeric regions.


Clinical librarianship in the UK: temporary trend or permanent profession? Part I: a review of the role of the clinical librarian.
This paper is the first of a two-part series of articles presenting the role of the clinical librarian (CL) in the UK today. It situates the CL concept historically, and specifically reports the findings from a study in 2002 (Skinner, The Role of the Clinical Librarian in the UK. MSc Dissertation. Loughborough University: Department of Information Science). The impetus for the 2002 study was the awareness of an increase in job advertisements within the NHS for roles seeking to enhance the practice of evidence-based medicine, which included elements of clinical librarianship. Therefore the research was undertaken to establish whether this increase was coincidental, or the beginning of a new professional role for librarians. A content analysis of CL job advertisements, examining job titles and duties was undertaken. Twenty-three advertisements were scrutinized, and these results are presented here. As a complementary investigation, a postal questionnaire was sent to a sample of practising CLs in the UK. Several duties can be classified as core to the role of the CL. However there is a great diversity of duties attached to this core, reflecting an absence of nationally accepted practice. Further work was necessary to assess current practice and how clinical librarianship can continue to grow at local and national levels. This is addressed in Part Two of this series.


Tradeoffs between Maize Silage Yield and Nitrate Leaching in a Mediterranean Nitrate-Vulnerable Zone under Current and Projected Climate Scenarios.
Future climatic changes may have profound impacts on cropping systems and affect the agronomic and environmental sustainability of current N management practices. The objectives of this work were to i) evaluate the ability of the SALUS crop model to reproduce experimental crop yield and soil nitrate dynamics results under different N fertilizer treatments in a farmer's field, ii) use the SALUS model to estimate the impacts of different N fertilizer treatments on NO3- leaching under future climate scenarios generated by twenty nine different global circulation models, and iii) identify the management system that best minimizes NO3- leaching and maximizes yield under projected future climate conditions. A field experiment (maize-triticale rotation) was conducted in a nitrate vulnerable zone on the west coast of Sardinia, Italy to evaluate N management strategies that include urea fertilization (NMIN), conventional fertilization with dairy slurry and urea (CONV), and no fertilization (N0). An ensemble of 29 global circulation models (GCM) was used to simulate different climate scenarios for two Representative Circulation Pathways (RCP6.0 and RCP8.5) and evaluate potential nitrate leaching and biomass production in this region over the next 50 years. Data collected from two growing seasons showed that the SALUS model adequately simulated both nitrate leaching and crop yield, with a relative error that ranged between 0.4% and 13%. Nitrate losses under RCP8.5 were lower than under RCP6.0 only for NMIN. Accordingly, levels of plant N uptake, N use efficiency and biomass production were higher under RCP8.5 than RCP6.0. Simulations under both RCP scenarios indicated that the NMIN treatment demonstrated both the highest biomass production and NO3- losses. The newly proposed best management practice (BMP), developed from crop N uptake data, was identified as the optimal N fertilizer management practice since it minimized NO3- leaching and maximized biomass production over the long term.


Natural selection contributed to immunological differences between hunter-gatherers and agriculturalists.
The shift from a hunter-gatherer to an agricultural mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture affected the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the early transcriptional response to viruses compared with that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune-response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations on the basis of the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.


Evaluation of a 3-Dimensional-Printed Head Simulation Technique for Teaching Flexible Nasopharyngoscopy to Radiation Oncology Residents.
Simulation-based medical education is an effective tool for medical teaching, but simulation-based medical education deployment in radiation oncology (RO) is limited. Flexible nasopharyngoscopy (FNP), an essential skill for RO residents, requires practice that typically occurs on volunteer patients, introducing the potential for stress and discomfort. We sought to develop a high-fidelity simulator and intervention that provides RO residents the opportunity to develop FNP skills in a low-pressure environment. Computed tomography images were used to create an anatomically accurate 3-dimensional-printed model of the head and neck region. An intervention incorporating didactic instruction, multimedia content, and FNP practice on the model was designed and administered to RO residents attending the Anatomy and Radiology Contouring Bootcamp. Participants completed pre- and postintervention evaluations of the training session and model fidelity, and self-assessments of FNP skill and confidence performing FNP. Participants were video recorded performing FNP pre- and postintervention. Videos were scored by a blinded observer on a predefined rubric. Changes in scores were evaluated using the Wilcoxon signed-rank test. Twenty-four participants from 17 institutions and 4 countries completed the intervention, 50% were women, and most were senior residents. Postintervention, FNP confidence and FNP performance improved significantly (mean ± standard deviation on a 10-point scale: 1.8 ± 1.8, P < .001; 2.2 ± 2.0, P < .001, respectively). Participants felt the model was helpful (mean ± standard deviation on a 5-point scale: 4.2 ± 0.6), anatomically correct (4.1 ± 0.9), and aided in spatial comprehension (4.3 ± 0.8). Overall satisfaction for the intervention was high (4.3 ± 0.8). Participants strongly agreed the intervention should be integrated into RO training programs (4.3 ± 0.8). A 3-dimensional-printed model and associated intervention were effective at improving FNP performance and the teaching method was rated highly by participants. RO residents may benefit from broader dissemination of this technique to improve trainee performance.


Long-term follow-up of post-cardiac surgery Mycobacterium chimaera infections: A 5-center case series.
In multiple countries, endovascular/disseminated Mycobacterium chimaera infections have occurred in post-cardiac surgery patients in association with contaminated, widely-distributed cardiac bypass heater-cooler devices. To contribute to long-term characterization of this recently recognized infection, we describe the clinical course of 28 patients with 3-7 years of follow-up for survivors. Identified at five hospitals in the United States 2010-2016, post-cardiac surgery patients in the cohort had growth of Mycobacterium avium complex (MAC)/M. chimaera from a sterile site or surgical wound, or a clinically compatible febrile illness with granulomatous inflammation on biopsy. Case follow-up was conducted in May 2019. Of 28 patients, infection appeared to be localized to the sternum in four patients. Among 18 with endovascular/disseminated infection who received combination anti-mycobacterial treatment and had sufficient follow-up, 39% appeared to have controlled infection (>12 months), 56% died, and one patient is alive with relapsed bacteremia. While the number of patients is small and interpretation is limited, four (67%) of six patients who had cardiac prosthesis removal/replacement appeared to have controlled infection compared to three (25%) of 12 with retained cardiac prosthesis (p >0.14; Fisher's exact test). Given poor response to treatment and potential for delayed relapses, post-cardiac surgery M. chimaera infection warrants aggressive treatment and long-term monitoring.


Controlled self-assembly of stomatosomes by use of single-component fluorinated dendritic amphiphiles.
A series of novel non-ionic amphiphiles with dendritic oligoglycerol head groups of different generations ([G1]-[G3]) and lipophilic/fluorophilic tail segments, comprising single or double tail alkyl chains, C8F17-perfluoro rod segments as well as flexible spacer groups of different lengths were designed and synthesized. We expected that the differences in the size of the dendritic head groups in combination with perfluorinated segments would have an impact on the supramolecular structures formed in aqueous solution if compared with the hydrogenated analogues. Investigating the self-assembly behavior mainly by cryogenic transmission electron microscopy (cryo-TEM) and cryo-electron tomography (cryo-ET) we found as a new result the formation of perforated bilayer vesicles (stomatosomes) and bicontinuous network structures. Surprisingly, we have observed stomatosome formation by self-assembly of single component fluorinated dendritic amphiphiles. These assembly structures turned out to be extremely robust against harsh conditions, although there are strong indications that they represent non-equilibrium structures, which eventually transform into a bicontinuous cubic network structure of double diamond symmetry. In general, the molecular asymmetry of amphiphiles tuned by chemical design induced the expected trend from spherical micelles through worm-like micelles to perforated bilayers and three-dimensional network structures.


Prolonged neoadjuvant chemotherapy with GM-CSF in locally advanced breast cancer.
Neoadjuvant chemotherapy improves survival in patients with locally advanced breast cancer (LABC). Usually three to four cycles of conventional-dose neoadjuvant chemotherapy are administered prior to local therapy, and another three cycles thereafter. In an attempt to improve results, we increased the dosages and applied GM-CSF, which, besides being a hematopoietic growth factor, has become increasingly known for its immunostimulatory effects, which might enhance the antitumor effect. Forty-two patients with stage IIIA or IIIB breast cancer were treated with doxorubicin (A) (90 mg/m2) and cyclophosphamide (C) (1,000 mg/m2) at three-weekly intervals. In the second and fourth cycle a 10% dose reduction of both agents was applied. On the second day GM-CSF 250 micrograms/m2/day was started and given for 10 days. Initially, some patients were treated with < or = four cycles, but as the study progressed and toxicity appeared tolerable, six cycles were given whenever possible. After the chemotherapy, patients underwent surgery and postoperative radiotherapy. The response rate for the whole group to AC was 98% (95% confidence interval 94%-100%), with a clinical complete response rate of 50% (95% confidence interval 35%-65%). Six patients had a pathological complete response. Median follow-up from the start of chemotherapy is 49 months (range 10-100). The disease-free survival (DFS) at three years is 57% and the overall survival (OS) at three years is 79%. There is a significant trend for improved DFS (p = 0.0000) and OS (p = 0.0002) with increasing number of cycles. The results of the present study with neoadjuvant dose-intensive AC chemotherapy and GM-CSF compare favorably with previous studies in patients with LABC. This is most apparent in patients who received six cycles of neoadjuvant chemotherapy. We hypothesize that these encouraging results are probably related to the prolonged presence of the primary tumor, and to the long-term administration of GM-CSF with the primary tumor and axillary lymph nodes in situ. Therefore, a randomized study is warranted. We already initiated an international randomized trial in patients with LABC in order to answer two questions. First, does prolonged neoadjuvant chemotherapy result in an improved DFS and OS in comparison with the conventional approach, and secondly, what is the effect of GM-CSF in this approach in comparison with G-CSF?


Palaeodiet reconstruction in a woman with probable celiac disease: a stable isotope analysis of bone remains from the archaeological site of Cosa (Italy).
Stable isotope analysis in the reconstruction of human palaeodiets can yield clues to early human subsistence strategies, origins and history of farming and pastoralist societies, and intra- and intergroup social differentiation. In the last 10 years, the method has been extended to the pathological investigation. Stable isotope analysis to better understand a diet-related disease: celiac disease in ancient human bones was carried out. To do this, we analyzed the nitrogen and carbon isotopic composition of human (n = 37) and faunal (n = 8) bone remains from the archaeological site of Cosa at Ansedonia, on the Tyrrhenian coast near Orbetello (Tuscany), including the skeletal remains of a young woman (late 1st century-early 2nd century Common Era [CE]) with morphological and genetic features suggestive of celiac disease. We compared the young woman's isotopic data with those of other individuals recovered at the same site but from two later time periods (6th century CE; 11-12th century CE) and with literature data from other Italian archaeological sites dating to the same period. Her collagen δ(13) C and δ(15) N values differed from those of the samples at the same site, and from most but not all of the contemporary sites. Although the woman's diet appears distinct, chronic malnutrition resulting from severe malabsorption of essential nutrients due to celiac disease may have affected the isotopic composition of her bone collagen.


Evaluating darunavir/ritonavir dosing regimens for HIV-positive pregnant women using semi-mechanistic pharmacokinetic modelling.
Darunavir 800 mg once (q24h) or 600 mg twice (q12h) daily combined with low-dose ritonavir is used to treat HIV-positive pregnant women. Decreased total darunavir exposure (17%-50%) has been reported during pregnancy, but limited data on unbound exposure are available. To evaluate total and unbound darunavir exposures following standard darunavir/ritonavir dosing and to explore the value of potential optimized darunavir/ritonavir dosing regimens for HIV-positive pregnant women. A population pharmacokinetic analysis was conducted based on data from 85 women. The final model was used to simulate total and unbound darunavir AUC0-τ and Ctrough during the third trimester of pregnancy, as well as to assess the probability of therapeutic exposure. Simulations predicted that total darunavir exposure (AUC0-τ) was 24% and 23% lower in pregnancy for standard q24h and q12h dosing, respectively. Unbound darunavir AUC0-τ was 5% and 8% lower compared with post-partum for standard q24h and q12h dosing, respectively. The probability of therapeutic exposure (unbound) during pregnancy was higher for standard q12h dosing (99%) than for q24h dosing (94%). The standard q12h regimen resulted in maximal and higher rates of therapeutic exposure compared with standard q24h dosing. Darunavir/ritonavir 600/100 mg q12h should therefore be the preferred regimen during pregnancy unless (adherence) issues dictate q24h dosing. The value of alternative dosing regimens seems limited.


Parp1 localizes within the Dnmt1 promoter and protects its unmethylated state by its enzymatic activity.
Aberrant hypermethylation of CpG islands in housekeeping gene promoters and widespread genome hypomethylation are typical events occurring in cancer cells. The molecular mechanisms behind these cancer-related changes in DNA methylation patterns are not well understood. Two questions are particularly important: (i) how are CpG islands protected from methylation in normal cells, and how is this protection compromised in cancer cells, and (ii) how does the genome-wide demethylation in cancer cells occur. The latter question is especially intriguing since so far no DNA demethylase enzyme has been found. Our data show that the absence of ADP-ribose polymers (PARs), caused by ectopic over-expression of poly(ADP-ribose) glycohydrolase (PARG) in L929 mouse fibroblast cells leads to aberrant methylation of the CpG island in the promoter of the Dnmt1 gene, which in turn shuts down its transcription. The transcriptional silencing of Dnmt1 may be responsible for the widespread passive hypomethylation of genomic DNA which we detect on the example of pericentromeric repeat sequences. Chromatin immunoprecipitation results show that in normal cells the Dnmt1 promoter is occupied by poly(ADP-ribosyl)ated Parp1, suggesting that PARylated Parp1 plays a role in protecting the promoter from methylation. In conclusion, the genome methylation pattern following PARG over-expression mirrors the pattern characteristic of cancer cells, supporting our idea that the right balance between Parp/Parg activities maintains the DNA methylation patterns in normal cells. The finding that in normal cells Parp1 and ADP-ribose polymers localize on the Dnmt1 promoter raises the possibility that PARylated Parp1 marks those sequences in the genome that must remain unmethylated and protects them from methylation, thus playing a role in the epigenetic regulation of gene expression.


Rationale and design of lifestyle intervention using mobile technology in patients with high cardiovascular risk: A pragmatic randomized clinical trial.
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality throughout the world and contributes a considerable burden to healthcare costs. Primary prevention strategies, particularly adopting healthy lifestyle habits, have great potential to reduce the risk of CVD. Patient compliance remains the major cause of the failure of primary prevention strategies. Telehealth interventions and gamification through mobile applications can increase adherence and reduce healthcare costs. The primary objective of this study is to compare the effect of lifestyle intervention using mobile technology plus usual care with usual care alone in patients with a high CVD risk.


Extended prophylaxis for venous thromboembolism after hospitalization for medical illness: A trial sequential and cumulative meta-analysis.
The efficacy, safety, and clinical importance of extended-duration thromboprophylaxis (EDT) for prevention of venous thromboembolism (VTE) in medical patients remain unclear. We compared the efficacy and safety of EDT in patients hospitalized for medical illness. Electronic databases of PubMed/MEDLINE, EMBASE, Cochrane Central, and ClinicalTrials.gov were searched from inception to March 21, 2019. We included randomized clinical trials (RCTs) reporting use of EDT for prevention of VTE. We performed trial sequential and cumulative meta-analyses to evaluate EDT effects on the primary efficacy endpoint of symptomatic VTE or VTE-related death, International Society on Thrombosis and Haemostasis (ISTH) major or fatal bleeding, and all-cause mortality. The pooled number needed to treat (NNT) to prevent one symptomatic or fatal VTE event and the number needed to harm (NNH) to cause one major or fatal bleeding event were calculated. Across 5 RCTs with 40,247 patients (mean age: 67-77 years, proportion of women: 48%-54%, most common reason for admission: heart failure), the duration of EDT ranged from 24-47 days. EDT reduced symptomatic VTE or VTE-related death compared with standard of care (0.8% versus 1.2%; risk ratio [RR]: 0.61, 95% confidence interval [CI]: 0.44-0.83; p = 0.002). EDT increased risk of ISTH major or fatal bleeding (0.6% versus 0.3%; RR: 2.04, 95% CI: 1.42-2.91; p < 0.001) in both meta-analyses and trial sequential analyses. Pooled NNT to prevent one symptomatic VTE or VTE-related death was 250 (95% CI: 167-500), whereas NNH to cause one major or fatal bleeding event was 333 (95% CI: 200-1,000). Limitations of the study include variation in enrollment criteria, individual therapies, duration of EDT, and VTE detection protocols across included trials. In this systematic review and meta-analysis of 5 randomized trials, we observed that use of a post-hospital discharge EDT strategy for a 4-to-6-week period reduced symptomatic or fatal VTE events at the expense of increased risk of major or fatal bleeding. Further investigations are still required to define the risks and benefits in discrete medically ill cohorts, evaluate cost-effectiveness, and develop pathways for targeted implementation of this postdischarge EDT strategy. PROSPERO CRD42018109151.


The relation between self-reported psychopathic traits and distorted response styles: a meta-analytic review.
A concern among researchers is that self-report measures may not be valid indicators of psychopathic traits due to the core features of psychopathy (e.g., lying, deception/manipulation). The current study addresses this issue by combining effects sizes from studies published on or before March 31, 2010 to examine the relation between scores of 3 widely used self-report psychopathy measures--the Psychopathic Personality Inventory (PPI; Lilienfeld & Andrews, 1996) and its revised version (PPI-R; Lilienfeld & Widows, 2005) and Levenson's Self-Report Psychopathy scale (LSRP; Levenson, Kiehl, & Fitzpatrick, 1995) and scores on measures assessing response style (i.e., faking good and faking bad). Effect sizes were obtained from 45 studies for total, Factor 1, and Factor 2 scores (faking good: k = 54, 55, and 55, respectively; faking bad: k = 51, 50, and 50, respectively). Based on a random effects model, a significant negative association was found between social desirability/faking good and both total (r(w) = -.11, p < .01) and F2 (r(w) = -.16, p < .01) scores, and moderation analyses suggested that effect sizes varied as a function of psychopathy scale and validity scale used. Significant positive associations were also found between faking bad and both total (r(w) = .27, p < .05) and F2 (r(w) = .32, p < .05) scores. Also, moderation analyses suggested that effect sizes varied as a function of study location, psychopathy scale, and validity scale. Despite several limitations (e.g., inclusion of only published studies, limited moderators, exclusion of other measures), the general findings temper concerns of positive response bias and underscore the validity of self-report psychopathy scales.


Posttraumatic stress symptoms in police staff 12-18 months after the Canterbury earthquakes.
Understanding posttraumatic stress disorder (PTSD) symptoms in police first-responders is an underdeveloped field. Using a cross-sectional survey, this study investigated demographic and occupational characteristics, coping resources and processes, along with first-responder roles and consequences 18 months following a disaster. Hierarchical linear regression (N = 576) showed that greater symptom levels were significantly positively associated with negative emotional coping (β = .31), a communications role (β = .08) and distress following exposure to resource losses (β = .14), grotesque scenes (β = .21), personal harm (β = .14), and concern for significant others (β = .17). Optimism alone was negatively associated (β = -.15), with the overall model being a modest fit (adjusted R(2) = .39). The findings highlight variables for further study in police.


Insulin resistance and hyperandrogenism have no substantive association with birth weight in adolescents with polycystic ovary syndrome.
To assess whether birth weight influences the metabolic and hormonal profile of adolescents with polycystic ovary syndrome (PCOS). Retrospective study. University outpatient clinic. One hundred seventy consecutive adolescents 12 to 19 years of age with PCOS, 15 of whom were small for gestational age (SGA), and 75 healthy female aged-matched adolescents as controls. Physical evaluations, fasting blood samples for measuring endocrine and metabolic parameters, and an oral glucose tolerance test. Physical, endocrine, and metabolic features. The birth weights of adolescents with PCOS as well as those with hyperinsulinemic or insulin resistance were similar to those of the control group. The PCOS SGA adolescents had basal insulin (15.93 ± 7.16 μU/mL vs. 10.97 ± 5.79 μU/mL) and homeostasis model assessment of insulin resistance values (3.2 ± 1.54 vs. 2.19 ± 1.28) that were statistically significantly higher than in the control group. The mean levels of total testosterone in the SGA adolescents with PCOS were above the upper limit of the normal range (0.80 ng/mL). Low birth weight may influence the appearance of hyperandrogenism and insulin resistance in a portion of adolescents with PCOS, but only 9% of the adolescents with PCOS in this study were SGA. In the majority of adolescents with PCOS, hyperinsulinemia and hyperandrogenism are related to factors other than birth weight alone.


Analysis and simulation of a fiber bundle method for creating a partially spatially coherent beam.
A fiber bundle arrangement containing a distribution of fiber lengths has been proposed in the literature to produce a partially spatially coherent beam. Light input to the bundle with limited temporal coherence is translated into limited spatial coherence. Expressions are developed for the bundle pupil autocorrelation function and far-field irradiance pattern. A numerical simulation approach is implemented and results are compared with a speckle-free result. The fiber bundle approach tends to create an irradiance pattern whose average shape matches the pattern produced by a single fiber. A "smoothed" far-field pattern is obtained if the fiber length difference is much greater than the source temporal coherence length.


Reproducing the morphology-dependent resonances of spheres with the discrete dipole approximation.
During the development and application of a scattering algorithm, its accuracy is normally validated by comparing with results of spherical particles given by the exact Mie theory. Being the simplest shape, sphere supports morphology-dependent resonances (MDRs), which cause sharp variations of the scattering properties in narrow size ranges. We show that MDRs may mislead the validation of any volume- or surface-discretization methods, including the discrete dipole approximation (DDA) and, thus, should be explicitly avoided. However, the brute-force DDA simulations can actually capture the narrow peaks in the extinction efficiency over the size parameter, but only if a dipole size parameter is smaller than twice the MDR width. That is much more computationally intensive than typical DDA simulations. We find that a single Lorentzian MDR peak may be split into two due to the symmetry breaking by the DDA discretization. Furthermore, instead of time-consuming high-resolution DDA simulations for reproducing MDR, we developed and validated a significantly more computationally efficient method. It is based, first, on fitting simulated data with one or two Lorentzian peaks combined with a cubic baseline. Second, we use Richardson extrapolation of peak parameters to zero dipole size, exploiting the smooth convergence of these parameters towards the reference Mie values. When applied to two MDRs with relative widths 2 × 10-3 and 9 × 10-4, the developed workflow, powered by intensive simulations, reproduces the peak positions with unprecedented accuracy - errors less than 0.07% and 0.4% of their widths, respectively. This extends the way for studying the evolution of the MDR under non-axisymmetric deformations of a sphere or a spheroid.


In situ expression of cytokines and cellular phenotypes in the lungs of mice with slowly progressive primary tuberculosis.
The cellular phenotypes and the expression of cytokines were studied in the lungs of mice, using immunohistochemistry, during different phases of slowly progressive primary murine tuberculosis infection. During the first phase the small focal lesions in healthy mice contained predominantly interleukin-2 (IL-2)-expressing cells. A small number of tumour necrosis factor-alpha (TNF-alpha)-, monocyte chemoattractant protein-1 (MCP-1)- and IL-10-expressing cells were also present. IL-4-expressing cells were not detected. During the second phase the mice became unwell, but the bacterial counts and the size of focal lesions stabilized. IL-4-expressing cells appeared. The IL-10-, TNF-alpha- and MCP-1-expressing cells increased in number. On progression to phase three, the mice became seriously unwell and died rapidly. The inflammation spread to approximately 80% of the lung parenchyma. There was a marked increase in the number of IL-10-expressing cells. Expression of other cytokines was similar to that observed in the second phase. In the lesions, 3-6% of the macrophages (Mphi) containing mycobacterial antigens expressed high levels of IL-10 and TNF-alpha. The absolute numbers of CD3-, CD4- and CD11b-expressing cells in the lesions increased with the progression of infection. The numbers of CD8+ cells were reduced in the last phase of infection. The kinetics of T-lymphocyte subsets and the pattern of cytokine expression changed with the type and degree of tissue injury. The small number of Mphi with a heavy load of mycobacterial antigens may be the cause of this disturbance in cytokine balance, thus leading to progression of inflammation.


Comorbid Diagnosis of Psychotic Disorders in Borderline Personality Disorder: Prevalence and Influence on Outcome.
A diagnosis of psychotic disorder is traditionally considered incompatible with borderline personality disorder (BPD), even though patients sometimes fulfill the diagnostic criteria for both disorders. How often this happens is barely known, as is the influence of comorbid psychotic disorders on the outcome of BPD. Since studies on isolated auditory verbal hallucinations in patients with BPD indicate that these perceptual symptoms have severe consequences and are associated with suicidal behavior and hospitalization, patients with comorbid psychotic disorders are unlikely to fare better. To examine the point prevalence of psychotic disorders in patients with BPD, their association with the outcome of BPD, and their predictive value for outcome. In a cross-sectional design, 84 female outpatients diagnosed with BPD were interviewed with the aid of the MINI-International Neuropsychiatric Interview to establish the point prevalence of comorbid psychotic and other comorbid disorders. After termination of their treatment at a specialized outpatient clinic, the type of referral was considered to be a "good" outcome when they were referred to their general practitioner or to basic psychiatric care for noncomplex patients, and a "poor" outcome when referred to a specialized psychiatric department or to a psychiatric district team for patients with severe psychiatric disorders. Psychotic disorders were present in 38% of the patients with BPD. With a prevalence of 20%, psychotic disorder not otherwise specified (NOS) was the most common subtype; the least common types were schizophrenia (2%), substance-induced psychotic disorder (2%), and brief psychotic disorder (1%). Among six types of comorbid disorders, only psychotic disorders were associated with a poor outcome; they were also predictors for a poor outcome, along with comorbid mood disorders, eating disorders, and somatoform disorders, as well as the severity of BPD, and, counterintuitively, more years of education. Psychotic disorders, notably of the psychotic disorder NOS subtype, are common among patients with BPD, and their presence is associated with a poor outcome. This implies that adequate diagnosis and treatment of both disorders is warranted in this subgroup with a dual diagnosis.


High-molecular-weight immunoreactive beta-endorphin in extracts of human placenta is a fragment of immunoglobulin G.
A high-molecular-weight protein with beta-endorphin- and adrenocorticotropin-immunoreactivities was isolated from extracts of human placenta after several purification steps, including immunoadsorption with a well-characterized antiserum raised to beta-endorphin. This protein was identified as the heavy chain of the human immunoglobulin class IgG1. These results have led to the recognition of homologies in the amino acid sequences of these physiologically unrelated molecules. They also suggest caution in accepting immunological competence as the sole criterion of the chemical identity of a ligand.


Optical properties and applications of photochromic glass.
Corning Glass Works has recently developed a series of inorganic bulk photochromic materials. The present paper is concerned with the results of an extensive laboratory investigation of their properties. It is shown that the fatigueless reversibility and the optical characteristics of these glasses hold definite. promise for several applications.


Can we improve neurological outcomes in severe traumatic brain injury? Something old (early prophylactic hypothermia) and something new (erythropoietin).
Traumatic brain injury is a leading cause of mortality and long-term morbidity, particularly affecting young people. With our best therapies, one half of the patients with severe traumatic brain injury are never capable of living independently. Two interventions, which have real potential to improve neurological outcomes in patients with traumatic brain injury, are (i) very early induction of prophylactic hypothermia and (ii) exogenous erythropoietin therapy. There is substantial experimental evidence, a plausible biological rationale, and supportive clinical evidence from clinical trials to suggest a possible beneficial effect of prophylactic hypothermia and also for exogenous erythropoietin therapy in severe traumatic brain injury. Despite the recent guidelines and publications recommending these interventions, critical care clinicians should be conservative towards implementing these therapies outside clinical trials due to substantial efficacy and safety concerns. Nevertheless the high morbidity and mortality associated with severe traumatic brain injury (TBI) demands that we investigate the safety and efficacy of these promising potential therapies as a matter of urgency.