Evaluation of the efficacy of a bioerodible bupivacaine polymer system on antinociception and inflammatory mediator release.
Pain due to tissue injury is often characterized by the presence of hyperalgesia and allodynia. It is hypothesized that these perceptual states are mediated by sensitization of peripheral terminals of primary afferent neurons together with several changes in the central nervous system. This provides a rationale for preemptive analgesia, whereby the blockade of primary afferent input prior to injury may result in a reduction of post-injury pain. One approach for prolonged blockade of primary afferent input is the use of bioerodible polymer systems providing regulated release of local anesthetics. Bioerodible polymer systems offer the theoretical advantage of controlled drug delivery maintained over prolonged periods. Local application of this system to the inflamed tissue compartment permits the use of smaller total drug doses. This may minimize systemic side effects, while maintaining prolonged peripherally-mediated antinociception. In the present study, we evaluated the effects of a bioerodible polymer/bupivacaine system (PLGA/bupivacaine) on several indices of inflammation and on hindpaw levels of the inflammatory mediators, substance P and bradykinin in the complete Freund's adjuvant model. We observed that PLGA/bupivacaine reduces inflammatory hyperalgesia, edema and hyperthermia in a temporal and dose-related fashion in awake animals. Moreover, we demonstrated that PLGA/bupivacaine has a prolonged inhibitory effect on the tissue levels of substance P and bradykinin in the inflamed hindpaws. The results of these studies clearly indicate the potential therapeutic utility of the PLGA bupivacaine system, with the single dose administration producing a prolonged suppression of hyperalgesia, edema and biochemical indices of inflammation.


Deception detection expertise.
A lively debate between Bond and Uysal (2007, Law and Human Behavior, 31, 109-115) and O'Sullivan (2007, Law and Human Behavior, 31, 117-123) concerns whether there are experts in deception detection. Two experiments sought to (a) identify expert(s) in detection and assess them twice with four tests, and (b) study their detection behavior using eye tracking. Paroled felons produced videotaped statements that were presented to students and law enforcement personnel. Two experts were identified, both female Native American BIA correctional officers. Experts were over 80% accurate in the first assessment, and scored at 90% accuracy in the second assessment. In Signal Detection analyses, experts showed high discrimination, and did not evidence biased responding. They exploited nonverbal cues to make fast, accurate decisions. These highly-accurate individuals can be characterized as experts in deception detection.


Volume of screening mammography and performance in the Quebec population-based Breast Cancer Screening Program.
In the Quebec Breast Cancer Screening Program (Programme quebecois de depistage du cancer du sein [PQDCS]), radiologists' and facilities' volumes of screening mammography vary considerably. We examined the relation of screening-mammography volume to rates of breast cancer detection and false-positive readings in the PQDCS. The study population included 307,314 asymptomatic women aged 50-69 years screened during 1998-2000. Breast cancer detection rates were analyzed by comparing all women with screening-detected breast cancer (n = 1709) and a 10% random sample of those without (n = 30,560). False-positive rates were analyzed by comparing the 3159 women with false-positive readings and the 27,401 others in the 10% random sample. Characteristics of participants, radiologists and facilities were obtained from the PQDCS information system. Data were analyzed by means of logistic regression. The rate of breast cancer detection appeared to be unrelated to the radiologist's screening-mammography volume but increased with the facility's screening-mammography volume. The breast cancer detection rate ratio for facilities performing 4000 or more screenings per year, compared with those performing fewer than 2000, was 1.28 (95% confidence interval [CI] 1.07-1.52). In contrast, the frequency of false-positive readings was unrelated to the facility's screening volume but was inversely related to the radiologist's screening volume: the rate ratio for readers of 1500 or more screenings per year compared with those reading fewer than 250 was 0.53 (95% CI 0.35-0.79). Radiologists' and facilities' caseloads showed independent and complementary associations with performance of screening mammography in the PQDCS. Radiologists who worked in larger facilities and read more screening mammograms had higher breast cancer detection rates while maintaining lower false-positive rates.


Size and form of the human temporomandibular joint in African-Americans and Caucasians.
The aim of this study was to examine contemporary human skull material for possible differences between Caucasians and African-Americans in respect to size and form of the temporomandibular condyles. The material consisted of a total of 129 Caucasian skulls (94 males and 35 females) and 76 African-American skulls (40 males and 36 females). Their mean age at death was 46 years for the Caucasians (range: 19-89 years) and 37 years for the African-Americans (range: 18-70 years). The mediolateral and anteroposterior dimensions of the 410 condyles were measured, and the condylar form was estimated using both anterior and superior views. No statistically significant differences could be found between Caucasians and African-Americans for any of the recorded variables. In conclusion, the present results lend no support for the existence of ethnic differences between the two groups examined in respect of temporomandibular joint size and form. It is likely that other factors such as evolution, overall cranial size, dietary differences, and genetic factors, irrespective of ethnicity, can explain the differences found in different skull samples.


The role of autoimmune phenomena in the pathogenesis of cataract.
Investigations were carried out to clarify the role of autoimmune phenomena in the pathogenesis of cataract in the adult human lens. Studies were carried out to determine the presence of serum antibodies to lens protein in patients with senile cataract, in patients with diabetes mellitus with and without cataract, and in healthy adult controls using the interfacial test and the gel-diffusion technique. Non-specific antibodies were removed by adsorption of sera with homogenized rat liver. A high proportion of healthy adults was found to have anti-lens protein antibodies (44.4% by the gel-diffusion method). In contrast, patients with cataract and diabetic patients with no cataract demonstrated double this incidence (82% and 80%), while all diabetic patients with cataract showed the presence of antibodies (P = 0.0002). The possible causes for the development of lens antibodies in normal healthy humans are discussed. Also, the causes for the higher incidence of lens antibodies in patients with cataract and in diabetic subjects with no clinical evidence of cataract are considered in relation to cataract formation. Homogenates of cataractous lenses when investigated revealed the presence of both IgG and IgM immunoglobulins, the former probably to a greater extent. Fluorescent microscopy on cryosections of senile and diabetic cataractous lenses revealed the presence of immunoglobulins within the lens. The antigen in the immune complexes isolated from homogenized cataractous lenses was characterized by the SDS-polyacrylamide gel electrophoresis method. A single band was consistently obtained and the molecular weight of the protein was estimated to be between 35,000 and 40,000. The strong possibility of auto-antibodies to lens protein being of aetiological significance in the pathogenesis of cataract is discussed.


Pancreaticoduodenectomy for cancer of the head of the pancreas. 201 patients.
This single-institution study examined the outcome after pancreaticoduodenectomy in patients with adenocarcinoma of the head of the pancreas. In recent years, pancreaticoduodenectomy for adenocarcinoma of the head of the pancreas has been associated with decreased morbidity and mortality and, in some centers, 5-year survival rates in excess of 20%. Two hundred one patients with pathologically verified adenocarcinoma of the head of the pancreas undergoing pancreaticoduodenectomy at The Johns Hopkins Hospital between 1970 and 1994 were analyzed (the last 100 resections were performed between March 1991 and April 1994). This is the largest single-institution experience reported to date. The overall postoperative in-hospital mortality rate was 5%, but has been 0.7% for the last 149 patients. The actuarial 5-year survival for all 201 patients was 21%, with a median survival of 15.5 months. There were 11 5-year survivors. Patients resected with negative margins (curative resections: n = 143) had an actuarial 5-year survival rate of 26%, with a median survival of 18 months, whereas those with positive margins (palliative resections; n = 58) fared significantly worse, with an actuarial 5-year survival rate of 8% and a median survival of 10 months (p < 0.0001). Survival has improved significantly from decade to decade (p < 0.002), with the 3-year actuarial survival of 14% in the 1970s, 21% in the 1980s, and 36% in the 1990s. Factors significantly favoring long-term survival by univariate analyses included tumor diameter < 3 cm, negative nodal status, diploid tumor DNA content, tumor S phase fraction < 18%, pylorus-preserving resection, < 800 mL intraoperative blood loss, < 2 units of blood transfused, negative resection margins, and use of postoperative adjuvant chemotherapy and radiation therapy. Multivariate analyses indicated the strongest predictors of long-term survival were diploid tumor DNA content, tumor diameter < 3 cm, negative nodal status, negative resection margins, and decade of resection. The survival of patients with pancreatic adenocarcinoma treated by pancreaticoduodenectomy is improving. Aspects of tumor biology, such as DNA content, tumor diameter, nodal status and margin status, are the strongest predictors of outcome.


Dietary fluoride supplements for Ohio children--the role of the physician.
1. All children should receive one form of systemic fluoride and appropriate forms of topical fluoride. 2. If a child is not receiving optimally fluoridated water, the physician or dentist should prescribe dietary fluoride supplements (tablets or drops). 3. The correct dosage must be determined based on patient age and fluoride content of the patient's main water source(s). 4. Special attention is necessary concerning fluoride intake for children breast-feeding or consuming infant formula. 5. To determine the correct fluoride dose, these steps should be followed: A. Always have a sample of the main drinking water source (usually home water) analyzed for the fluoride content before prescribing a fluoride supplement, if you do not have other specific knowledge of water fluoride content. The Ohio Department of Health, Division of Laboratories can provide water fluoride-testing services. B. When the fluoride content of the water has been determined, the fluoride level and the child's age should be compared to the Supplemental Fluoride Dosage Schedule to identify the correct supplement dose. 6. The Division of Dental Health, Ohio Department of Health can provide a list of communities that are optimally fluoridated. Please contact: Ohio Department of Health Division of Dental Health 246 N. High Street Columbus, Ohio 43266-0588 (614) 466-4180


End-stage renal disease attributed to acute tubular necrosis in the United States, 2001-2010.
Though end-stage renal disease (ESRD) is increasingly attributed to acute tubular necrosis (ATN), contemporary trends in the rates of incidence and recovery of renal function are poorly defined. Hence, we set out to describe the clinical epidemiology of ESRD due to ATN between 2001 and 2010. We examined United States Renal Data System data (n = 1,070,490) for 2001 through 2010 to calculate the incidence rates and rates of renal recovery and death for patients with ESRD due to ATN treated with renal replacement therapy (RRT, n = 27,603). Standardized incidence ratios increased between 2001-2002 and 2009-2010 in the overall population (ratio 2.14), having risen in all demographic subgroups examined. Recovery of renal function was more likely in patients with ATN than in matched controls (cumulative incidence 23% vs. 2% at 12 weeks, 34% vs. 4% at 1 year), as was death (cumulative incidence 38% vs. 27% at 1 year). Hazards ratios for renal recovery increased stepwise with year of RRT inception to 1.34 (95% confidence interval 1.24-1.45) for 2009-2010 (vs. 2001-2002). In contrast, hazards ratios for death declined stepwise to 0.83 (0.79-0.87) in 2009-2010. While the incidence of ESRD attributed to ATN has increased, prospects of renal recovery and survival have also increased. Despite substantial mortality risk on RRT, renal recovery is not a rare occurrence.


Genotype effects of glucokinase regulator on lipid profiles and glycemic status are modified by circulating calcium levels: results from the Korean Genome and Epidemiology Study.
Single nucleotide polymorphisms (SNPs) in the glucokinase regulator (GCKR) are associated with major cardiovascular risk factors (ie, lipid profile and glycemic status). Recently, GCKR was shown to be related to circulating calcium levels involved in lipid and glycemic controls. Therefore, we hypothesized that GCKR SNPs are associated with major cardiovascular risk factors in the Korean population, and the association is modified by circulating calcium levels. Epidemiological data and GCKR SNPs (rs780093T>C, rs780094 T>C, and rs1260326 T>C) were collected from a subset of Ansung-Ansan cohort in the Korean Genome and Epidemiology Study (n = 7815). Consistent with the results of previous studies, GCKR SNPs were significantly associated with decreased total cholesterol and triglyceride levels and increased glucose levels and insulin resistance. Minor C allele carriers, particularly CC homozygotes, had lower serum calcium levels than TT homozygotes for all 3 SNPs. Particularly, the effect of GCKR SNPs on total cholesterol, triglyceride, fasting glucose, and insulin resistance was apparent when serum calcium levels were in normal range (8.8-10.1 mg/dL). When serum calcium levels were high (≥10.2 mg/dL), CC homozygotes also had significantly lower triglyceride and higher fasting glucose than TT homozygotes. However, the associations were not observed when serum calcium levels were low (<8.8 mg/dL). In conclusion, GCKR SNPs are associated with lipid profiles and glycemic status in the Korean population, and the genetic effect is modified by basal circulating calcium levels, particularly in normal or high ranges. It provides important information for individualized prevention and management of cardiovascular risk associated with GCKR SNPs.


Evidence for an elastic projection mechanism in the chameleon tongue.
To capture prey, chameleons ballistically project their tongues as far as 1.5 body lengths with accelerations of up to 500 m s(-2). At the core of a chameleon's tongue is a cylindrical tongue skeleton surrounded by the accelerator muscle. Previously, the cylindrical accelerator muscle was assumed to power tongue projection directly during the actual fast projection of the tongue. However, high-speed recordings of Chamaeleo melleri and C. pardalis reveal that peak powers of 3000 W kg(-1) are necessary to generate the observed accelerations, which exceed the accelerator muscle's capacity by at least five- to 10-fold. Extrinsic structures might power projection via the tongue skeleton. High-speed fluoroscopy suggests that they contribute less than 10% of the required peak instantaneous power. Thus, the projection power must be generated predominantly within the tongue, and an energy-storage-and-release mechanism must be at work. The key structure in the projection mechanism is probably a cylindrical connective-tissue layer, which surrounds the entoglossal process and was previously suggested to act as lubricating tissue. This tissue layer comprises at least 10 sheaths that envelop the entoglossal process. The outer portion connects anteriorly to the accelerator muscle and the inner portion to the retractor structures. The sheaths contain helical arrays of collagen fibres. Prior to projection, the sheaths are longitudinally loaded by the combined radial contraction and hydrostatic lengthening of the accelerator muscle, at an estimated mean power of 144 W kg(-1) in C. melleri. Tongue projection is triggered as the accelerator muscle and the loaded portions of the sheaths start to slide over the tip of the entoglossal process. The springs relax radially while pushing off the rounded tip of the entoglossal process, making the elastic energy stored in the helical fibres available for a simultaneous forward acceleration of the tongue pad, accelerator muscle and retractor structures. The energy release continues as the multilayered spring slides over the tip of the smooth and lubricated entoglossal process. This sliding-spring theory predicts that the sheaths deliver most of the instantaneous power required for tongue projection. The release power of the sliding tubular springs exceeds the work rate of the accelerator muscle by at least a factor of 10 because the elastic-energy release occurs much faster than the loading process. Thus, we have identified a unique catapult mechanism that is very different from standard engineering designs. Our morphological and kinematic observations, as well as the available literature data, are consistent with the proposed mechanism of tongue projection, although experimental tests of the sheath strain and the lubrication of the entoglossal process are currently beyond our technical scope.


How effective is dose-intensive/myeloablative therapy against Ewing's sarcoma/primitive neuroectodermal tumor metastatic to bone or bone marrow? The Memorial Sloan-Kettering experience and a literature review.
Attempts to improve outcomes of patients with Ewing's sarcoma/primitive neuroectodermal tumor (ES/PNET) metastatic to bone/bone marrow (BM) have focused on chemotherapy dose intensification strategies. We now present results achieved with that approach, as carried out at Memorial Sloan-Kettering Cancer Center (MSKCC) and as reported in the literature. Twenty-one unselected MSKCC patients with newly diagnosed ES/PNET metastatic to bone/BM received the "P6" protocol which includes cycles of cyclophosphamide (4.2 g/m(2))/doxorubicin (75 mg/m(2))/vincristine and cycles of ifosfamide (9 g/m(2))/etoposide (500 mg/m(2)). Patients in complete/very good partial remission (CR/VGPR) after P6 received myeloablative therapy with either total-body irradiation (TBI) (hyperfractionated 15 Gy)/melphalan (180 mg/m(2)) or thiotepa (900 mg/m(2))/carboplatin (1,500 mg/m(2)). We reviewed the literature. Only one MSKCC patient became a long-term event-free survivor; all but one relapse was in a distant site. Initial responses to P6 were CR/VGPR in 19 patients, but eight of them plus two others developed PD while receiving or shortly after completing P6. Eight patients were treated with TBI/melphalan: four relapsed 2 to 7 months after transplantation; two died early of toxicity; one died of pulmonary failure 17 months after transplantation (no evidence of ES/PNET); and one remains in CR at more than 7 years. The three patients treated with thiotepa/carboplatin relapsed 3 to 4 months after transplantation. All reports on large series of unselected patients with ES/PNET metastatic to bone/BM showed similarly unsatisfactory results. Poor outcome was seen with use of active agents for ES/PNET-cyclophosphamide, ifosfamide, doxorubicin, dactinomycin, vincristine, etoposide - at standard dosages for prolonged periods of time and at higher dosages in intensive regimens for short or prolonged periods of time. No improvements in event-free survival rates occurred with successive cooperative group or large single-institutional studies that used increasingly aggressive chemotherapeutic approaches. Inclusion of ifosfamide with or without etoposide made no difference nor did consolidation of remission with myeloablative chemoradiotherapy. Secondary leukemia emerged as a major risk with dose-intensive regimens. The MSKCC experience and findings reported in the literature suggest that dose-intensive use of the chemotherapy agents with established activity against ES/PNET is reaching its efficacy and toxicity limits. A major impact on prognosis awaits the development of entirely novel therapies.


The use of metabolomics in population-based research.
The NIH has made a significant commitment through the NIH Common Fund's Metabolomics Program to build infrastructure and capacity for metabolomics research, which should accelerate the field. Given this investment, it is the ideal time to start planning strategies to capitalize on the infrastructure being established. An obvious gap in the literature relates to the effective use of metabolomics in large-population studies. Although published reports from population-based studies are beginning to emerge, the number to date remains relatively small. Yet, there is great potential for using metabolomics in population-based studies to evaluate the effects of nutritional, pharmaceutical, and environmental exposures (the "exposome"); conduct risk assessments; predict disease development; and diagnose diseases. Currently, the majority of the metabolomics studies in human populations are in nutrition or nutrition-related fields. This symposium provided a timely venue to highlight the current state-of-science on the use of metabolomics in population-based research. This session provided a forum at which investigators with extensive experience in performing research within large initiatives, multi-investigator grants, and epidemiology consortia could stimulate discussion and ideas for population-based metabolomics research and, in turn, improve knowledge to help devise effective methods of health research.


Discovery of novel ligands for mouse olfactory receptor MOR42-3 using an in silico screening approach and in vitro validation.
The ligands for many olfactory receptors remain largely unknown despite successful heterologous expression of these receptors. Understanding the molecular receptive range of olfactory receptors and deciphering the olfactory recognition code are hampered by the huge number of odorants and large number of olfactory receptors, as well as the complexity of their combinatorial coding. Here, we present an in silico screening approach to find additional ligands for a mouse olfactory receptor that allows improved definition of its molecular receptive range. A virtual library of 574 odorants was screened against a mouse olfactory receptor MOR42-3. We selected the top 20 candidate ligands using two different scoring functions. These 40 odorant candidate ligands were then tested in vitro using the Xenopus oocyte heterologous expression system and two-electrode voltage clamp electrophysiology. We experimentally confirmed 22 of these ligands. The candidate ligands were screened for both agonist and antagonist activity. In summary, we validated 19 agonists and 3 antagonists. Two of the newly identified antagonists were of low potency. Several previously known ligands (mono- and dicarboxylic acids) are also confirmed in this study. However, some of the newly identified ligands were structurally dissimilar compounds with various functional groups belonging to aldehydes, phenyls, alkenes, esters and ethers. The high positive predictive value of our in silico approach is promising. We believe that this approach can be used for initial deorphanization of olfactory receptors as well as for future comprehensive studies of molecular receptive range of olfactory receptors.


Thalamocortical and corticothalamic pathways differentially contribute to goal-directed behaviors in the rat.
Highly distributed neural circuits are thought to support adaptive decision-making in volatile and complex environments. Notably, the functional interactions between prefrontal and reciprocally connected thalamic nuclei areas may be important when choices are guided by current goal value or action-outcome contingency. We examined the functional involvement of selected thalamocortical and corticothalamic pathways connecting the dorsomedial prefrontal cortex (dmPFC) and the mediodorsal thalamus (MD) in the behaving rat. Using a chemogenetic approach to inhibit projection-defined dmPFC and MD neurons during an instrumental learning task, we show that thalamocortical and corticothalamic pathways differentially support goal attributes. Both pathways participate in adaptation to the current goal value, but only thalamocortical neurons are required to integrate current causal relationships. These data indicate that antiparallel flow of information within thalamocortical circuits may convey qualitatively distinct aspects of adaptive decision-making and highlight the importance of the direction of information flow within neural circuits.


Cyclophilin: a specific cytosolic binding protein for cyclosporin A.
Cyclophilin, a specific cytosolic binding protein responsible for the concentration of the immunosuppressant cyclosporin A by lymphoid cells, was purified to homogeneity from bovine thymocytes. Cation-exchange high-performance liquid chromatography resolved a major and minor cyclophilin species that bind cyclosporin A with a dissociation constant of about 2 X 10(-7) moles per liter and specific activities of 77 and 67 micrograms per milligram of protein, respectively. Both cyclophilin species have an apparent molecular weight of 15,000, an isoelectric point of 9.6, and nearly identical amino acid compositions. A portion of the NH2-terminal amino acid sequence of the major species was determined. The cyclosporin A-binding activity of cyclophilin is sulfhydryl dependent, unstable at 56 degrees C and at pH 4 or 9.5, and sensitive to trypsin but not to chymotrypsin digestion. Cyclophilin specifically binds a series of cyclosporin analogs in proportion to their activity in a mixed lymphocyte reaction. Isolation of cyclophilin from the cytosol of thymocytes suggests that the immunosuppressive activity of cyclosporin A is mediated by an intracellular mechanism, not by a membrane-associated mechanism.


Conservation of structure and protein-protein interactions mediated by the secreted mycobacterial proteins EsxA, EsxB, and EspA.
Mycobacterium tuberculosis EsxA and EsxB proteins are founding members of the WXG100 (WXG) protein family, characterized by their small size (approximately 100 amino acids) and conserved WXG amino acid motif. M. tuberculosis contains 11 tandem pairs of WXG genes; each gene pair is thought to be coexpressed to form a heterodimer. The precise role of these proteins in the biology of M. tuberculosis is unknown, but several of the heterodimers are secreted, which is important for virulence. However, WXG proteins are not simply virulence factors, since nonpathogenic mycobacteria also express and secrete these proteins. Here we show that three WXG heterodimers have structures and properties similar to those of the M. tuberculosis EsxBA (MtbEsxBA) heterodimer, regardless of their host species and apparent biological function. Biophysical studies indicate that the WXG proteins from M. tuberculosis (EsxG and EsxH), Mycobacterium smegmatis (EsxA and EsxB), and Corynebacterium diphtheriae (EsxA and EsxB) are heterodimers and fold into a predominately alpha-helical structure. An in vivo protein-protein interaction assay was modified to identify proteins that interact specifically with the native WXG100 heterodimer. MtbEsxA and MtbEsxB were fused into a single polypeptide, MtbEsxBA, to create a biomimetic bait for the native heterodimer. The MtbEsxBA bait showed specific association with several esx-1-encoded proteins and EspA, a virulence protein secreted by ESX-1. The MtbEsxBA fusion peptide was also utilized to identify residues in both EsxA and EsxB that are important for establishing protein interactions with Rv3871 and EspA. Together, the results are consistent with a model in which WXG proteins perform similar biological roles in virulent and nonvirulent species.


The force pyramid: a spatial analysis of force application during virtual reality brain tumor resection.
OBJECTIVE Virtual reality simulators allow development of novel methods to analyze neurosurgical performance. The concept of a force pyramid is introduced as a Tier 3 metric with the ability to provide visual and spatial analysis of 3D force application by any instrument used during simulated tumor resection. This study was designed to answer 3 questions: 1) Do study groups have distinct force pyramids? 2) Do handedness and ergonomics influence force pyramid structure? 3) Are force pyramids dependent on the visual and haptic characteristics of simulated tumors? METHODS Using a virtual reality simulator, NeuroVR (formerly NeuroTouch), ultrasonic aspirator force application was continually assessed during resection of simulated brain tumors by neurosurgeons, residents, and medical students. The participants performed simulated resections of 18 simulated brain tumors with different visual and haptic characteristics. The raw data, namely, coordinates of the instrument tip as well as contact force values, were collected by the simulator. To provide a visual and qualitative spatial analysis of forces, the authors created a graph, called a force pyramid, representing force sum along the z-coordinate for different xy coordinates of the tool tip. RESULTS Sixteen neurosurgeons, 15 residents, and 84 medical students participated in the study. Neurosurgeon, resident and medical student groups displayed easily distinguishable 3D "force pyramid fingerprints." Neurosurgeons had the lowest force pyramids, indicating application of the lowest forces, followed by resident and medical student groups. Handedness, ergonomics, and visual and haptic tumor characteristics resulted in distinct well-defined 3D force pyramid patterns. CONCLUSIONS Force pyramid fingerprints provide 3D spatial assessment displays of instrument force application during simulated tumor resection. Neurosurgeon force utilization and ergonomic data form a basis for understanding and modulating resident force application and improving patient safety during tumor resection.


The Northeast Atlantic is running out of excess carbonate in the horizon of cold-water corals communities.
The oceanic uptake of atmospheric carbon dioxide (CO2) emitted by human activities alters the seawater carbonate system. Here, the chemical status of the Northeast Atlantic is examined by means of a high-quality database of carbon variables based on the GO-SHIP A25 section (1997-2018). The increase of atmospheric CO2 leads to an increase in ocean anthropogenic carbon (Cant) and a decrease in carbonate that is unequivocal in the upper and mid-layers (0-2,500 m depth). In the mid-layer, the carbonate content in the Northeast Atlantic is maintained by the interplay between the northward spreading of recently conveyed Mediterranean Water with excess of carbonate and the arrival of subpolar-origin waters close to carbonate undersaturation. In this study we show a progression to undersaturation with respect to aragonite that could compromise the conservation of the habitats and ecosystem services developed by benthic marine calcifiers inhabiting that depth-range, such as the cold-water corals (CWC) communities. For each additional ppm in atmospheric pCO2 the waters surrounding CWC communities lose carbonate at a rate of - 0.17 ± 0.02 μmol kg-1 ppm-1. The accomplishment of global climate policies to limit global warming below 1.5-2 ℃ will avoid the exhaustion of excess carbonate in the Northeast Atlantic.


The mTOR inhibitor rapamycin significantly improves facial angiofibroma lesions in a patient with tuberous sclerosis.
Tuberous sclerosis complex (TSC) is an autosomal dominant disorder with an incidence of approximately one in 6000. It arises from a genetic abnormality involving either the TSC1 gene on chromosome 9 or the TSC2 gene on chromosome 16. The protein product of TSC1 is hamartin and that of TSC2 is tuberin. In cells, hamartin and tuberin form a complex which inhibits the mammalian target of rapamycin (mTOR), a central controller of cell growth and proliferation. Angiofibroma affects 70-80% of patients with TSC, typically on the face. We report a patient with TSC with recurrent life-threatening haemorrhage from both kidneys due to extensive angiomyolipoma formation leading to bilateral nephrectomy and renal transplantation. Immunosuppressive treatment with rapamycin, a specific mTOR inhibitor, initiated because of renal transplantation, reduced facial angiofibroma dramatically.


A monument to not exhume: Silence, speech, and issues surrounding the mass grave of communist fighters at the Battle of Florina (1949), Northern Greece.
The paper opens by establishing a fact through fieldwork: a 70-year-old mass grave containing the remains of several hundred communist fighters who died in the battle of Florina (12 February 1949) was recently marked by a monument commemorating the fallen combatants. The erection of the monument (inaugurated in 2016) bypassed other sequences typically present in similar cases. None of the steps conventionally encouraged by post-conflict peacebuilding initiatives: exhuming the human remains in order to identify them, dignify them, move them (or return them to their families), and finally reinter them-was undertaken. A central piece of the memorial site built around the (quite large) spot of the mass grave, the monument de facto seals the human remains underground. In order to understand the ethnographical facts, we follow several trends of explanation. After looking at the conflict (the Greek Civil war), we show the intricacies of local panorama in which political struggle was underpinned by long-standing ethnic conflict. The nexus of memory-and-history is analyzed under two angles, the hidden memory of the defeated and the various claim on the "historical truth" laid by historical and new political formations. The struggles over "historical truth," in relation with the extremely sensitive issue of the unity of the nation (and the blame laid on some populations for "national treason") are viewed as one of the reasons for the lack of any demand for, or the practice of, transitional justice. Political agendas, along with the continuing marginalization of the most directly concerned group, are in fact obstacles to exhumation: if not feared, the identification after the removal of the dead from the mass grave was not supported by any social force or group. Other elements: specific ritual treatment of the dead in Greek culture, issues of land property and land use-are brought in line to suggest that, instead of exhuming the dead bodies, the field containing them could be more easily transformed into burial ground. The local response, as well as the initiatives taken by political actors, did all meet in one point: transforming the mass grave into a funerary site by granting it the legal status of a "green space." It is this consensus that explains why a monument to the dead was erected-so as not to have to exhume them.


A Drug Safety Rating System Based on Postmarketing Costs Associated with Adverse Events and Patient Outcomes.
Given the multiple limitations associated with relatively homogeneous preapproval clinical trials, inadequate data disclosures, slow reaction times from regulatory bodies, and deep-rooted bias against disclosing and publishing negative results, there is an acute need for the development of analytics that reflect drug safety in heterogeneous, real-world populations. To develop a drug safety statistic that estimates downstream medical costs associated with serious adverse events (AEs) and unfavorable patient outcomes associated with the use of 706 FDA-approved drugs. All primary suspect case reports for each drug were collected from the FDA's Adverse Event Reporting System database (FAERS) from 2010-2014. The Medical Dictionary for Regulatory Activities (MedDRA) was used to code serious AEs and outcomes, which were tallied for each case report. Medical costs associated with AEs and poor patient outcomes were derived from Agency for Healthcare Research and Quality (AHRQ) survey data, and their corresponding ICD-9-CM codes were mapped to MedDRA terms. Nonserious AEs and outcomes were not included. For each case report, either the highest AE cost or, if no eligible AE was listed, the highest outcome cost was used. All costed cases were aggregated for each drug and divided by the number of patients exposed to obtain a downstream estimated direct medical cost burden per exposure. Each drug was assigned a corresponding 1-100 point total. The 706 drugs showed an exponential distribution of downstream costs, and the data were transformed using the natural log to approximate a normal distribution. The minimum score was 8.29, and the maximum score was 99.25, with a mean of 44.32. Drugs with the highest individual scores tended to be kinase inhibitors, thalidomide analogs, and endothelin receptor antagonists. When scores were analyzed across Established Pharmacologic Class (EPC), the kinase inhibitor and endothelin receptor antagonist classes had the highest total. However, other EPCs with median scores of 75 and above included hepatitis C virus NS3/4A protease inhibitor, recombinant human interferon beta, vascular endothelial growth factor-directed antibody, and tumor necrosis factor blocker. When Anatomical Therapeutic Chemical classifications were analyzed, antineoplastic drugs were outliers with approximately 80% of their individual scores 60 and above, while approximately 20%-30% of blood and anti-infective drugs had scores of 60 and above. Within-drug class results served to differentiate similar drugs. For example, 6 serotonin reuptake inhibitors had a score range of 35 to 53. This scoring system is based on estimated direct medical costs associated with postmarketing AEs and poor patient outcomes and thereby helps fill a large information gap regarding drug safety in real-world patient populations.


Effects of simvastatin and 6-hydroxydopamine on histaminergic H1 receptor binding density in rat brains.
Statins have been widely used for the treatment of a variety of medical conditions including psychoneurological disorders beyond their original use in lowering cholesterol. Histamine receptors play an important role in the regulation of neural activity, however, it is unknown whether statins act on histamine receptors, particularly for their neural regulatory effects. This study examined the effects of simvastatin and 6-hydroxydopamine (6-OHDA) lesions on histamine H1 receptors using [(3)H] pyrilamine binding autoradiography. Compared to the saline group, simvastatin (1 mg/kg/day) significantly decreased H1 receptor bindings in the primary motor cortex (M1), ventromedial hypothalamic nucleus (VMH), caudate putamen (CPu), accumbens core (AcbC) and prefrontal cortex (PfC) (all p<0.05); however 10 mg/kg/day simvastatin increased H1 receptor density only in the medial amygdaloid nucleus (Mep) (p<0.05), but had no significant effect in other regions examined. The 6-OHDA lesion did not alter H1 receptor binding density in most brain areas, except a trend decrease in the hippocampus (p=0.07) and a trend increase in the cingulate cortex (p=0.06). These results suggested that simvastatin has different effects on the H1 receptors in different rat brain regions depending on the doses. Therefore, simvastatin can modulate histaminergic neurotransmission in the brain, and support the role of H1 receptors in psychoneurological disorders.


Biliary and plasma copper and zinc in pregnant Simmental and Angus cattle.
Three each of 3-year-old Angus and Simmental heifers, surgically modified to collect bile, were used to measure the effects of pregnancy and breed on bile flow, biliary copper and zinc excretion and plasma copper and zinc concentrations. Bile copper excretion was significantly higher at 7-mo of pregnancy when samples from both breeds were pooled. From then onwards it declined to its lowest, one week post-partum. During pregnancy, plasma copper concentration increased slightly, reaching its highest level at 7-mo of pregnancy and then decreased slightly until full term. In pooled samples from both breeds, the correlation between increase in bile copper excretion and plasma copper concentration from 0 to 7-mo of pregnancy was high (r = 0.85) and significant (p < 0.05). Plasma zinc concentration decreased to the lowest level around 6-mo of pregnancy but increased thereafter until full term. In cows that were dried off one week after parturition, major shifts in bile and plasma copper and zinc parameters occurred at one week following and these coincided with a marked decline of bile flow and bile copper and zinc excretion. By 3-mo post-partum, biliary copper and zinc excretion and plasma copper and zinc concentrations had reached levels observed prior to pregnancy. When the data from all samples were pooled, the bile flow and bile copper excretion were significantly (p < 0.05) higher in Simmental, and plasma copper and zinc concentration higher in the Angus.


Iterative optimization yields Mcl-1-targeting stapled peptides with selective cytotoxicity to Mcl-1-dependent cancer cells.
Bcl-2 family proteins regulate apoptosis, and aberrant interactions of overexpressed antiapoptotic family members such as Mcl-1 promote cell transformation, cancer survival, and resistance to chemotherapy. Discovering potent and selective Mcl-1 inhibitors that can relieve apoptotic blockades is thus a high priority for cancer research. An attractive strategy for disabling Mcl-1 involves using designer peptides to competitively engage its binding groove, mimicking the structural mechanism of action of native sensitizer BH3-only proteins. We transformed Mcl-1-binding peptides into α-helical, cell-penetrating constructs that are selectively cytotoxic to Mcl-1-dependent cancer cells. Critical to the design of effective inhibitors was our introduction of an all-hydrocarbon cross-link or "staple" that stabilizes α-helical structure, increases target binding affinity, and independently confers binding specificity for Mcl-1 over related Bcl-2 family paralogs. Two crystal structures of complexes at 1.4 Å and 1.9 Å resolution demonstrate how the hydrophobic staple induces an unanticipated structural rearrangement in Mcl-1 upon binding. Systematic sampling of staple location and iterative optimization of peptide sequence in accordance with established design principles provided peptides that target intracellular Mcl-1. This work provides proof of concept for the development of potent, selective, and cell-permeable stapled peptides for therapeutic targeting of Mcl-1 in cancer, applying a design and validation workflow applicable to a host of challenging biomedical targets.


The primate serotonergic system: a review of human and animal studies and a report on Macaca fascicularis.
This chapter has reviewed biochemical and morphological studies of the human and monkey serotonergic system. In addition, the serotonin-producing neurons of M fascicularis were analyzed, using immunocytochemistry, radioautography, and measurements of synaptosomal serotonin reuptake and supernatant tryptophan hydroxylase activity. The major sections of the chapter covered cell bodies, pathways, subcortical distribution, and cortical distribution, and a gross brain dissection guide of M fascicularis is included. An atlas of the 5-HT-IR cell bodies was presented in Figures 7 to 33. Rostral and caudal groups of nuclei were discussed. The rostral group consists principally of the nuclei raphe dorsalis (B7 and B6), centralis superior (B8, B5, and part of B7), and prosupralemniscus (B9). These groups ascend mainly in tracts lying outside the medial forebrain bundle (MFB). In M fascicularis, 25% of the fibers within the MFB are myelinated. The caudal 5-HT-IR nuclei consist principally of the nuclei in a dorsal cluster (raphe obscurus, B2) and in a ventral cluster (pallidus, B1, and magnus B3). The dorsal 5-HT-IR cells in raphe obscurus are associated with the MLF, and cells extend into cervical spinal cord (lamina IX and X) with the descending MLF and the TTS. Fibers from the raphe obscurus innervate the motoneurons in both the cranial nuclei (X, XII) and the ventral horn. The ventral 5-HT-IR cells lie mainly medial to the medial leminiscal fibers. A large number of these cells extend laterally into paragigantocellularis lateralis and here extend caudally lying below the lateral reticular nuclei. Cells from this group are seen dorsally joining the internal arcuate fibers. The raphe magnus of the ventral cluster projects to the dorsal horn and is believed to mediate the serotonin-induced analgesia. The descending fibers from both of these clusters are occasionally myelinated. Also, in our tryptophan- and pargyline-pretreated monkeys, small 5 HT-IR cells were visible in the area postrema. Human and monkey biochemical data (detailed summary in Tables 1-6) provide evidence for the presence of serotonin fibers in all cortical and subcortical regions. In subcortical regions, the midbrain, medulla, amygdala, and substantia nigra have the highest, whereas the cerebellum, spinal cord, and ventral pons have the lowest amount of serotonin and its metabolite, 5-HIAA. In the basal ganglion, the globus pallidus has the highest rate of 5-HT synthesis. The temporal lobe receives the most serotonin of the major cortical lobes.(ABSTRACT TRUNCATED AT 400 WORDS)


CAPRI rounds 3-5 reveal promising successes and future challenges for RosettaDock.
CAPRI Rounds 3, 4, and 5 are the first public test of the published RosettaDock algorithm. The targets cover a wide range of sizes and shapes. For most targets, published biological information indicated the region of the binding site on at least one docking partner. The RosettaDock algorithm produced high accuracy predictions for three targets, medium-accuracy predictions for two targets, and an acceptable prediction for one target. RosettaDock predicted all five targets with less than 450 residues to high or medium accuracy, but it predicted only one of seven targets with above 450 residues to acceptable accuracy. RosettaDock's high-accuracy predictions for small to moderately large targets reveal the predictive power and fidelity of the algorithm, especially the high-resolution refinement and scoring protocol. In addition, RosettaDock can predict complexes from at least one homology-modeled docking partner with comparable accuracy to unbound cases of similar size. Larger targets present a more intensive sampling problem, and some large targets present repulsive barriers to entering the binding site. Ongoing improvements to RosettaDock's low-resolution search may alleviate this problem. This first public test suggests that RosettaDock can be useful in a significant range of applications in biochemistry and cell biology.


Notch4 intracellular domain binding to Smad3 and inhibition of the TGF-beta signaling.
We present evidence that Notch4ICD attenuates TGF-beta signaling. Cells expressing the activated form of the Notch4 receptor (ICD4) were resistant to the growth-inhibitory effects of TGF-beta. Notch4ICD was found to bind to Smad2, Smad3 and Smad4 but with higher affinity to Smad3. Deletion analysis showed that binding of Smad3 to ICD4 was mediated by its MH2 domain and was not dependent on the presence of the RAM23 region in ICD4. Using two TGF-beta/Activin reporter luciferase assays, RT-PCR and Western blot analysis, we demonstrate that ICD4 and ICD4 deltaRAM23 inhibit Smad-binding element and 3TP luciferase reporter activity and PAI-1 gene expression. MCF-7 human breast cancer cells express Notch4ICD (ICD4) and are resistant to the growth-inhibitory effects of TGF-beta. Blockage of Notch4 processing to ICD4 by gamma-secretase inhibitor renders MCF-7 cells sensitive to growth inhibition by TGF-beta. The interplay between these two signaling pathways may be a significant determinant during mammary tumorigenesis.


Posttraumatic stress disorder in tort actions: forensic minefield.
The authors discuss posttraumatic stress disorder (PTSD) as a basis for personal injury litigation. Three case examples raise issues related to: (1) the controversy surrounding expansion of tort liability, (2) the courtroom use of psychiatric nomenclature as represented in the DSM (e.g., PTSD), and (3) ethical concerns regarding psychiatric expert witnesses. Psychiatrists became easy targets when problems related to personal injury "stress" cases developed. A careful analysis, however, demonstrates that the issues are complex and multifaceted. For example, tort liability expansion was primarily instituted to compel a greater provision of liability insurance, not to reward stress claims. The increasing use of psychiatry's DSM in the courtroom has occurred despite explicit precautions against forensic application. Finally, the need for psychiatric expert witnesses has increased because courts have gradually usurped some psychiatric clinical prerogatives and because there has been a trend toward greater consideration of emotional pain and suffering. Although psychiatric expert witnesses have not been beyond reproach, critics have attempted to impeach the entire psychiatric profession for the questionable actions of the minority. The authors provide a detailed analysis of current problems, offer suggestions for improvement, and provide an educational counterpoint to the "hysterical invective" that often greets psychiatric testimony.


Iranian drug use survey in workplaces: A study protocol.
Background: Addiction is a serious concern in workplaces, as it can lead to accidents, absenteeism, and loss of productivity, neglect, delay, arguing, unhappiness, production cuts, and irregular working pattern. This national survey was conducted to assess the prevalence and pattern of drug use among employees of industrial environments in Iran. Methods: In this cross sectional study, the sample size was determined to be 13489 using multistage cluster sampling method during November 2013 and November 2014. Data were collected by trained interviewers using a structured questionnaire developed by the research team. Urine drug test was done for participants using laboratory rapid kits. A total of 13 286 questionnaires were completed with remarkable responsiveness such that only 1.2% of them were excluded due to defects in urine drug tests, and the rest were analyzed after the review. Results: The response rate to the questionnaires was 98.4% and 13 128 individuals took the urinary drug test. Many participants who had positive urine test did not express drug use and positive tests were more than self-reported cases. Compared to information about the pattern of drug use, data on the estimated prevalence of drug use was more reliable. Conclusion: This study presents the protocol of a well-designed national survey, including sampling procedure, appropriate instrument and test, field work, and discussion on the strengths and limitations of the study, and thus its results can be used effectively by policymakers.


Functional quantum nodes for entanglement distribution over scalable quantum networks.
We demonstrated entanglement distribution between two remote quantum nodes located 3 meters apart. This distribution involves the asynchronous preparation of two pairs of atomic memories and the coherent mapping of stored atomic states into light fields in an effective state of near-maximum polarization entanglement. Entanglement is verified by way of the measured violation of a Bell inequality, and it can be used for communication protocols such as quantum cryptography. The demonstrated quantum nodes and channels can be used as segments of a quantum repeater, providing an essential tool for robust long-distance quantum communication.


Direct-Patterning SWCNTs Using Dip Pen Nanolithography for SWCNT/Silicon Solar Cells.
Dip pen nanolithography (DPN) is used to pattern single-walled carbon nanotube (SWCNT) lines between the n-type Si and SWCNT film in SWCNT/Si solar cells. The SWCNT ink composition, loading, and DPN pretreatment are optimized to improve patterning. This improved DPN technique is then used to successfully pattern >1 mm long SWCNT lines consistently. This is a 20-fold increase in the previously reported direct-patterning of SWCNT lines using the DPN technique, and demonstrates the scalability of the technique to pattern larger areas. The degree of the uniformity of SWCNTs in these lines is further characterized by Raman spectroscopy and scanning electron microscopy. The patterned SWCNT lines are used as thin conductive pathways in SWCNT/Si solar cells, similar to front contact electrodes. The critical parameters of these solar cells are measured and compared to control cells without SWCNT lines. The addition of SWCNT lines increases power conversion efficiency by 40% (relative). Importantly, the SWCNT lines reduce average series resistance by 44%, and consequently increase average fill factor by 24%.


Genetic evidence for hybrid trait speciation in heliconius butterflies.
Homoploid hybrid speciation is the formation of a new hybrid species without change in chromosome number. So far, there has been a lack of direct molecular evidence for hybridization generating novel traits directly involved in animal speciation. Heliconius butterflies exhibit bright aposematic color patterns that also act as cues in assortative mating. Heliconius heurippa has been proposed as a hybrid species, and its color pattern can be recreated by introgression of the H. m. melpomene red band into the genetic background of the yellow banded H. cydno cordula. This hybrid color pattern is also involved in mate choice and leads to reproductive isolation between H. heurippa and its close relatives. Here, we provide molecular evidence for adaptive introgression by sequencing genes across the Heliconius red band locus and comparing them to unlinked wing patterning genes in H. melpomene, H. cydno, and H. heurippa. 670 SNPs distributed among 29 unlinked coding genes (25,847bp) showed H. heurippa was related to H. c. cordula or the three species were intermixed. In contrast, among 344 SNPs distributed among 13 genes in the red band region (18,629bp), most showed H. heurippa related with H. c. cordula, but a block of around 6,5kb located in the 3' of a putative kinesin gene grouped H. heurippa with H. m. melpomene, supporting the hybrid introgression hypothesis. Genealogical reconstruction showed that this introgression occurred after divergence of the parental species, perhaps around 0.43Mya. Expression of the kinesin gene is spatially restricted to the distal region of the forewing, suggesting a mechanism for pattern regulation. This gene therefore constitutes the first molecular evidence for adaptive introgression during hybrid speciation and is the first clear candidate for a Heliconius wing patterning locus.


Allergic Respiratory Inflammation and Remodeling.
Asthma and rhinitis are inflammatory diseases of the respiratory tract. Respiratory inflammation of the adaptive and innate immune system is the focus of this review, and chronic inflammation is not limited to the respiratory tissue. The inflammatory response, which consists of phagocytes, eosinophils, mast cells, and lymphocytes, spreads along the respiratory tract, leading to tissue damage. Mast cells and eosinophils are commonly recognized for their detrimental role in allergic reactions on activation through the high- and low-affinity receptors for IgE FcɛRI. These cells rapidly produce and secrete many of the mediators responsible for the typical symptoms of asthma and rhinitis. However, increasing amount of evidence demonstrate that mast cells and leukocytes have vital roles in host defense against pathogenesis. Histological methods are used to study leukocytes and receptor expression pattern in different respiratory tract compartments. The overall aim of this review was to understand the relationship between upper and lower respiratory tract inflammation and remodeling in patients with allergic and non-allergic asthma and rhinitis. In conclusion, this review discusses the relationship between the upper and lower airway in respiratory disease and focuses on the effect of respiratory processes on laryngeal inflammation, remodeling, function, and symptoms; however, they also have a central role in the initiation of the allergic immune response. Our findings suggest that there are differences that contribute to the development of immunopathological mechanisms of these clinically distinct forms of asthma, rhinitis, and chronic obstructive pulmonary disease.


A minimal cysteine motif required to activate the SKOR K+ channel of Arabidopsis by the reactive oxygen species H2O2.
Reactive oxygen species (ROS) are essential for development and stress signaling in plants. They contribute to plant defense against pathogens, regulate stomatal transpiration, and influence nutrient uptake and partitioning. Although both Ca(2+) and K(+) channels of plants are known to be affected, virtually nothing is known of the targets for ROS at a molecular level. Here we report that a single cysteine (Cys) residue within the Kv-like SKOR K(+) channel of Arabidopsis thaliana is essential for channel sensitivity to the ROS H(2)O(2). We show that H(2)O(2) rapidly enhanced current amplitude and activation kinetics of heterologously expressed SKOR, and the effects were reversed by the reducing agent dithiothreitol (DTT). Both H(2)O(2) and DTT were active at the outer face of the membrane and current enhancement was strongly dependent on membrane depolarization, consistent with a H(2)O(2)-sensitive site on the SKOR protein that is exposed to the outside when the channel is in the open conformation. Cys substitutions identified a single residue, Cys(168) located within the S3 α-helix of the voltage sensor complex, to be essential for sensitivity to H(2)O(2). The same Cys residue was a primary determinant for current block by covalent Cys S-methioylation with aqueous methanethiosulfonates. These, and additional data identify Cys(168) as a critical target for H(2)O(2), and implicate ROS-mediated control of the K(+) channel in regulating mineral nutrient partitioning within the plant.


Clinical applications of musculoskeletal modelling for the shoulder and upper limb.
Musculoskeletal models have been developed to estimate internal loading on the human skeleton, which cannot directly be measured in vivo, from external measurements like kinematics and external forces. Such models of the shoulder and upper extremity have been used for a variety of purposes, ranging from understanding basic shoulder biomechanics to assisting in preoperative planning. In this review, we provide an overview of the most commonly used large-scale shoulder and upper extremity models and categorise the applications of these models according to the type of questions their users aimed to answer. We found that the most explored feature of a model is the possibility to predict the effect of a structural adaptation on functional outcome, for instance, to simulate a tendon transfer preoperatively. Recent studies have focused on minimising the mismatch in morphology between the model, often derived from cadaver studies, and the subject that is analysed. However, only a subset of the parameters that describe the model's geometry and, perhaps most importantly, the musculotendon properties can be obtained in vivo. Because most parameters are somehow interrelated, the others should be scaled to prevent inconsistencies in the model's structure, but it is not known exactly how. Although considerable effort is put into adding complexity to models, for example, by making them subject-specific, we have found little evidence of their superiority over current models. The current trend in development towards individualised, more complex models needs to be justified by demonstrating their ability to answer questions that cannot already be answered by existing models.


Membrane-type matrix metalloproteinases (MT-MMPs) in cell invasion.
Activated gelatinase A is reportedly associated with tumor spread. We identified a novel matrix metalloproteinase that localizes on the cell surface and mediate the activation of progelatinase A. Thus, this progelatinase A activator was named membrane-type matrix metalloproteinase (MT1-MMP). Following the first-discovery of MT1-MMP, two other MT-MMPs which can activate progelatinase A were identified (MT2- and MT3-MMP, respectively). Among these three MT-MMPs, MT1-MMP is most often overexpressed in malignant tumor tissues, including lung and stomach carcinomas that contain activated gelatinase A. This suggests that MT1-MMP is most closely associated with the activation of progelatinase A in these tumor tissues. The expression of MT1-MMP also induced binding of gelatinase A to the cell surface by functioning as a receptor. The cell surface localization of proteinases has advantages over pericellular proteolysis. MT1-MMP and its family may play a central role in the cell surface localization and activation of progelatinase A and via this mechanism, tumor cells use exogenous progelatinase A to mediate the proteolysis associated with invasion and metastasis.


Behind the Scenes of Online Therapeutic Feedback in Blended Therapy for Depression: Mixed-Methods Observational Study.
In Internet-delivered cognitive behavioral therapies (iCBT), written feedback by therapists is a substantial part of therapy. However, it is not yet known how this feedback should be given best and which specific therapist behaviors and content are most beneficial for patients. General instructions for written feedback are available, but the uptake and effectiveness of these instructions in iCBT have not been studied yet. This study aimed to identify therapist behaviors in written online communication with patients in blended CBT for adult depression in routine secondary mental health care, to identify the extent to which the therapists adhere to feedback instructions, and to explore whether therapist behaviors and adherence to feedback instructions are associated with patient outcome. Adults receiving blended CBT (10 online sessions in combination with 5 face-to-face sessions) for depression in routine mental health care were recruited in the context of the European implementation project MasterMind. A qualitative content analysis was used to identify therapist behaviors in online written feedback messages, and a checklist for the feedback instruction adherence of the therapists was developed. Correlations were explored between the therapist behaviors, therapist instruction adherence, and patient outcomes (number of completed online sessions and symptom change scores). A total of 45 patients (73%, 33/45 female, mean age 35.9 years) received 219 feedback messages given by 19 therapists (84%, 16/19 female). The most frequently used therapist behaviors were informing, encouraging, and affirming. However, these were not related to patient outcomes. Although infrequently used, confronting was positively correlated with session completion (ρ=.342, P=.02). Therapists adhered to most of the feedback instructions. Only 2 feedback aspects were correlated with session completion: the more therapists adhere to instructions containing structure (limiting to 2 subjects and sending feedback within 3 working days) and readability (short sentences and short paragraphs), the less online sessions were completed (ρ=-.340, P=.02 and ρ=-.361, P=.02, respectively). No associations were found with depression symptom change scores. The therapist behaviors found in this study are comparable to previous research. The findings suggest that online feedback instructions for therapists provide sufficient guidance to communicate in a supportive and positive manner with patients. However, the instructions might be improved by adding more therapeutic techniques besides the focus on style and form.


Assistive positioning as a control parameter of social-communicative interactions between students with profound multiple disabilities and classroom staff.
This study examined the effects of assistive positioning on social-communicative interactions between 10 students, 6 to 12 years of age, with profound multiple disabilities, and their classroom staff. Interactions were videotaped in the students' classrooms when each student was positioned using a wheelchair, a sidelyer, and a mat on the floor. Data were analyzed by repeated-measures analysis of variance. During unstructured interactions, adults initiated communication at higher rates when students were positioned in their wheelchairs. During structured interactions, when students were given standardized opportunities for interaction, students functioning at lower levels of communication development were more communicative when they were supine on a mat than when in their wheelchairs or a sidelyer. In dynamic systems terms, position served as a control parameter of both adult and student communicative behaviors, which should be considered when recommending use of assistive positioning equipment for students with severe disabilities.


Delayed enhancement magnetic resonance imaging is a significant prognostic factor in patients with non-ischemic cardiomyopathy.
Delayed enhancement (DE) on cardiac magnetic resonance imaging (CMR) is a marker of myocardial fibrosis. The absence of DE in CMR is a predictor of left ventricular (LV) functional improvement in patients with non-ischemic cardiomyopathy (NICM), so in the present study it was investigated whether presence of DE has prognostic significance in patients with NICM at long-term follow-up. The 79 patients (56.4+/-13.5 years, 48 males) with NICM (LV ejection fraction <35%, no significant coronary artery disease) were monitored for occurrence of cardiac events. CMR was performed to assess DE. Cardiac events were defined as rehospitalization (because of worsening of heart failure), cardiac transplantation or death. There were 37 patients without and 42 patients with DE. The mean follow-up duration was 19+/-10 months. There was 1 event (2.7%, 1 rehospitalization) in the DE (-) group, whereas 13 events (30.9%, 1 death, 1 transplantation, 11 rehospitalizations) occurred in the DE (+) group. The event-free survival was significantly longer in the DE (-) group than in the DE (+) group (38.9+/-1.0 vs 28.4+/-2.7 months, P<0.01). Multivariate regression analysis revealed that presence of DE was the most potent, independent predictor of cardiac events (hazard ratio 8.06, confidence interval 1.03+/-63.41, P<0.05). The presence of DE in CMR is a significant predictor of future cardiac events in patients with NICM.


Effect of self-demodulation on the subharmonic response of contrast agent microbubbles.
Subharmonic (SH) emission from the ultrasound contrast agent (UCA) is of interest since it is produced only by the UCA and not by tissue, opposite to harmonic imaging modes where both tissue and microbubble show harmonics. In this work, the use of the self-demodulation (S-D) signal as a means of microbubble excitation at the SH frequency to enhance the SH emission of UCA is studied. The S-D wave is a low-frequency signal produced by the weak nonlinear propagation of an ultrasound wave. It is proportional to the second time derivative of the squared envelope of the transmitted signal. A diluted population of BR14 UCA (Bracco Research SA, Geneva, Switzerland) was insonified by a 10 MHz transducer focused at 76 mm firing bursts with different envelopes, durations and peak pressure amplitudes. The center frequency of the S-D signal changes from low frequencies (around 0.5 MHz) toward the transmitted frequency (10 MHz) by modifying the envelope function from gaussian to rectangular. For 6 and 20 transmitted cycles, the SH response is enhanced up to 25 and 22 dB, respectively, when using a rectangular envelope instead of a gaussian one. The experimental results are confirmed by the numerical simulation. The effects of the excitation duration and pressure amplitude are also studied. This study shows that a suitable design of the envelope of the transmit excitation to generate a S-D signal at the SH frequency can enhance the SH emission of UCA, and the SH imaging is feasible at high frequencies with a shorter transmit burst (six-cycle) and low acoustic pressure (∼100 KPa).


The temporal dynamics of humoral immunity to Rickettsia typhi infection in murine typhus patients.
This study examined individuals with Rickettsia typhi infection in the Lao People's Democratic Republic (Lao PDR) to (a) investigate humoral immune dynamics; (b) determine the differences in reference diagnostic results and recommend appropriate cut-offs; (c) determine differences in immune response after different antibiotic treatments; and (d) determine appropriate diagnostic cut-off parameters for indirect immunofluorescence assay (IFA). Sequential serum samples from 90 non-pregnant, adults were collected at seven time-points (days 0, 7, 14, 28, 90, 180 and 365) as part of a clinical antibiotic treatment trial. Samples were tested using IFA to determine IgM and IgG antibody reciprocal end-point titres against R. typhi and PCR. For all 90 individuals, reciprocal R. typhi IgM and IgG antibody titres ranged from <400 to ≥3200. The median half-life of R. typhi IgM was 126 days (interquartile range 36-204 days) and IgG was 177 days (interquartile range 134-355 days). Overall median patient titres for R. typhi IgM and IgG were significantly different (p < 0.0001) and at each temporal sample collection point (range p < 0.0001 to p 0.0411). Using Bayesian latent class model analysis, the optimal diagnostic cut-off reciprocal IFA titer on patient admission for IgM was 800 (78.6%, 95% CI 71.6%-85.2% sensitivity; 89.9%, 95% CI 62.5%-100% specificity), and for IFA IgG 1600 (77.3%; 95% CI 68.2%-87.6% sensitivity; 99%, 95% CI 95%-100% specificity). This study suggests suitable diagnostic cut-offs for local diagnostic laboratories and other endemic settings and highlights antibody persistence following acute infection. Further studies are required to validate and define cut-offs in other geographically diverse locations.


Multimodal assessment of microscopic morphology and retinal function in patients with geographic atrophy.
To correlate retinal function and visual sensitivity with retinal morphology revealed by ultrahigh-resolution imaging with adaptive optics-optical coherence tomography (AO-OCT), on patients with geographic atrophy. Five eyes from five subjects were tested (four with geographic atrophy [66.3 ± 6.4 years, mean ± 1 SD] and one normal [61 years]). Photopic and scotopic multifocal electroretinograms (mfERGs) were recorded. Visual fields were assessed with microperimetry (mP) combined with a scanning laser ophthalmoscope for high-resolution confocal retinal fundus imaging. The eye tracker of the microperimeter identified the preferred retinal locus that was then used as a reference for precise targeting of areas for advanced retinal imaging. Images were obtained with purpose-built, in-house, ultrahigh resolution AO-OCT. Fundus autofluorescence (FAF) and color fundus (CF) photographs were also acquired. The AO-OCT imaging provided detailed cross-sectional structural representation of the retina. Up to 12 retinal layers were identified in the normal subject while many severe retinal abnormalities (i.e., calcified drusen, drusenoid pigment epithelium detachment, outer retinal tubulation) were identified in the retinae of the GA patients. The functional tests showed preservation of sensitivities, although somewhat compromised, at the border of the GA. The images provided here advance our knowledge of the morphology of retinal layers in GA patients. While there was a strong correlation between altered retinal structure and reduction in visual function, there were a number of examples in which the photoreceptor inner/outer segment (IS/OS) junctions lost reflectivity at the margins of GA, while visual function was still demonstrated. This was shown to be due to changes in photoreceptor orientation near the GA border.


Cation, magnetic, and charge ordering in MnFe3O5.
The recently-discovered high pressure material MnFe3O5 displays a rich variety of magnetically ordered states on cooling. Fe spins order antiferromagnetically below a Néel transition at 350 K. A second transition at 150 K marks Mn spin order that leads to spin canting of some of the Fe spins and ferrimagnetism. A further transition at 60 K is driven by charge ordering of Fe2+ and Fe3+ over two inequivalent Fe sites, with further canting of all spins. Electrical resistivity measurements reveal semiconducting behaviour in MnFe3O5 with a change in activation energy at 285 K.


Explaining the declined affordability of housing for low-income private renters across Western Europe.
The private rented sector (PRS) recently enjoyed a revival, in particular in the years before and after the Great Financial Crisis (GFC). At the same time however, affordability concerns have come to the fore. The main aim of this paper is to explain trends in housing affordability for lower-income households in the PRS across Western European countries, from a supply versus demand perspective. To this end we: (1) related trends in housing affordability to wider changes in housing systems, welfare regimes, demographic indicators and housing market financialisation; and (2) decomposed affordability trends in terms of rents and incomes, controlling for compositional shifts. We incorporated the spatial dimension by distinguishing between urban and rural regions. Although we could not explicitly test for the more fine-grained mechanisms relating housing market financialisation to increased 'unaffordability' of PRS-housing, our findings nevertheless warrant future research into this topic. In particular in countries with strong financialisation (Ireland, the Netherlands, Spain and Portugal) decreasing affordability arises from the fact that during the period 1995-2007 private rent increases were not compensated for sufficiently by income growth. We furthermore found that across urban regions, between 1995 and 2007, affordability worsened through demand pressure arising from in-migration. Changes after the GFC (up to 2013) were more limited and diverse.


Do Americans Understand That Global Warming Is Harmful to Human Health? Evidence From a National Survey.
Global warming has significant negative consequences for human health, with some groups at greater risk than others. The extent to which the public is aware of these risks is unclear; the limited extant research has yielded discrepant findings. This paper describes Americans' awareness of the health effects of global warming, levels of support for government funding and action on the issue, and trust in information sources. We also investigate the discrepancy in previous research findings between assessments based on open- versus closed-ended questions. A nationally representative survey of US adults (N = 1275) was conducted online in October 2014. Measures included general attitudes and beliefs about global warming, affective assessment of health effects, vulnerable populations and specific health conditions (open- and closed-ended), perceived risk, trust in sources, and support for government response. Most respondents (61%) reported that, before taking the survey, they had given little or no thought to how global warming might affect people's health. In response to a closed-ended question, many respondents (64%) indicated global warming is harmful to health, yet in response to an open-ended question, few (27%) accurately named one or more specific type of harm. In response to a closed-ended question, 33% indicated some groups are more affected than others, yet on an open-ended question only 25% were able to identify any disproportionately affected populations. Perhaps not surprising given these findings, respondents demonstrated only limited support for a government response: less than 50% of respondents said government should be doing more to protect against health harms from global warming, and about 33% supported increased funding to public health agencies for this purpose. Respondents said their primary care physician is their most trusted source of information on this topic, followed by the Centers for Disease Control and Prevention, the World Health Organization, and their local public health department. Most Americans report a general sense that global warming can be harmful to health, but relatively few understand the types of harm it causes or who is most likely to be affected. Perhaps as a result, there is only moderate support for an expanded public health response. Primary care physicians and public health officials appear well positioned to educate the public about the health relevance of climate change.


Gastrointestinal adverse effects of short-term aspirin use: a meta-analysis of published randomized controlled trials.
Aspirin is widely used for short-term treatment of pain, fever or colds, but there are only limited data regarding the safety of this use. To summarize the available data on this topic, we conducted a meta-analysis of the published clinical trial literature regarding the gastrointestinal adverse effects of short-term use of aspirin in comparison with placebo and other medications commonly used for the same purpose. An extensive literature search identified 119,310 articles regarding possible adverse effects of aspirin, among which 23,131 appeared to possibly include relevant data. An automated text-mining procedure was used to score the references for potential relevance for the meta-analysis. The 3,983 highest-scoring articles were reviewed individually to identify those with data that could be included in this analysis. Ultimately, 78 relevant articles were identified that contained gastrointestinal adverse event data from clinical trials of aspirin versus placebo or an active comparator. Odds ratios (ORs) computed using a Mantel-Haenszel estimator were used to summarize the comparative effects on dyspepsia, nausea/vomiting, and abdominal pain, considered separately and also aggregated as 'minor gastrointestinal events'. Gastrointestinal bleeds, ulcers, and perforations were also investigated. Data were obtained regarding 19,829 subjects (34 % treated with aspirin, 17 % placebo, and 49 % an active comparator). About half of the aspirin subjects took a single dose. Aspirin was associated with a higher risk of minor gastrointestinal events than placebo or active comparators: the summary ORs were 1.46 (95 % confidence interval [CI] 1.15-1.86) and 1.81 (95 % CI 1.61-2.04), respectively. Ulcers, perforation, and serious bleeding were not seen after use of aspirin or any of the other interventions. During short-term use, aspirin is associated with a higher frequency of gastrointestinal complaints than other medications commonly used for treatment of pain, colds, and fever. Serious adverse events were not observed with aspirin or any of the comparators.


Sleep homeostasis during daytime food entrainment in mice.
Twenty-four hour rhythms of physiology and behavior are driven by the environment and an internal endogenous timing system. Daily restricted feeding (RF) in nocturnal rodents during their inactive phase initiates food anticipatory activity (FAA) and a reorganization of the typical 24-hour sleep-wake structure. Here, we investigate the effects of daytime feeding, where food access was restricted to 4 hours during the light period ZT4-8 (Zeitgeber time; ZT0 is lights on), on sleep-wake architecture and sleep homeostasis in mice. Following 10 days of RF, mice were returned to ad libitum feeding. To mimic the spontaneous wakefulness associated with FAA and daytime feeding, mice were then sleep deprived between ZT3-6. Although the amount of wake increased during FAA and subsequent feeding, total wake time over 24 hours remained stable as the loss of sleep in the light phase was compensated for by an increase in sleep in the dark phase. Interestingly, sleep that followed spontaneous wake episodes during the dark period and the extended period of wake associated with FAA, exhibited lower levels of slow-wave activity (SWA) when compared to baseline or after sleep deprivation, despite a similar duration of waking. This suggests an evolutionary mechanism of reducing sleep drive during negative energy balance to enable greater arousal for food-seeking behaviors. However, the total amount of sleep and SWA accumulated during the 24 hours was similar between baseline and RF. In summary, our study suggests that despite substantial changes in the daily distribution and quality of wake induced by RF, sleep homeostasis is maintained.


Recent developments in brain tumor predisposing syndromes.
The etiologies of brain tumors are in the most cases unknown, but improvements in genetics and DNA screening have helped to identify a wide range of brain tumor predisposition disorders. In this review we are discussing some of the most common predisposition disorders, namely: neurofibromatosis type 1 and 2, schwannomatosis, rhabdoid tumor predisposition disorder, nevoid basal cell carcinoma syndrome (Gorlin), tuberous sclerosis complex, von Hippel-Lindau, Li-Fraumeni and Turcot syndromes. Recent findings from the GLIOGENE collaboration and the newly identified glioma causing gene POT1, will also be discussed. Genetics. We will describe these disorders from a genetic and clinical standpoint, focusing on the difference in clinical symptoms depending on the underlying gene or germline mutation. Central nervous system (CNS) tumors. Most of these disorders predispose the carriers to a wide range of symptoms. Herein, we will focus particularly on tumors affecting the CNS and discuss improvements of targeted therapy for the particular disorders.


Viruses transfer the antiviral second messenger cGAMP between cells.
Cyclic GMP-AMP synthase (cGAS) detects cytosolic DNA during virus infection and induces an antiviral state. cGAS signals by synthesis of a second messenger, cyclic GMP-AMP (cGAMP), which activates stimulator of interferon genes (STING). We show that cGAMP is incorporated into viral particles, including lentivirus and herpesvirus virions, when these are produced in cGAS-expressing cells. Virions transferred cGAMP to newly infected cells and triggered a STING-dependent antiviral program. These effects were independent of exosomes and viral nucleic acids. Our results reveal a way by which a signal for innate immunity is transferred between cells, potentially accelerating and broadening antiviral responses. Moreover, infection of dendritic cells with cGAMP-loaded lentiviruses enhanced their activation. Loading viral vectors with cGAMP therefore holds promise for vaccine development.


Sculpting humoral immunity through dengue vaccination to enhance protective immunity.
Dengue viruses (DENV) are the most important mosquito transmitted viral pathogens infecting humans. DENV infection produces a spectrum of disease, most commonly causing a self-limiting flu-like illness known as dengue fever; yet with increased frequency, manifesting as life-threatening dengue hemorrhagic fever (DHF). Waning cross-protective immunity from any of the four dengue serotypes may enhance subsequent infection with another heterologous serotype to increase the probability of DHF. Decades of effort to develop dengue vaccines are reaching the finishing line with multiple candidates in clinical trials. Nevertheless, concerns remain that imbalanced immunity, due to the prolonged prime-boost schedules currently used in clinical trials, could leave some vaccinees temporarily unprotected or with increased susceptibility to enhanced disease. Here we develop a DENV serotype 1 (DENV-1) DNA vaccine with the immunodominant cross-reactive B cell epitopes associated with immune enhancement removed. We compare wild-type (WT) with this cross-reactivity reduced (CRR) vaccine and demonstrate that both vaccines are equally protective against lethal homologous DENV-1 challenge. Under conditions mimicking natural exposure prior to acquiring protective immunity, WT vaccinated mice enhanced a normally sub-lethal heterologous DENV-2 infection resulting in DHF-like disease and 95% mortality in AG129 mice. However, CRR vaccinated mice exhibited redirected serotype-specific and protective immunity, and significantly reduced morbidity and mortality not differing from naїve mice. Thus, we demonstrate in an in vivo DENV disease model, that non-protective vaccine-induced immunity can prime vaccinees for enhanced DHF-like disease and that CRR DNA immunization significantly reduces this potential vaccine safety concern. The sculpting of immune memory by the modified vaccine and resulting redirection of humoral immunity provide insight into DENV vaccine-induced immune responses.


Intravenous safety and pharmacokinetics of a novel dimerizer drug, AP1903, in healthy volunteers.
AP1903 is a novel gene-targeted drug that is being developed for use in drug-regulated cell therapies. An intravenous, single-blind, placebo- and saline-controlled, ascending-dose study was performed to evaluate the safety, tolerability, and pharmacokinetics of AP1903. Twenty-eight normal healthy male volunteers were randomized into five dosage groups of AP1903 (0.01, 0.05, 0.1, 0.5, and 1 mg/kg). Within each group, 4 volunteers received a single dose of AP1903, 1 volunteer received an equal volume of placebo, and 1 received an equal volume of normal saline. The only exception was in the 0.5 mg/kg group, in which 4 volunteers were dosed: 3 received AP1903 and 1 received normal saline. All dosages were administered as intravenous infusions over 2 hours. Clinical safety parameters were monitored, and serial blood and urine samples were collected for analysis of AP1903. No drug-related adverse events were observed at any of the dose levels with the possible exception of facial flushing in 1 volunteer at the 1.0 mg/kg dose level. AP1903 plasma levels were directly proportional to the administered dose, with mean Cmax values ranging from approximately 10 to 1,275 ng/mL over the 0.01 to 1.0 mg/kg dose range. Following the infusion period, blood concentrations revealed a rapid distribution phase, with plasma levels being reduced to approximately 18%, 7%, and 1% of the maximal concentration at 0.5, 2, and 10 hours postdose, respectively. AP1903 was shown to be safe and well tolerated at all dose levels and demonstrated a favorable pharmacokinetic profile at doses well above the anticipated therapeutic dose.


Habitual dietary calcium intakes and calcium metabolism in healthy adults Chinese: a systematic review and meta-analysis.
To investigate the metabolic differences of calcium requirements between Chinese and Westerners, we examined systematically the characteristics of calcium metabolism in Chinese adults with habitual dietary calcium intakes. We searched PubMed, Cochrane Library, SinoMed, and National Index to Chinese Newspapers & Periodicals, from inception to March 17, 2015, as well as the bibliographies of any relevant papers and journals, for trials assessing calcium metabolism in healthy Chinese adults within 18-60 years of age on the typical Chinese diet. We extracted a standardized dataset from metabolic studies that reported intake, retention, urinary excretion, faecal excretion and/or fractional absorption of calcium. We pooled data with a random effects meta-analysis. Of 2,046 citations identified by the search strategy, 12 studies (comprising 137 participants, 13 aggregate data deriving from 257 individual data) met the inclusion criteria. Metabolic data with self-chosen or typical Chinese diets were analyzed. Mean daily intakes of calcium ranged between 288 and 948 mg. Mean calcium retentions of each study were between 13 and 294 mg/d. The overall pooled value for dietary intake, urinary excretion, faecal excretion, retention and fractional absorption of calcium were 583 mg/d, 117 mg/d, 381 mg/d, 72 mg/d and 33.3%. Dietary calcium intake and faecal calcium excretion explained almost 85% of the heterogeneity of calcium retention. Chinese adults could maintain a positive calcium balance with plant-based diets at calcium intakes as low as 300 mg/d through increasing fractional calcium absorption and decreasing calcium excretion in urine and faeces.


Impact of 5-HT3 receptor antagonists on chemotherapy-induced nausea and vomiting: a retrospective cohort study.
1st generation 5-hydroxytryptamine receptor antagonists (5-HT3 RAs), and palonosetron, a 2nd generation 5-HT3 RA, are indicated for the prevention of chemotherapy (CT)-induced nausea and vomiting (CINV) associated with moderately (MEC) and highly emetogenic CT agents (HEC). This study explores the impact of step therapy policies requiring use of an older 5-HT3 RA before palonosetron on risk of CINV associated with hospital or emergency department (ED) admissions. Patients who received cyclophosphamide post breast cancer (BC) surgery or who were diagnosed with lung cancer on carboplatin (LC-carboplatin) or cisplatin (LC-cisplatin) were selected from PharMetrics' (IMS LifeLink) claims dataset (2005-2008). Patients were followed for 6 months from initial CT administration for CINV events identified through ICD-9-CM codes. Patients were grouped into those initiated with older, generic 5-HT3 RAs (ondansetron, granisetron, and dolasetron) and those initiated and maintained on palonosetron throughout study follow-up. CINV events and CINV days were analyzed using multivariate regressions controlling for demographic and clinical variables. Eligible patients numbered 3,606 in BC, 4,497 in LC-carboplatin and 1,154 in LC-cisplatin cohorts, with 52%, 40%, and 34% in the palonosetron group, respectively. There was no significant difference between the two 5-HT3 RA groups in age or Charlson Comorbidity Index among the two MEC cohorts (BC and LC-carboplatin). Among the LC-cisplatin cohort, palonosetron users were older with more males than the older 5-HT3 RA group (age: 60.1 vs. 61.3; males, 66.9% vs. 56.9%). Compared to the older 5-HT3 RAs, the palonosetron groups incurred 22%-51% fewer 5-HT3 RA pharmacy claims, had fewer patients with CINV events (3.5% vs. 5.5% in BC, 9.5% vs. 12.8% in LC-carboplatin, 16.4% vs. 21.7% in LC-cisplatin), and had lower risk for CINV events (odds ratios 0.62, 0.71, or 0.71, respectively; p<0.05). The BC and LC-carboplatin palonosetron groups experienced 50% and 30% fewer CINV days than the generic 5-HT3 RA group (p<0.05). Patients with breast or lung cancer initiated and maintained on palonosetron were at significantly lower risk for potentially costly CINV versus those on older 5-HT3 RAs. Further studies on impact of step therapy policy are warranted in order to minimize the clinical and economic burden of CINV.


Diagnostic-driven management of invasive fungal disease in hematology in the era of prophylaxis and resistance emergence: Dutch courage?
Patients receiving intensive anti-leukemic treatment or recipients of allogeneic hematopoietic stem cell transplantation (HSCT) are prone to develop invasive fungal disease caused by both Aspergillus and non-Aspergillus moulds. Overall mortality following invasive mould disease (IMD) is high; adequate and timely antifungal treatment seems to ameliorate the outcome, yet early diagnosis in the haematological patient remains a challenge for most clinicians. Prophylaxis and the empiric addition of antifungal therapy to neutropaenic patients with fever persisting or recurring during broad-spectrum antibiotic treatment is therefore standard of care in many institutions. However, aside from the potential for overtreatment and important side effects, the emergence of resistance to medical triazoles in Aspergillus fumigatus poses a risk for inadequate initial treatment. Initial voriconazole therapy in patients with azole-resistant invasive aspergillosis was recently shown to be associated with a 23% increased mortality rate compared to the patients with azole-susceptible infection, despite changing to appropriate antifungal therapy once resistance was detected. Moreover, fever is not always present with IMD; therefore, cases may be missed when relying solely on this symptom for starting diagnostic procedures and antifungal treatment. At our institution, a diagnostic-driven treatment approach for IMD was implemented relying on clinical but also laboratory markers to start antifungal treatment. We describe the basis and clinical implementation of our diagnostic-driven approach in this review.


Mechanism for prevention of alcohol-induced liver injury by dietary methyl donors.
Alcohol-induced liver injury (ALI) has been associated with, among other molecular changes, abnormal hepatic methionine metabolism, resulting in decreased levels of S-adenosylmethionine (SAM). Dietary methyl donor supplements such as SAM and betaine mitigate ALI in animal models; however, the mechanisms of protection remain elusive. It has been suggested that methyl donors may act via attenuation of alcohol-induced oxidative stress. We hypothesized that the protective action of methyl donors is mediated by an effect on the oxidative metabolism of alcohol in the liver. Male C57BL/6J mice were administered a control high-fat diet or diet enriched in methyl donors with or without alcohol for 4 weeks using the enteral alcohol feeding model. As expected, attenuation of ALI and an increase in reduced glutathione:oxidized glutathione ratio were achieved with methyl donor supplementation. Interestingly, methyl donors led to a 35% increase in blood alcohol elimination rate, and while there was no effect on alcohol metabolism in the stomach, a profound effect on liver alcohol metabolism was observed. The catalase-dependent pathway of alcohol metabolism was induced, yet the increase in CYP2E1 activity by alcohol was blunted, which may be mitigating production of oxidants. Additional factors contributing to the protective effects of methyl donors in ALI were increased activity of low- and high-K(m) aldehyde dehydrogenases leading to lower hepatic acetaldehyde, maintenance of the efficient mitochondrial energy metabolism, and promotion of peroxisomal beta-oxidation. Profound changes in alcohol metabolism represent additional important mechanism of the protective effect of methyl donors in ALI.


Clinical and immunologic correlates of response to PD-1 blockade in a patient with metastatic renal medullary carcinoma.
Renal medullary carcinoma (RMC) is a rare kidney tumor that occurs in adolescent and young adults, typically in association with sickle cell trait. RMC exhibits rapid disease progression, frequent metastases at diagnosis, and dismal clinical outcomes. Currently available therapies, including cisplatin-based combination chemotherapy, multi-tyrosine kinase, and mTOR inhibitor strategies demonstrate either transient responses or minimal activity. Therefore, further molecular characterization and additional treatment strategies are urgently needed in this aggressive disease. The role of immune system surveillance and responsiveness to anti-PD-1 therapies in RMC are completely unexplored. A 29 year old male with sickle cell trait presented with painless hematuria that ultimately resulted in a diagnosis of RMC. He underwent total nephrectomy and adjuvant cytotoxic chemotherapy with carboplatin, gemcitabine, paclitaxel, and bevacizumab. As is common in this aggressive form of kidney cancer he recurred with biopsy proven lymph node metastasis. He was started on checkpoint inhibitor therapy with nivolumab that inhibits program cell death protein 1 (PD-1), and on his first follow-up imaging he was found to have a partial response that on subsequent scans ultimately resulted in a complete response lasting greater than nine months. In this report, we present a patient with metastatic RMC who exhibited a clinical response to nivolumab, as well as the genetic and immunologic correlates of the pre-treatment tumor. Provocatively, robust immune infiltrate and expression of immune checkpoints were observed, despite the presence of a low mutation burden. Here, we report the first case of immune microenvironment profiling and response to anti-PD-1 in a patient with RMC to our knowledge. This case suggests that anti-PD-1 based therapies may have clinical activity in RMC.


Prevalence of rheumatoid arthritis and rheumatoid factor in women: evidence for a secular decline.
To determine the current prevalence of rheumatoid arthritis (RA) and rheumatoid factor positivity in the United Kingdom middle aged female population and to compare this with previous estimates to assess whether the disease is becoming less prevalent. A cross sectional prevalence study was undertaken. All women aged 45-64 from the age and sex register of a large 11,000 general practitioner group practice in Chingford, East London were contacted and responders examined clinically and radiographically for the presence of RA by a single observer. Blood was also taken for rheumatoid factor testing (sheep cell agglutination test (SCAT), latex, and IgG). The prevalence in non-attenders was assessed from general practitioner and local hospital records. A diagnosis of definite or classical RA according to 1958 American Rheumatism Association criteria was used, and seropositivity was defined by a SCAT rheumatoid factor of 1/32 or more. From the 1003 women examined (response rate of 78.8%), 12 women had definite RA (1.2%, 95% confidence interval 0.6 to 1.8). Of these, 7/12 had definite erosive changes on radiography and 3/12 had a positive SCAT (> 1/32). Three cases of RA were also found in the 284 non-responders (prevalence 1.1%) by case-finding techniques. The rate of SCAT positivity in the whole study group was 0.5%. The rates of RA and SCAT positivity currently found in this group were less than those obtained in previous surveys. In the only previous large scale United Kingdom survey, performed in the north of England between 1958 and 1960, 406 women aged 45-64 were examined and 10 cases of definite RA were found, a prevalence of 2.5%. In the patients with RA 68% had erosions and 63% positive SCAT. The population SCAT positive rate in this and other surveys sampled between 1954 and 1961 was in the range of 4-5%, since when there has been a progressive decline according to a number of other studies. The prevalence of RA and rheumatoid factor in middle aged women is lower than previously believed and supports a variety of other data which indicate that RA is declining in incidence and severity.