Long-term survival and impact of ursodeoxycholic acid treatment for recurrent primary biliary cirrhosis after liver transplantation.
The recurrence of primary biliary cirrhosis (PBC) in the hepatic allograft may impact patient and graft survival with long-term follow-up. The efficacy of ursodeoxycholic acid (UDCA) for treatment of recurrent PBC after liver transplantation (LT) remains less well known. The aims of this study were as follows: 1) to determine the significance of recurrent PBC on overall survival among PBC patients who underwent LT, and 2) to determine the efficacy of UDCA treatment after LT in patients with recurrent PBC. A retrospective cohort study was conducted of 154 PBC patients who underwent LT with at least 1 yr of follow-up after transplantation from 1985 through 2005. A total of 52 patients with recurrent PBC were identified. After adjusting for age and gender, recurrent PBC was not associated with death or liver retransplantation (hazard ratio, 0.97, 95% confidence interval, 0.41-2.31; P = 0.9). A total of 38 patients with recurrent PBC received UDCA at an average dose of 12 mg/kg/day for a mean duration of 55 months. Over a 36-month period, an estimated 52% of UDCA-treated patients experienced normalization of serum alkaline phosphatase and alanine aminotransferase compared to 22% of untreated patients. There was no significant difference in the rate of histological progression between subgroups. UDCA did not influence patient and graft survival. In conclusion, the development of recurrent PBC has little impact on long-term survival or need for retransplantation. While UDCA therapy is associated with biochemical improvement, its role in delaying histologic progression remains unknown. In this short period of treatment, UDCA was not associated with improved patient and graft survival compared to untreated patients.


GPU based real-time quadrature transform method for 3-D surface measurement and visualization.
In this article, we propose a massively parallel, real-time algorithm for the estimation of the dynamic phase map of a vibrating object. The algorithm implements a Fourier-based quadrature transform and temporal phase unwrapping technique. CUDA, a graphic processing unit programming architecture was used to implement the algorithm. It was tested on a fringe pattern sequence using three devices with different capabilities, achieving a processing rate greater than 1600 frames per second (fps).


Microsecretory Adenocarcinoma: A Novel Salivary Gland Tumor Characterized by a Recurrent MEF2C-SS18 Fusion.
Salivary gland adenocarcinoma not otherwise specified (NOS) is a heterogenous group, likely containing distinct tumors not yet characterized. A growing number of low to intermediate-grade salivary carcinomas are now known to harbor tumor-specific gene fusions. On occasion, identifying a novel fusion allows for recognition of a new salivary tumor type, in addition to representing a potential diagnostic tool. We sought to characterize a distinctive salivary gland adenocarcinoma that would previously have been regarded as adenocarcinoma NOS. On the basis of the recognition of 5 morphologically identical, distinct low-grade salivary adenocarcinomas, we used targeted RNA sequencing (RNA-Seq) to determine whether these could be differentiated from other fusion-associated salivary gland tumors. RNA-Seq was performed on all 5 low-intermediate grade adenocarcinomas NOS with near-identical histologic appearances, as well as 23 low-intermediate grade control adenocarcinoma NOS cases that did not resemble the index cases. All 5 index cases harbored a novel MEF2C-SS18 gene fusion, which was independently confirmed by reverse transcriptase-polymerase chain reaction. The MEF2C-SS18-positive cases arose in the oral cavity (4/5) and parotid gland (1/5) of 3 women and 2 men ranging from 21 to 80 years (mean: 46) and shared near-identical histologic features: intercalated duct-like cells with eosinophilic to clear cytoplasm and small, uniform oval nuclei, infiltrative microcysts and cords, abundant intraluminal secretions, and cellular fibromyxoid stroma. Mitotic rates were low; necrosis was absent. All MEF2C-SS18-positive tumors were positive for S100 and p63 and negative for p40, smooth muscle actin, calponin, and mammaglobin. One of the 23 control cases, a parotid tumor, was found to contain a SS18-ZBTB7A gene fusion; it demonstrated similar, but not identical histologic and immunophenotypic features compared with the MEF2C-SS18 cases. The remaining control cases were negative for SS18 and MEF2C rearrangements. A novel MEF2C-SS18 gene fusion and unique histologic and immunophenotypic features characterize a heretofore undefined low-grade salivary adenocarcinoma for which we propose the term "microsecretory adenocarcinoma." RNA-Seq helped establish this entity as a distinct tumor type, and identified one possibly related case with a different SS18-related fusion. The recognition of microsecretory adenocarcinoma and its separation from other adenocarcinomas NOS will facilitate a more complete understanding of the clinical and pathologic characteristics of this previously unrecognized neoplasm.


Measurement properties of the minimal disease activity criteria for psoriatic arthritis.
To comprehensively assess evidence on the measurement properties of the minimal disease activity (MDA) criteria, a composite measure of the state of disease activity in psoriatic arthritis (PsA). A targeted literature review was conducted to identify studies that informed the validity and/or ability of the MDA to detect change among patients known to have experienced a change in clinical status. The search was conducted using MEDLINE and Embase databases (published as of October 2017). Pertinent articles provided by investigators and identified from select conference proceedings were also evaluated. A total of 20 publications met the inclusion criteria. The MDA criteria were consistently associated with other indicators of disease activity/severity. The ability of the MDA criteria to detect change was supported in randomised controlled trials (n=10), with a greater percentage of patients randomised to active treatments achieving MDA relative to patients in comparator arms. Long-term observational studies (n=2) provided additional support for the ability of the MDA to detect within-subject change in the real-world settings. Evidence supports the MDA as a valid measure of disease activity in PsA that can detect between-group and within-subject change. The MDA is a comprehensive measure and clinically meaningful endpoint to assess the impact of interventions on PsA disease activity.


A New Perspective on Embodied Social Attention.
Over the years observational studies have made great progress in characterizing children's visual experiences and their sensitivity to social cues and their role in language development. Recent technological advancements have allowed researchers to study these issues from the child's perspective, leading to a new understanding of the dynamic involvement of bodily events. A number of recent studies have suggested that bodily actions play an important role in perception and that social partners' bodily actions may become synchronized. In the present perspective paper, we will provide a new perspective on how children's own views are generated individually and play a dynamic role in learning. By doing so, we first discuss the role of early social input in language learning as it has been treated in the literature and then introduce recent studies in which typically developing hearing children, deaf children of deaf families, and children with autism were observed in a social context using the new child-centered technology. The hypothesis of a link between sensorimotor experiences and embodied attention - specifically how different bodies produce different kinds of attention - will be discussed. Understanding the role of bodily events (the child's and the child's social partners') in early visual experiences will provide insight into the development of learning mechanisms and the processes involved in learning disabilities.


Left ventricular longitudinal shortening: relation to stroke volume and ejection fraction in ageing, blood pressure, body size and gender in the HUNT3 study.
Aims of this cross-sectional study were to assess: the relative contribution of left ventricular (LV) systolic long-axis shortening (mean mitral annular plane systolic excursion, MAPSE) to stroke volume (SV), the mechanisms for preserved ejection fraction (EF) despite reduced MAPSE, the age dependency of myocardial volume and myocardial systolic compression. Linear dimensions and longitudinal and cross-sectional M-modes were acquired in 1266 individuals without history of heart disease, diabetes or known hypertension from the third wave of the Nord-Trøndelag Health Study. Measurements were entered into a half-ellipsoid LV model for volume calculations, and volumes were related to age, body size (body surface area, BSA), sex and blood pressure (BP). Mean BP and proportion with hypertensive values increased with increasing age. MAPSE contributed to 75% of SV, with no relation to age or BSA as both MAPSE and SV decreased with increasing age. LV end-diastolic volume (LVEDV) and SV increased with BSA and decreased with higher age; EF was not related to age or BSA. Myocardial volume increased with higher age and BSA, with an additional gender dependency. The association of age with myocardial volume was not significant when corrected for BP, while both systolic and diastolic BP were significant associated with myocardial volume. Myocardial compression was less than 3%. MAPSE contributes approximately 75% and short axis shortening 25% to SV. Both decline with age, but their percentage contributions to SV are unchanged. EF is preserved by the simultaneous decrease in LVEDV and SV. Myocardial volume is positively associated with age, but this is only related to higher BP, which may have implications for BP treatment in ageing. The myocardium is near incompressible.


Comparative study of alloimmunization against red cell antigens in sickle cell disease & thalassaemia major patients on regular red cell transfusion.
: Sickle cell disease (SCD) patients require red cell transfusion during different clinical complications of the disease. Such patients are at a high risk for developing alloantibody against red cell antigens. From India, there are limited data available on alloantibody formation in multiply transfused SCD patients. The present study was thus undertaken to fill up this lacunae by looking at the development of red cell alloantibodies in SCD and β-thalassaemia patients on regular transfusion. : All sickle cell disease patients undergoing red cell transfusion between 2008 and 2016, were included. During this period, a large number of β-thalassaemia major patients also underwent regular red cell transfusion. These thalassaemia patients were also included to compare the tendency of antibody formation between SCD and β-thalassaemia major patients. All patients before regular transfusion were regularly assessed for the development of red cell antibody. Red cell antigen, antibody screen crossmatch and antibody identification were done using the standard technique. : A total of 138 patients with SCD aged between 4 and 53 yr (mean 17.6 yr) consisting of 83 males and 55 females (male:female, 1.5:1) along with 333 transfusion-dependent β-thalassaemia patients were studied. Over the last eight years, 15 patients with SCD and four patients with thalassaemia developed alloantibody (P <0.001). Antibody specificity of their alloantibodies was against Rhc, RhE, Kell, Fya and Fyb only. Sickle cell disease patients with and without alloantibody required on the average 11.8 and 8.6 units of red cell concentrate, respectively (P <0.05). : About 11 per cent of the transfused sickle cells patients developed alloantibodies. The antibody specificity was restricted to Rh, Kell and Duffy blood group systems. Extended antigen matching involving Rh, Kell and Duffy antigens may prevent alloantibody in such patients.


Engineering of therapeutic proteins production in Escherichia coli.
Low cost and simplicity of cultivating bacteria make the E. coli expression system a preferable choice for production of therapeutic proteins both on a lab scale and in industry. In addition straightforward recombinant DNA technology offers engineering tools to produce protein molecules with modified features. The lack of posttranslational modification mechanisms in bacterial cells such as glycosylation, proteolytic protein maturation or limited capacity for formation of disulfide bridges may, to a certain extent, be overcome with protein engineering. Protein engineering is also often employed to improve protein stability or to modulate its biological action. More sophisticated modifications may be achieved by genetic fusions of two proteins. This article presents a variety of examples of genetic engineering of therapeutic proteins. It emphasizes the importance of designing a construct without any unnecessary amino acid residues.


The characteristics of the patients with radiologically severe cervical ossification of the posterior longitudinal ligament of the spine: A CT-based multicenter cross-sectional study.
Ossification of the posterior longitudinal ligament of the spine (OPLL) is characterized by heterotopic bone formation in the posterior longitudinal ligament of the spine. We know that the size and distribution of the ossified lesions in patients with OPLL are different in each case. However, the characteristics of the patients with radiologically severe cervical OPLL remain unknown. The participants of our study were symptomatic patients with cervical OPLL who were diagnosed by standard radiographs of the cervical spine. Whole-spine CT data and demographic data such as age and sex were obtained from 20 institutions belonging to the Japanese Multicenter Research Organization for Ossification of the Spinal Ligament. According to the number of the levels involved by OPLL, we stratified the patients into two subgroups: severe group (S-group) and non-severe group (NS-group) to delineate the characteristics of radiologically severe patients with cervical OPLL. We also evaluated the most compressed level and the degree of occupying ratio of cervical spinal canal by OPLL at the most compressed level. A total of 234 patients with a mean age of 65 years were recruited. The S-group consisted of 48 patients (21%, 12 females and 36 males) and the NS-group consisted of 92 patients (79%, 22 females and 70 males). The mean age of males in the S-group (68 years old) was significantly higher than that of males in the NS-group (64 years old); however there was no significant difference in the mean age in females between the S-group (69 years old) and the NS-group (66 years old). No significant difference of body mass index, ossification of the nuchal ligament-positivity and presence of diabetes mellitus were found between the S- and the NS-group. It is likely that the manner of extension of cervical OPLL is different between male and female patients.


Teaching resources. Protein phosphatases.
This Teaching Resource provides lecture notes and slides for a class covering the structure and function of protein phosphatases and is part of the course "Cell Signaling Systems: A Course for Graduate Students." The lecture begins with a discussion of the importance of phosphatases in physiology, recognized by the award of a Nobel Prize in 1992, and then proceeds to describe the two types of protein phosphatases: serine/threonine and tyrosine phosphatases. The information covered includes the structure, regulation, and substrate specificity of protein phosphatases, with an emphasis on their importance in disease and clinical settings.


Trypanosoma cruzi: metacyclogenesis in vitro--I. Changes in the properties of metacyclic trypomastigotes maintained in the laboratory by different methods.
In this work we have studied the modifications in the biological properties of Trypanosoma cruzi when the parasite is maintained for a long time in axenic culture. The studies were done with a clone from an avirulent strain (Dm30L) and a non-cloned virulent strain (EP) of T. cruzi. Both parasites were maintained, for at least three years, by successive triatomine/mouse alternate passage (control condition), or by serial passage in axenic medium (culture condition), or only in the mouse (mouse condition). The comparison between parasites of culture and control condition showed that metacyclogenesis capacity was reduced in the former and that the resulting metacyclics displayed an attenuated virulence. In order to compare the virulence of metacyclics from the urine of the insect vector, Rhodnius prolixus were infected by artificial feeding with parasites of the control or culture condition. After three triatomine/triatomine passages, there was observed an almost identical biological behavior for these parasites, hence indicating that the maintenance of T. cruzi for a long time in axenic culture affects the differentiation capacity and the virulence of the parasite. Additionally, it was demonstrated that it is possible to maintain T. cruzi exclusively through passages in the invertebrate host.


Evidence for a possible role of the brain kallikrein-kinin system in the modulation of the cerebral circulation.
Experiments by others have shown that exogenous bradykinin dilates cerebral arterioles and that the brain contains kininogen and kallikrein, the latter being the enzyme which converts kininogen to bradykinin. The objective of these experiments was to determine if bradykinin produced from endogenous brain kininogen can affect the cerebral microcirculation. Rabbit pial arteriolar diameter was measured with a microscope using the closed cranial window technique. Topical application of bradykinin (10(-8)-10(-5) M) induced a dose-dependent vasodilation (8-46%) which was completely inhibited by the cyclooxygenase enzyme inhibitors indomethacin and meclofenamic acid. Topical application of 1 U of tissue kallikrein per milliliter of artificial cerebrospinal fluid induced 43% dilation, which could be prevented by local treatment with indomethacin or the proteinase inhibitor aprotinin. The action of aprotinin and indomethacin was specific, since aprotinin did not affect the dilation produced by bradykinin, and indomethacin did not affect dilation produced by adenosine. A second application of kallikrein had no effect on cerebral diameter, yet the arterioles still responded normally to exogenous bradykinin, indicating that the first application of kallikrein depleted brain kininogen. We suggest that activation of brain kallikrein and subsequent formation of kinin from brain kininogen may be important in modulation of cerebral blood flow or generation of cerebral edema.


Endorsement by Central European experts of the revised ESCEO algorithm for the management of knee osteoarthritis.
Osteoarthritis (OA) is characterized by deterioration of the joints and associated with considerable pain and disability. OA is a chronic disease that requires intervention with both non-pharmacological and pharmacological treatment modalities and, inevitably, disease progression may necessitate successive treatments throughout the course of the disease. There is increasing data on the shortfalls of current pharmacological treatment of OA, and safety concerns associated with analgesic therapy use in OA arising from increasing evidence of gastrointestinal, cardiovascular, hepatic and renal adverse events with paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs). Consequently, symptomatic slow-acting drugs for OA (SYSADOAs) may now be considered as a first-line treatment for knee OA, with a particular emphasis placed on the outstanding benefit: risk ratio of pharmaceutical-grade glucosamine and chondroitin sulfate formulations. In this short communication we review recent publications concerned with the safety of paracetamol, NSAIDs and SYSADOAs. Greater understanding of the benefits and limitations of current medications will lead to better disease management in OA. Furthermore, adherence to guideline recommendations across Europe and internationally, such as those from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO), will promote evidence-based medicine and patient-centric care, ultimately leading to greater physician and patient satisfaction.


Metal vapor synthesis of ultrasmall Pd nanoparticles functionalized with N-heterocyclic carbenes.
The synthesis of N-heterocyclic carbene (NHC)-stabilized palladium nanoparticles (PdNPs) by an entirely new strategy comprising the NHC functionalization of ligand-free PdNPs obtained by metal vapor synthesis is described. Detailed characterization confirms the formation of very small monodisperse PdNPs (2.3 nm) and the presence of the NHC ligand on the Pd surface. The stable NHC-functionalized PdNPs dispersed onto a carbon support showed high activity in the hydrogenation of limonene with enhanced regioselectivity in comparison to bare PdNPs on carbon.


Raised IgA in idiopathic pulmonary haemosiderosis.
Levels of immunoglobulin G, A, and M were studied in 31 children with idiopathic pulmonary haemosiderosis and in 35 relatives. A selective increase in serum IgA was observed in the patients. IgA levels in saliva did not show any difference compared with those of normal children.


Structure of the Pho85-Pho80 CDK-cyclin complex of the phosphate-responsive signal transduction pathway.
The ability to sense and respond appropriately to environmental changes is a primary requirement of all living organisms. In response to phosphate limitation, Saccharomyces cerevisiae induces transcription of a set of genes involved in the regulation of phosphate acquisition from the ambient environment. A signal transduction pathway (the PHO pathway) mediates this response, with Pho85-Pho80 playing a vital role. Here we report the X-ray structure of Pho85-Pho80, a prototypic structure of a CDK-cyclin complex functioning in transcriptional regulation in response to environmental changes. The structure revealed a specific salt link between a Pho85 arginine and a Pho80 aspartate that makes phosphorylation of the Pho85 activation loop dispensable and that maintains a Pho80 loop conformation for possible substrate recognition. It further showed two sites on the Pho80 cyclin for high-affinity binding of the transcription factor substrate (Pho4) and the CDK inhibitor (Pho81) that are markedly distant to each other and the active site.


Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study.
The optimal management of stage I follicular lymphoma, according to consensus guidelines, is based on uncontrolled experiences of select institutions. Diverse treatment approaches are used despite guidelines that recommend radiation therapy (XRT). We analyzed outcomes of patients with stage I follicular lymphoma enrolled onto the National LymphoCare database. Of 471 patients with stage I follicular lymphoma, 206 patients underwent rigorous staging as defined by both a bone marrow aspirate and biopsy and an imaging study (a computed tomography [CT] scan of the whole body, a positron emission tomography [PET]/CT scan, or both). Rigorously staged patients had superior progression-free survival (PFS) compared with nonrigorously staged patients (hazard ratio [HR], 0.63). Treatments given to rigorously staged patients were rituximab/chemotherapy (R-chemo; 28%), XRT (27%), observation (17%), systemic therapy + XRT (13%), rituximab monotherapy (12%), and other (3%). With a median follow-up of 57 months for PFS, there were 44 progression events (in 21% of patients) for rigorously staged patients. For these patients, PFS was significantly improved with either R-chemo or systemic therapy + XRT compared with patients receiving XRT alone after adjustment for histology, LDH, and the presence of B symptoms. There were no differences in overall survival. In this largest, prospectively enrolled group of patients with stage I follicular lymphoma, variable treatment approaches resulted in similar excellent outcomes, which challenges the paradigm that XRT should be standard for this presentation.


Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection.
Somatic inactivation of the glutathione S-transferase-pi gene (GSTP1) via CpG island hypermethylation occurs early during prostate carcinogenesis, present in approximately 70% of high-grade prostatic intraepithelial neoplasia (high-grade PIN) lesions and more than 90% of adenocarcinomas. Recently, there has been a resurgence of the concept that foci of prostatic atrophy (referred to as proliferative inflammatory atrophy or PIA) may be precursor lesions for the development of prostate cancer and/or high-grade PIN. Many of the cells within PIA lesions contain elevated levels of GSTP1, glutathione S-transferase-alpha (GSTA1), and cyclooxygenase-II proteins, suggesting a stress response. Because not all PIA cells are positive for GSTP1 protein, we hypothesized that some of the cells within these regions acquire GSTP1 CpG island hypermethylation, increasing the chance of progression to high-grade PIN and/or adenocarcinoma. Separate regions (n =199) from 27 formalin-fixed paraffin-embedded prostates were microdissected by laser-capture microdissection (Arcturus PixCell II). These regions included normal epithelium (n = 48), hyperplasticepithelium from benign prostatic hyperplasia nodules (n = 22), PIA (n = 64), high-grade PIN (n = 32), and adenocarcinoma (n = 33). Genomic DNA was isolated and assessed for GSTP1 CpG island hypermethylation by methylation-specific polymerase chain reaction. GSTP1 CpG island hypermethylation was not detected in normal epithelium (0 of 48) or in hyperplastic epithelium (0 of 22), but was found in 4 of 64 (6.3%) PIA lesions. The difference in the frequency of GSTP1 CpG island hypermethylation between normal or hyperplastic epithelium and PIA was statistically significant (P = 0.049). Similar to studies using nonmicrodissected cases, hypermethylation was found in 22 of 32 (68.8%) high-grade PIN lesions and in 30 of 33 (90.9%) adenocarcinoma lesions. Unlike normal or hyperplastic epithelium, GSTP1 CpG island hypermethylation can be detected in some PIA lesions. These data support the hypothesis that atrophic epithelium in a subset of PIA lesions may lead to high-grade PIN and/or adenocarcinoma. Because these atrophic lesions are so prevalent and extensive, even though only a small subset contains this somatic DNA alteration, the clinical impact may be substantial.


Pincher-generated Nogo-A endosomes mediate growth cone collapse and retrograde signaling.
Nogo-A is one of the most potent myelin-associated inhibitors for axonal growth, regeneration, and plasticity in the adult central nervous system. The Nogo-A-specific fragment NogoDelta20 induces growth cone collapse, and inhibits neurite outgrowth and cell spreading by activating RhoA. Here, we show that NogoDelta20 is internalized into neuronal cells by a Pincher- and rac-dependent, but clathrin- and dynamin-independent, mechanism. Pincher-mediated macroendocytosis results in the formation of NogoDelta20-containing signalosomes that direct RhoA activation and growth cone collapse. In compartmentalized chamber cultures, NogoDelta20 is endocytosed into neurites and retrogradely transported to the cell bodies of dorsal root ganglion neurons, triggering RhoA activation en route and decreasing phosphorylated cAMP response element binding levels in cell bodies. Thus, Pincher-dependent macroendocytosis leads to the formation of Nogo-A signaling endosomes, which act both within growth cones and after retrograde transport in the cell body to negatively regulate the neuronal growth program.


Validation of the Dutch version of the quick mild cognitive impairment screen (Qmci-D).
Differentiating mild cognitive impairment (MCI) from dementia is important, as treatment options differ. There are few short (<5 min) but accurate screening tools that discriminate between MCI, normal cognition (NC) and dementia, in the Dutch language. The Quick Mild Cognitive Impairment (Qmci) screen is sensitive and specific in differentiating MCI from NC and mild dementia. Given this, we adapted the Qmci for use in Dutch-language countries and validated the Dutch version, the Qmci-D, against the Dutch translation of the Standardised Mini-Mental State Examination (SMMSE-D). The Qmci was translated into Dutch with a combined qualitative and quantitative approach. In all, 90 participants were recruited from a hospital geriatric clinic (25 with dementia, 30 with MCI, 35 with NC). The Qmci-D and SMMSE-D were administered sequentially but randomly by the same trained rater, blind to the diagnosis. The Qmci-D was more sensitive than the SMMSE-D in discriminating MCI from dementia, with a significant difference in the area under the curve (AUC), 0.73 compared to 0.60 (p = 0.024), respectively, and in discriminating dementia from NC, with an AUC of 0.95 compared to 0.89 (p = 0.006). Both screening instruments discriminated MCI from NC with an AUC of 0.86 (Qmci-D) and 0.84 (SMMSE-D). The Qmci-D shows similar,(good) accuracy as the SMMSE-D in separating NC from MCI; greater,(albeit fair), accuracy differentiating MCI from dementia, and significantly greater accuracy in separating dementia from NC. Given its brevity and ease of administration, the Qmci-D seems a useful cognitive screen in a Dutch population. Further study with a suitably powered sample against more sensitive screens is now required.


Visual and spatial modulation of tactile extinction: behavioural and electrophysiological evidence.
Crossing the hands over the midline reduces left tactile extinction to double simultaneous stimulation in right-brain-damaged patients, suggesting that spatial attentional biases toward the ipsilesional (right) side of space contribute to the patients' contralesional (left) deficit. We investigated (1) whether the position of the left hand, and its vision, affected processing speed of tactile stimuli, and (2) the electrophysiological underpinnings of the effect of hand position. (1) Four right-brain-damaged patients with spatial neglect and contralesional left tactile extinction or somatosensory deficits, and eight neurologically unimpaired participants, performed a speeded detection task on single taps delivered on their left index finger. In patients, placing the left hand in the right (heteronymous) hemi-space resulted in faster reaction times (RTs) to tactile stimuli, compared to placing that hand in the left (homonymous) hemi-space, particularly when the hand was visible. By contrast, in controls placing the left hand in the heteronymous hemi-space increased RTs. (2) Somatosensory event-related potentials (ERPs) were recorded from one patient and two controls in response to the stimulation of the left hand, placed in the two spatial positions. In the patient, the somatosensory P70, N140, and N250 components were enhanced when the left hand was placed in the heteronymous hemi-space, whereas in controls these components were not modulated by hand position. The novel findings are that in patients placing the left hand in the right, ipsilesional hemi-space yields a temporal advantage in processing tactile stimuli, and this effect may rely on a modulation of stimulus processing taking place as early as in the primary somatosensory cortex, as indexed by evoked potentials. Furthermore, vision enhances tactile processing specifically when the left hand is placed in the hemi-space toward which the patients' attentional biases are pathologically directed, namely rightwards.


Nivolumab Plus Ipilimumab for Treatment-Naïve Metastatic Uveal Melanoma: An Open-Label, Multicenter, Phase II Trial by the Spanish Multidisciplinary Melanoma Group (GEM-1402).
This study aimed to assess the efficacy of the combination of nivolumab (nivo) plus ipilimumab (ipi) as a first-line therapy with respect to the 12-month overall survival (OS) in patients with metastatic uveal melanoma (MUM) who are not eligible for liver resection. This was a single-arm, phase II trial led by the Spanish Multidisciplinary Melanoma Group (GEM) on nivo plus ipi for systemic treatment-naïve patients of age > 18 years, with histologically confirmed MUM, Eastern Cooperative Oncology Group-PS 0/1, and confirmed progressive metastatic disease (M1). Nivo (1 mg/kg once every 3 weeks) and ipi (3 mg/kg once every 3 weeks) were administered during four inductions, followed by nivo (3 mg/kg once every 2 weeks) until progressive disease, toxicity, or withdrawal. The primary end point was 12-month OS. OS, progression-free survival (PFS), and overall response rate were evaluated every 6 weeks using RECIST (v1.1). Safety was also evaluated. Logistic regression and Cox proportional hazard models comprising relevant clinical factors were used to evaluate the potential association with response to treatment and survival. Cytokines were quantified in serum samples for their putative role in immune modulation/angiogenesis and/or earlier evidence of involvement in immunotherapy. A total of 52 patients with a median age of 59 years (range, 26-84 years) were enrolled. Overall, 78.8%, 56%, and 32% of patients had liver M1, extra-liver M1, and elevated lactate dehydrogenase. Stable disease was the most common outcome (51.9%). The primary end point was 12-month OS, which was 51.9% (95% CI, 38.3 to 65.5). The median OS and PFS were 12.7 months and 3.0 months, respectively. PFS was influenced by higher LDH values. Nivo plus ipi in the first-line setting for MUM showed a modest improvement in OS over historical benchmarks of chemotherapy, with a manageable toxicity profile.


High performance refractive index sensor based on low Q-factor ring resonators and FFT processing of wavelength scanning data.
We extend our previous simulation study and we present experimental results regarding our Fast Fourier Transform method for the calculation of the resonance shifts in biosensors based on micro-ring resonators (MRRs). For the simulation study, we use a system model with a tunable laser at 850 nm, an MRR with 1.5∙104 quality factor, and a detection system with 50 dB maximum signal-to-noise ratio, and investigate the impact on the system performance of factors like the number of the resonance peaks inside the scanning window, the wavelength dependence of the laser power, and the asymmetry of the transfer functions of the MRRs. We find that the performance is improved by a factor of 2 when we go from single- to four-peak transfer functions, and that the impact of the wavelength dependence of the laser power is very low. We also find that the presence of asymmetries can lead to strong discontinuities of the transfer functions at the edges of the scanning window and can significantly increase the measurement errors, making necessary the use of techniques for their elimination. Using these conclusions, we build a system with sensing MRRs on TriPleX platform, and we experimentally validate our method using sucrose solutions with different concentrations. Involving techniques in order to exclude the noise originating from the microfluidic system, we achieve a wavelength resolution close to 0.08 pm, when the system operates with 0.5 pm scanning step. In combination with the sensitivity of the MRRs, which is measured to be equal to 93.7 nm/RIU, this wavelength resolution indicates the possibility for a limit of detection close to 8.5·10-7 RIU, which represents to the best of our knowledge a record performance for this type of optical sensors and this level of scanning steps.


Motivation to access laparoscopic skills training: Results of a Canadian survey of obstetrics and gynecology residents.
Competency based medical education (CBME) requires novel approaches to surgical education. Significant investment has been made in laparoscopic simulation, which has been shown to foster skill development prior to patient encounters. However, research suggests variable voluntary use of these resources by residents, and little is known about the motivational factors that influence their utilization. The purpose of this study was to characterize factors that motivate residents to seek laparoscopic simulation experience outside of the formal curriculum. We developed a questionnaire grounded in Expectancy Value Theory, an established psychological theory of motivation, by adapting validated measures to fit the study context. We conducted a cross sectional survey of Canadian obstetrics and gynecology residents. We invited residents enrolled in English-language obstetrics and gynecology training programs in Canada to participate. All residents engaged in clinical duties during Winter 2018 were invited to complete the questionnaire. Forty-four Obstetrics and Gynecology (Ob/Gyn) residents participated in the study. Residents reported limited use of simulation resources and identified multiple barriers including lack of time, access, and supervision. They expressed concern about development of bad habits during independent practice, and simulation use was positively correlated with perceived utility. Compared to junior residents, senior residents reported greater enjoyment of laparoscopic surgery, less emotional costs, and higher self-efficacy for learning laparoscopy. Residents' perception of utility and barriers impede voluntary simulation use and overall use was limited. As programs undertake curricula redevelopment for CBME, mitigating barriers and improving perceived utility of laparoscopic simulation is vital to increase use and enhance skill development.


End-Devonian extinction and a bottleneck in the early evolution of modern jawed vertebrates.
The Devonian marks a critical stage in the early evolution of vertebrates: It opens with an unprecedented diversity of fishes and closes with the earliest evidence of limbed tetrapods. However, the latter part of the Devonian has also been characterized as a period of global biotic crisis marked by two large extinction pulses: a "Big Five" mass extinction event at the Frasnian-Famennian stage boundary (374 Ma) and the less well-documented Hangenberg event some 15 million years later at the Devonian-Carboniferous boundary (359 Ma). Here, we report the results of a wide-ranging analysis of the impact of these events on early vertebrate evolution, which was obtained from a database of vertebrate occurrences sampling over 1,250 taxa from 66 localities spanning Givetian to Serpukhovian stages (391 to 318 Ma). We show that major vertebrate clades suffered acute and systematic effects centered on the Hangenberg extinction involving long-term losses of over 50% of diversity and the restructuring of vertebrate ecosystems worldwide. Marine and nonmarine faunas were equally affected, precluding the existence of environmental refugia. The subsequent recovery of previously diverse groups (including placoderms, sarcopterygian fish, and acanthodians) was minimal. Tetrapods, actinopterygians, and chondrichthyans, all scarce within the Devonian, undergo large diversification events in the aftermath of the extinction, dominating all subsequent faunas. The Hangenberg event represents a previously unrecognized bottleneck in the evolutionary history of vertebrates as a whole and a historical contingency that shaped the roots of modern biodiversity.


Mechanical Stimulation Increases Knee Meniscus Gene RNA-level Expression in Adipose-derived Stromal Cells.
Efforts have been made to engineer knee meniscus tissue for injury repair, yet most attempts have been unsuccessful. Creating a cell source that resembles the complex, heterogeneous phenotype of the meniscus cell remains difficult. Stem cell differentiation has been investigated, mainly using bone marrow mesenchymal cells and biochemical means for differentiation, resulting in no solution. Mechanical stimulation has been investigated to an extent with no conclusion. Here, we explore the potential for and effectiveness of mechanical stimulation to induce the meniscal phenotype in adipose-derived stromal cells. Human adipose-derived stromal cells were chosen for their fibrogenic nature and conduciveness for chondrogenesis. Biochemical and mechanical stimulation were investigated. Biochemical stimulation included fibrogenic and chondrogenic media. For mechanical stimulation, a custom-built device was used to apply constant, cyclical, uniaxial strain for up to 6 hours. Strain and frequency varied. Under biochemical stimulation, both fibrogenic (collagen I, versican) and chondrogenic (collagen II, Sox9, aggrecan) genes were expressed by cells exposed to either fibrogenic or chondrogenic biochemical factors. Mechanical strain was found to preferentially promote fibrogenesis over chondrogenesis, confirming that tensile strain is an effective fibrogenic cue. Three hours at 10% strain and 1 Hz in chondrogenic media resulted in the highest expression of fibrochondrogenic genes. Although mechanical stimulation did not seem to affect protein level expression, biochemical means did affect protein level presence of collagen fibers. Mechanical stimulation can be a useful differentiation tool for mechanoresponsive cell types as long as biochemical factors are also integrated.


A human disease model of drug toxicity-induced pulmonary edema in a lung-on-a-chip microdevice.
Preclinical drug development studies currently rely on costly and time-consuming animal testing because existing cell culture models fail to recapitulate complex, organ-level disease processes in humans. We provide the proof of principle for using a biomimetic microdevice that reconstitutes organ-level lung functions to create a human disease model-on-a-chip that mimics pulmonary edema. The microfluidic device, which reconstitutes the alveolar-capillary interface of the human lung, consists of channels lined by closely apposed layers of human pulmonary epithelial and endothelial cells that experience air and fluid flow, as well as cyclic mechanical strain to mimic normal breathing motions. This device was used to reproduce drug toxicity-induced pulmonary edema observed in human cancer patients treated with interleukin-2 (IL-2) at similar doses and over the same time frame. Studies using this on-chip disease model revealed that mechanical forces associated with physiological breathing motions play a crucial role in the development of increased vascular leakage that leads to pulmonary edema, and that circulating immune cells are not required for the development of this disease. These studies also led to identification of potential new therapeutics, including angiopoietin-1 (Ang-1) and a new transient receptor potential vanilloid 4 (TRPV4) ion channel inhibitor (GSK2193874), which might prevent this life-threatening toxicity of IL-2 in the future.


Randomised phase II trial of CAPTEM or FOLFIRI as SEcond-line therapy in NEuroendocrine CArcinomas and exploratory analysis of predictive role of PET/CT imaging and biological markers (SENECA trial): a study protocol.
Patients with metastatic or locally advanced, non-resectable, grade 3 poorly differentiated gastroenteropancreatic (GEP) and lung neuroendocrine carcinomas (NECs) are usually treated with in first-line platinum compounds. There is no standard second-line treatment on progression. Accurate biomarkers are needed to facilitate diagnosis and prognostic assessment of patients with NEC. The SEcond-line therapy in NEuroendocrine CArcinomas (SENECA) study is a randomised, non-comparative, multicentre phase II trial designed to evaluate the efficacy and safety of folinic acid, 5-fluorouracil and irinotecan (FOLFIRI) or capecitabine plus temozolomide (CAPTEM) regimens after failure of first-line chemotherapy in patients with lung NEC and GEP-NEC. Secondary aims are to correlate the serum miRNA profile and primary mutational status of MEN1, DAXX, ATRX and RB-1 with prognosis and outcome and to investigate the prognostic and predictive role of the Ki-67 score and 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) or 68Ga-PET/CT. The main eligibility criteria are age ≥18 years; metastatic or locally advanced, non-resectable, grade 3 lung or GEP-NECs; progression to first-line platinum-based chemotherapy. A Bryant and Day design taking into account treatment activity and toxicity was used to estimate the sample size. All analyses will be performed separately for each treatment group in the intention-to-treat population. A total of 112 patients (56/arm) will be randomly assigned (1:1) to receive FOLFIRI every 14 days or CAPTEM every 28 days until disease progression or unacceptable toxicity or for a maximum of 6 months. Patients undergo testing for specific biomarkers in primary tumour tissue and for miRNA in blood samples. MiRNA profiling will be performed in the first 20 patients who agree to participate in the biological substudy. The SENECA trial, supported by Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST), was authorised by the locals Ethics Committee and the Italian Medicines Agency (AIFA). Results will be widely disseminated via peer-reviewed manuscripts, conference presentations and reports to relevant authorities.The study is currently open in Italy. NCT03387592; Pre-results. EudraCT-2016-000767-17. Clinical Study Protocol Version 1, 7 November 2016.


Adenosine and inosine exert cytoprotective effects in an in vitro model of liver ischemia-reperfusion injury.
Liver ischemia represents a common clinical problem. In the present study, using an in vitro model of hepatic ischemia-reperfusion injury, we evaluated the potential cytoprotective effect of the purine metabolites, such as adenosine and inosine, and studied the mode of their pharmacological actions. The human hepatocellular carcinoma-derived cell line HepG2 was subjected to combined oxygen-glucose deprivation (COGD; 0-14-24 h), followed by re-oxygenation (0-4-24 h). Adenosine or inosine (300-1,000 µM) were applied in pretreatment. Cell viability and cytotoxicity were measured by the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide and lactate dehydrogenase methods, respectively. The results showed that both adenosine and inosine exerted cytoprotective effects, and these effects were not related to receptor-mediated actions, since they were not prevented by selective adenosine receptor antagonists. On the other hand, the adenosine deaminase inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine hydrochloride (EHNA, 10 µM) markedly and almost fully reversed the protective effect of adenosine during COGD, while it did not influence the cytoprotective effect of inosine in the same assay conditions. These results suggest that the cytoprotective effects are related to intracellular actions, and, in the case of adenosine also involve intracellular conversion to inosine. The likely interpretation of these findings is that inosine serves as an alternative source of energy to produce ATP during hypoxic conditions. The protective effects are also partially dependent on adenosine kinase, as the inhibitor 4-amino-5-(3-bromophenyl)-7-(6‑morpholino-pyridin-3-yl)pyrido[2,3-d]pyrimidine, 2HCl (ABT 702, 30 µM) significantly reversed the protective effect of both adenosine and inosine during hypoxia and re-oxygenation. Collectively, the current results support the view that during hypoxia, adenosine and inosine exert cytoprotective effects via receptor-independent, intracellular modes of action, which, in part, depend on the restoration of cellular bioenergetics. The present study supports the view that testing of inosine for protection against various forms of warm and cold liver ischemia is relevant.


Spinal hemiepiphysiodesis decreases the size of vertebral growth plate hypertrophic zone and cells.
Hemiepiphysiodesis is a potential method to treat idiopathic juvenile scoliosis early. The purpose of the present study was to investigate a mechanism of curve creation in the pig thoracic model of spinal hemiepiphysiodesis by determining whether the structure of the vertebral growth plate varied with distance from the stapled, concave side of the spine. The hypotheses were that the heights of the hypertrophic zone, hypertrophic cells, and disc would be decreased on the treated side of the treated level as compared with both an unstapled control level and the side opposite the staple. Custom spine staples were implanted into six midthoracic vertebrae in each of five skeletally immature pigs. After eight weeks, the spines were harvested and histological sections were prepared. Hypertrophic zone height, hypertrophic cell height and width, and disc height were measured at discrete coronal plane locations at stapled and unstapled thoracic levels. Differences between stapled and unstapled levels and locations were compared with use of mixed linear modeling for repeated measures, followed by regression models to determine growth plate intercept and slope across the plane by thoracic level. Zone height, cell height, and cell width were lowest on the stapled side of the stapled level, with significant differences in the overall statistical model (p < 0.02). Disc heights were significantly reduced (p < 0.0001) at the stapled levels across the coronal plane. Unilateral control of intervertebral joint motion decreased growth plate height, cell size, and disc height.


Surface biofunctionalization by covalent co-immobilization of oligopeptides.
Functionalization of implants with multiple bioactivities is desired to obtain surfaces with improved biological and clinical performance. Our objective was developing a simple and reliable method to obtain stable multifunctional coatings incorporating different oligopeptides. We co-immobilized on titanium surface oligopeptides of known cooperative bioactivities with a simple and reliable method. Appropriately designed oligopeptides containing either RGD or PHSRN bioactive sequences were mixed and covalently bonded on CPTES-silanized surfaces. Coatings made of only one of the two investigated peptides and coatings with physisorbed oligopeptides were produced and tested as control groups. We performed thorough characterization of the obtained surfaces after each step of the coating preparation and after mechanically challenging the obtained coatings. Fluorescence labeling of RGD and PHSRN peptides with fluorescence probes of different colors enabled the direct visualization of the co-immobilization of the oligopeptides. We proved that the coatings were mechanically stable. The surfaces with co-immobilized RGD and PHSRN peptides significantly improved osteoblasts response in comparison with control surfaces, which assessed the effectiveness of our coating method to bio-activate the implant surfaces. This same simple method can be used to obtain other multi-functional surfaces by co-immobilizing oligopeptides with different targeted bioactivities--cell recruitment and differentiation, biomineral nucleation, antimicrobial activity--and thus, further improving the clinical performance of titanium implants.


SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo.
FLT3 (fms-related tyrosine kinase/Flk2/Stk-2) is a receptor tyrosine kinase (RTK) primarily expressed on hematopoietic cells. In blasts from acute myelogenous leukemia (AML) patients, 2 classes of FLT3 activating mutations have been identified: internal tandem duplication (ITD) mutations in the juxtamembrane domain (25%-30% of patients) and point mutations in the kinase domain activation loop (7%-8% of patients). FLT3-ITD mutations are the most common molecular defect identified in AML and have been shown to be an independent prognostic factor for decreased survival. FLT3-ITD is therefore an attractive molecular target for therapy. SU11248 is a recently described selective inhibitor with selectivity for split kinase domain RTKs, including platelet-derived growth factor receptors, vascular endothelial growth factor receptors, and KIT. We show that SU11248 also has potent activity against wild-type FLT3 (FLT3-WT), FLT3-ITD, and FLT3 activation loop (FLT3-Asp835) mutants in phosphorylation assays. SU11248 inhibits FLT3-driven phosphorylation and induces apoptosis in vitro. In addition, SU11248 inhibits FLT3-induced VEGF production. The in vivo efficacy of SU11248 was investigated in 2 FLT3-ITD models: a subcutaneous tumor xenograft model and a bone marrow engraftment model. We show that SU11248 (20 mg/kg/d) dramatically regresses FLT3-ITD tumors in the subcutaneous tumor xenograft model and prolongs survival in the bone marrow engraftment model. Pharmacokinetic and pharmacodynamic analysis in subcutaneous tumors showed that a single administration of an efficacious drug dose potently inhibits FLT3-ITD phosphorylation for up to 16 hours following a single dose. These results suggest that further exploration of SU11248 activity in AML patients is warranted.


Cancer incidence and mortality: A cohort study in China, 2008-2013.
The National Central Cancer Registry of China (NCCR) was the only available source of cancer monitoring in China, even though only about 70% of cancer registration sites were qualified by now. In this study, based on a national large prospective cohort-the China Kadoorie Biobank (CKB), we aimed to provide additional cancer statistics and compare the difference of cancer burden between urban and rural areas of China. A total of 497,693 cancer-free participants aged 35-74 years were recruited and successfully followed up from 2004 to 2013 in 5 urban and 5 rural areas across China. Except for traditional registration systems, the national health insurance system and active follow-up were used to determine new cancer incidents and related deaths. The mortality-to-incidence ratio (MIR) was used to compare the differences of cancer burden between urban and rural areas of China. We found that cancer mortality coincided well between our cohort and NCCR, while the incidence was much higher in our cohort. Based on CKB, we found the MIR of all cancers was 0.54 in rural areas, which was approximately one-third higher than that in urban areas with 0.39. Cancer profiles in urban areas were transiting to Western distributions, which were characterized with high incidences of breast cancer and colorectal cancer; while cancers of the esophagus, liver and cervix uteri were still common in rural areas of China. Our results provide additional cancer statistics of China and demonstrate the differences of cancer burden between urban and rural areas of China.


Understanding how distance to facility and quality of care affect maternal health service utilization in Kenya and Haiti: A comparative geographic information system study.
In 2000, the United Nations established eight Millennium Development Goals (MDG) to combat worldwide poverty, disease, and lack of primary education. Goal number five aimed to reduce the maternal mortality ratio by three quarters and provide universal access to reproductive healthcare services by 2015. While there has been some progress, MDG 5 fell far short of target goals, highlighting the necessity of further improvement in global maternal health. Using Geographic Information Systems (GIS), this study aims to understand how distance to facility and quality of care, which are components of access, affect maternal service utilization in two of the world's poorest countries, Haiti and Kenya. Furthermore, this study examines how this relationship may change or hold between urban and rural regions. Data from the United States Agency for International Development Demographic and Health Survey and Service Provision Assessment were linked spatially in a GIS model, drawing comparisons among distance to facility, quality of care, and maternal health service utilization. Results show that in both rural and urban regions, access to maternal health service and maternal health service utilization share a similar spatial pattern. In urban regions, pockets of maternal health disparities exist despite close distance to facility and standard quality of care. In rural regions, there are areas with long distances to facilities and low quality of care, resulting in poor maternal service usage. This study highlights the usefulness of GIS as a tool to evaluate disparities in maternal healthcare provision and usage.


Impact of an asbestos cement factory on mesothelioma incidence: global assessment of effects of occupational, familial, and environmental exposure.
Few studies have examined the incidence of malignant mesothelioma (MM) associated with distinct sources of asbestos exposure (occupational, familial, or environmental). We assessed the impact of asbestos exposure-global and by source-on the incidence of MM in Broni, an Italian town in which an asbestos cement factory once operated (1932-1993). Based on data collected by the Lombardy Mesothelioma Registry, we calculated the number of observed and expected MM cases among workers, their cohabitants, and people living in the area in 2000-2011. We identified 147 MM cases (17.45 expected), 138 pleural and nine peritoneal, attributable to exposure to asbestos from the factory. Thirty-eight cases had past occupational exposure at the factory (2.33 expected), numbering 32 men (26 pleural, six peritoneal) and six women (four pleural, two peritoneal). In the families of the workers, there were 37 MM cases (4.23 expected), numbering five men (all pleural) and 32 women (31 pleural, one peritoneal). Among residents in Broni or in the adjacent/surrounding towns, there were 72 cases of pleural MM (10.89 expected), numbering 23 men and 49 women. The largest MM excess was found in the towns of Broni (48 observed, 3.68 expected) and Stradella (16 observed, 1.85 expected). This study documents the large impact of the asbestos cement factory, with about 130 excess MM cases in a 12-year period. The largest MM burden was among women, from non-occupational exposure. Almost half of the MM cases were attributable to environmental exposure.


Enzyme-Substrate Binding Kinetics Indicate That Photolyase Recognizes an Extrahelical Cyclobutane Thymidine Dimer.
Escherichia coli DNA photolyase is a DNA-repair enzyme that repairs cyclobutane pyrimidine dimers (CPDs) that are formed on DNA upon exposure of cells to ultraviolet light. The light-driven electron-transfer mechanism by which photolyase catalyzes the CPD monomerization after the enzyme-substrate complex has formed has been studied extensively. However, much less is understood about how photolyase recognizes CPDs on DNA. It has been clearly established that photolyase, like many other DNA-repair proteins, requires flipping of the CPD site into an extrahelical position. Photolyase is unique in that it requires the two dimerized pyrimidine bases to flip rather than just a single damaged base. In this paper, we perform direct measurements of photolyase binding to CPD-containing undecamer DNA that has been labeled with a fluorophore. We find that the association constant of ∼2 × 10(6) M(-1) is independent of the location of the CPD on the undecamer DNA. The binding kinetics of photolyase are best described by two rate constants. The slower rate constant is ∼10(4) M(-1) s(-1) and is most likely due to steric interference of the fluorophore during the binding process. The faster rate constant is on the order of 2.5 × 10(5) M(-1) s(-1) and reflects the binding of photolyase to the CPD on the DNA. This result indicates that photolyase finds and binds to a CPD lesion 100-4000 times slower than other DNA-repair proteins. In light of the existing literature, we propose a mechanism in which photolyase recognizes a CPD that is flipped into an extrahelical position via a three-dimensional search.


Abdominal sonography in examination of children with blunt abdominal trauma.
The objective of our study was to evaluate abdominal sonography for the detection of fluid and organ injury in children with blunt abdominal trauma. Fifty-one consecutive children with blunt abdominal trauma requiring abdominal CT were prospectively examined with sonography. Sonograms and CTs were independently evaluated by two radiologists for fluid and organ injury; CT examinations were considered abnormal if either was identified. Differences in CT interpretation were settled by a third observer. Using CT as the truth standard, we calculated the sensitivity, specificity, and negative predictive value of sonography for both observers. Agreement of the sonographic interpretations was evaluated using kappa statistic. In 33.3% of patients, CT revealed fluid, organ injury, or both. The sensitivity and specificity of sonography when detection of fluid was the sole parameter evaluated was 58.8% and 79.4%, respectively, for observer 1 and 47.1% and 79.4%, respectively, for observer 2. In contrast, the sensitivity and specificity of sonography when detection of both fluid and organ injury was evaluated was 64.7% and 79.4%, respectively, for observer 1 and 70.6% and 70.6%, respectively, for observer 2. The negative predictive value of sonography was 79.4% and 75.0% with evaluation limited to detection of fluid and 81.8% and 82.8% with evaluation of fluid and organ abnormality for observers 1 and 2 , respectively. Agreement was excellent for sonographic identification of fluid (kappa = 0.82) but poor for detection of organ injury (kappa = 0.34). The low sensitivity and negative predictive value of sonography when assessing for either fluid alone or fluid and organ injury suggest that a normal screening sonography alone in the setting of blunt abdominal trauma fails to confidently exclude the presence of an intraabdominal injury.


Glucocorticoid receptors in lung cancer: new perspectives.
Proper expression of the glucocorticoid receptor (GR) plays an essential role in the development of the lung. GR expression and signalling in the lung is manipulated by administration of synthetic glucocorticoids (Gcs) for the treatment of neonatal, childhood and adult lung diseases. In lung cancers, Gcs are also commonly used as co-treatment during chemotherapy. This review summarises the effect of Gc monotherapy and co-therapy on lung cancers in vitro, in mouse models of lung cancer, in xenograft, ex vivo and in vivo The disparity between the effects of pre-clinical and in vivo Gc therapy is commented on in light of the recent discovery of GR as a novel tumour suppressor gene.


Response of grassland ecosystem to monsoonal precipitation variability during the Mid-Late Holocene: Inferences based on molecular isotopic records from Banni grassland, western India.
Banni, located in the arid western India, is one of the largest tropical grasslands of the Asian continent. The net primary production in this grassland ecosystem is currently mediated by precipitation during the Indian summer monsoon (ISM). However, timing of the grassland expansion and its link to the intensity of monsoonal precipitation remains enigmatic due to the paucity of datasets. The major objective of this study is to understand the changes in monsoonal precipitation and vegetation for the last 4600 cal yr BP using hydrogen and carbon isotopic composition of n-alkanes (δDn-alkane and δ13Cn-alkane) measured from two core sediments (Chachi and Luna) in Banni region. The δ13CC29 and δ13CC31 values for Chachi core sediments vary from -30.9 ‰ to -27.2 ‰ and -34.4 ‰ to -25 ‰ respectively. The δ13Cn-alkane values from the core sediments are converted into %C4 plants based on a binary mixing model using the end-member δ13Cn-alkane values derived from the dominant modern vegetation in the Banni region. The prominent feature of the paleovegetation curve is the marked increase in the δ13Cn-alkane values after 2500 cal yr BP, which suggests proliferation of C4 grasses in this region. Similar changes after 2500 cal yr BP have also been observed in the δDn-alkane values. The δDC29 values are used to calculate δD value of paleoprecipitation that varied from 10 ‰ to -60.2 ‰. A significant increase in the δD values of paleoprecipitation (ca. 25 ‰) indicates a weakened ISM precipitation after ca. 2500 cal yr BP. The regional aridification and frequent fire events may have helped the expansion of C4 plant dominated grassland ecosystem in Banni region. Correlation between paleoclimatic records suggests that the southward migration of intertropical convergence zone and more frequent warm phases of El-Nino Southern Oscillation have triggered the weakening of monsoonal precipitation in the tropical region.


Follow-up Recommendations for Completely Resected Gastroenteropancreatic Neuroendocrine Tumors.
There is no consensus on optimal follow-up for completely resected gastroenteropancreatic neuroendocrine tumors. Published guidelines for follow-up are complex and emphasize closer surveillance in the first 3 years after resection. Neuroendocrine tumors have a different pattern and timescale of recurrence, and thus require more practical and tailored follow-up. The Commonwealth Neuroendocrine Tumour Collaboration convened an international multidisciplinary expert panel, in collaboration with the North American Neuroendocrine Tumor Society, to create patient-centered follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. This panel used the RAND/UCLA (University of California, Los Angeles) Appropriateness Method to generate recommendations. A large international survey was conducted outlining current the surveillance practice of neuroendocrine tumor practitioners and shortcomings of the current guidelines. A systematic review of available data to date was supplemented by recurrence data from 2 large patient series. The resultant guidelines suggest follow-up for at least 10 years for fully resected small-bowel and pancreatic neuroendocrine tumors and also identify clinical situations in which no follow-up is required. These recommendations stratify follow-up strategies based on evidence-based prognostic factors that allow for a more individualized patient-centered approach to this complex and heterogeneous malignant neoplasm.


Sequencing of small RNAs of the fern Pleopeltis minima (Polypodiaceae) offers insight into the evolution of the microrna repertoire in land plants.
MicroRNAs (miRNAs) are short, single stranded RNA molecules that regulate the stability and translation of messenger RNAs in diverse eukaryotic groups. Several miRNA genes are of ancient origin and have been maintained in the genomes of animal and plant taxa for hundreds of millions of years, playing key roles in development and physiology. In the last decade, genome and small RNA (sRNA) sequencing of several plant species have helped unveil the evolutionary history of land plants. Among these, the fern group (monilophytes) occupies a key phylogenetic position, as it represents the closest extant cousin taxon of seed plants, i.e. gymno- and angiosperms. However, in spite of their evolutionary, economic and ecological importance, no fern genome has been sequenced yet and few genomic resources are available for this group. Here, we sequenced the small RNA fraction of an epiphytic South American fern, Pleopeltis minima (Polypodiaceae), and compared it to plant miRNA databases, allowing for the identification of miRNA families that are shared by all land plants, shared by all vascular plants (tracheophytes) or shared by euphyllophytes (ferns and seed plants) only. Using the recently described transcriptome of another fern, Lygodium japonicum, we also estimated the degree of conservation of fern miRNA targets in relation to other plant groups. Our results pinpoint the origin of several miRNA families in the land plant evolutionary tree with more precision and are a resource for future genomic and functional studies of fern miRNAs.


Platelet ultrastructural morphometry for diagnosis of partial delta-storage pool disease in patients with mild platelet dysfunction and/or thrombocytopenia of unknown origin. A study of 24 cases.
Exact diagnosis is sometimes difficult in patients presenting with a slight bleeding diathesis, prolonged bleeding times, non-specific aggregometric abnormalities, and/or mild thrombocytopenia. The objective of this study was to evaluate the use of platelet ultrastructural morphometry in detecting a partial d-storage pool disease in such patients. Platelets from 52 patients and 15 controls were fixed immediately in glutaraldehyde in White's saline without anticoagulant and processed for transmission electron microscopy. Using computer-assisted morphometry, the size and shape of the platelets were measured, as were the size and number per platelet of the dense- and a-granules. Ultrastructural morphology of the above and other intraplatelet structures was observed. Twenty-four cases were diagnosed as having a partial d-storage pool disease. Mean platelet area (2.28 microm(2)) and maximum diameter (2.58 microm) were significantly greater in patients than in control subjects (1.64 microm(2) and 2. 25 microm, respectively) but discoid shape was preserved. Mean dense-granule number was decreased, both per platelet and per microm(2) of platelet area (patients 0.22 and 0.09; controls 0.42 and 0.24). Seven patients also had a marked decrease in a-granules, resulting in a significantly lower mean number of granules per microm(2 )(patients 2.43; controls 3.15). Additionally, the patients' platelets had significant increases in both lipid droplets and surface-connected canalicular system. A partial dense-granule deficiency, sometimes associated with partial a-granule deficiency, should be borne in mind faced with patients who have a slight bleeding diathesis, non-specific platelet dysfunction tests and/or mild thrombocytopenia of unknown origin. Platelet ultrastructural morphometry is useful in diagnosing this condition.


Participation bias and its impact on the assembly of a genetic specimen repository for a myocardial infarction cohort.
To assess participation bias in the assembly of a specimen repository for genetic studies and to examine the association of participation with outcome within the Olmsted County myocardial infarction (MI) cohort. From January 1, 1979, to May 31, 2006, 3081 persons had MI in Olmsted County, MN. Face-to-face contact was used to recruit patients who were hospitalized for an acute event. Persons who had had an MI before establishment of this repository were contacted by mail. At initial contact, we sought consent to use blood samples for genetic studies. Persons who refused were contacted by mail and were asked to consent to the use of stored tissue samples. For deceased subjects, stored tissue was collected when available. Of the 3081 persons in the Olmsted County MI cohort, 1994 participated in the study; 1007 (50.5%) blood and 987 (49.5%) tissue specimens were provided. Participants were more likely to be younger men with hypertension, comorbidities, and non-ST-segment elevation MI (all, P<.05). Participants who provided blood specimens were more likely to have non-ST-segment elevation MI and lower Killip class than those who provided tissue. After adjustment for age, sex, hypertension, ST-segment elevation, Killip class, and comorbidities, participation was not associated with outcome. Participants who provided blood specimens were less likely to have heart failure (hazard ratio, 0.49; 95% confidence interval, 0.40-0.59; P<.01) or to die (hazard ratio, 0.16; 95% confidence interval, 0.12-0.21; P<.01) than those who provided tissue. A variety of sources can be used to assemble community specimen repositories. Baseline characteristics differed between participants and nonparticipants and, among participants, by specimen source. Participants who provided blood specimens had better outcomes than those who provided tissue specimens. No survival advantage was observed for participants after combining blood and tissue specimens.


transformation between diphosphinoamines and iminobiphosphines: a reversible P-N-P <--> N=P-P rearrangement triggered by protonation/deprotonation.
The protonation of diphosphinoamines attached to pyridine at the ortho-position quantitatively affords the corresponding iminobiphosphine isomers. The starting material can be recovered quantitatively by deprotonation with base. The system represents a new type of molecular switch.


Equilibrium states of open quantum systems in the strong coupling regime.
In this work we investigate the late-time steady states of open quantum systems coupled to a thermal reservoir in the strong coupling regime. In general such systems do not necessarily relax to a Boltzmann distribution if the coupling to the thermal reservoir is nonvanishing or equivalently if the relaxation time scales are finite. Using a variety of nonequilibrium formalisms valid for non-Markovian processes, we show that starting from a product state of the closed system = system+environment, with the environment in its thermal state, the open system which results from coarse graining the environment will evolve towards an equilibrium state at late times. This state can be expressed as the reduced state of the closed system thermal state at the temperature of the environment. For a linear (harmonic) system and environment, which is exactly solvable, we are able to show in a rigorous way that all multitime correlations of the open system evolve towards those of the closed system thermal state. Multitime correlations are especially relevant in the non-Markovian regime, since they cannot be generated by the dynamics of the single-time correlations. For more general systems, which cannot be exactly solved, we are able to provide a general proof that all single-time correlations of the open system evolve to those of the closed system thermal state, to first order in the relaxation rates. For the special case of a zero-temperature reservoir, we are able to explicitly construct the reduced closed system thermal state in terms of the environmental correlations.


Activation of integrin alphaIIbbeta3 by modulation of transmembrane helix associations.
Transmembrane helices of integrin alpha and beta subunits have been implicated in the regulation of integrin activity. Two mutations, glycine-708 to asparagine-708 (G708N)and methionine-701 to asparagine-701, in the transmembrane helix of the beta3 subunit enabled integrin alphaIIbbeta3 to constitutively bind soluble fibrinogen. Further characterization of the G708N mutant revealed that it induced alphaIIbbeta3 clustering and constitutive phosphorylation of focal adhesion kinase. This mutation also enhanced the tendency of the transmembrane helix to form homotrimers. These results suggest that homomeric associations involving transmembrane domains provide a driving force for integrin activation. They also suggest a structural basis for the coincidence of integrin activation and clustering.


Severe Obesity in Cancer Care.
Increasing weight and body fat composition has an impact on cancer detection and staging. Obese women are less likely to engage in breast and cervical screening practices. Excessive adipose tissue makes physical assessment more difficult, and patients with a BMI greater than 35 kg/m2 may have deeper and wider pelvic structures, which make internal examinations problematic. A retrospective review of 324 primary surgical patients found that patients with a BMI greater than 40 kg/m2 are seven times less likely to undergo complete surgical staging for endometrial cancer compared with individuals with a BMI less than 40 kg/m2. In addition, healthcare provider bias against the need for screening, feelings of discomfort and embarrassment, as well as patient's fears of guilt, humiliation, and shame pose significant barriers to addressing the issue of obesity in clinical care with patients and family members. .


Comparison of impact and cost-effectiveness of rotavirus supplementary and routine immunization in a complex humanitarian emergency, Somali case study.
A humanitarian emergency involves a complete breakdown of authority that often disrupts routine health care delivery, including immunization. Diarrheal diseases are a principal cause of morbidity and mortality among children during humanitarian emergencies. The objective of this study was to assess if vaccination against rotavirus, the most common cause of severe diarrhea among children, either as an addition to routine immunization program (RI) or supplemental immunization activity (SIA) would be cost-effective during a humanitarian emergency to decrease diarrhea morbidity and mortality, using Somalia as a case study. An impact and cost-effectiveness analysis was performed comparing no vaccine; two-dose rotavirus SIA and two-dose of RI for the 424,592 births in the 2012 Somali cohort. The main summary measure was the incremental cost per disability-adjusted life-year (DALY) averted. Univariate sensitivity analysis examined the extent to which the uncertainty in the variables affected estimates. If introduced in Somalia, a full-series rotavirus RI and SIA would save 908 and 359 lives, respectively, and save US$63,793 and US$25,246 in direct medical costs, respectively. The cost of a RI strategy would be US$309,458. Because of the high operational costs, a SIA strategy would cost US$715,713. US$5.30 per DALY would be averted for RI and US$37.62 per DALY averted for SIA. Variables that most substantially influenced the cost-effectiveness for both RI and SIA were vaccine program costs, mortality rate, and vaccine effectiveness against death. Based on our model, rotavirus vaccination appears to be a cost-effective intervention as either RI or SIA, as defined by the World Health Organization as one to three times the per capita Gross Domestic Product (Somalia $112 in 2011). RI would have greater health impact and is more cost effective than SIA, assuming feasibility of reaching the target population. However, given the lack of infrastructure, whether RI is realistic in this setting remains unanswered, and alternative approaches like SIA should be further examined.


Evaluating the utility of mid-infrared spectral subspaces for predicting soil properties.
We propose four methods for finding local subspaces in large spectral libraries. The proposed four methods include (a) cosine angle spectral matching; (b) hit quality index spectral matching; (c) self-organizing maps and (d) archetypal analysis methods. Then evaluate prediction accuracies for global and subspaces calibration models. These methods were tested on a mid-infrared spectral library containing 1907 soil samples collected from 19 different countries under the Africa Soil Information Service project. Calibration models for pH, Mehlich-3 Ca, Mehlich-3 Al, total carbon and clay soil properties were developed for the whole library and for the subspace. Root mean square error of prediction was used to evaluate predictive performance of subspace and global models. The root mean square error of prediction was computed using a one-third-holdout validation set. Effect of pretreating spectra with different methods was tested for 1st and 2nd derivative Savitzky-Golay algorithm, multiplicative scatter correction, standard normal variate and standard normal variate followed by detrending methods. In summary, the results show that global models outperformed the subspace models. We, therefore, conclude that global models are more accurate than the local models except in few cases. For instance, sand and clay root mean square error values from local models from archetypal analysis method were 50% poorer than the global models except for subspace models obtained using multiplicative scatter corrected spectra with which were 12% better. However, the subspace approach provides novel methods for discovering data pattern that may exist in large spectral libraries.


Combined optical and acoustical detection of single microbubble dynamics.
A detailed understanding of the response of single microbubbles subjected to ultrasound is fundamental to a full understanding of the contrast-enhancing abilities of microbubbles in medical ultrasound imaging, in targeted molecular imaging with ultrasound, and in ultrasound-mediated drug delivery with microbubbles. Here, single microbubbles are isolated and their ultrasound-induced radial dynamics recorded with an ultra-high-speed camera at up to 25 million frames per second. The sound emission is recorded simultaneously with a calibrated single element transducer. It is shown that the sound emission can be predicted directly from the optically recorded radial dynamics, and vice versa, that the nanometer-scale radial dynamics can be predicted from the acoustic response recorded in the far field.


Not letting the left leg know what the right leg is doing: limb-specific locomotor adaptation to sensory-cue conflict.
We investigated the phenomenon of limb-specific locomotor adaptation in order to adjudicate between sensory-cue-conflict theory and motor-adaptation theory. The results were consistent with cue-conflict theory in demonstrating that two different leg-specific hopping aftereffects are modulated by the presence of conflicting estimates of self-motion from visual and nonvisual sources. Experiment 1 shows that leg-specific increases in forward drift during attempts to hop in place on one leg while blindfolded vary according to the relationship between visual information and motor activity during an adaptation to outdoor forward hopping. Experiment 2 shows that leg-specific changes in performance on a blindfolded hopping-to-target task are similarly modulated by the presence of cue conflict during adaptation to hopping on a treadmill. Experiment 3 shows that leg-specific aftereffects from hopping additionally produce inadvertent turning during running in place while blindfolded. The results of these experiments suggest that these leg-specific locomotor aftereffects are produced by sensory-cue conflict rather than simple motor adaptation.


Demonstration and evaluation of a method for assessing mediated moderation.
Mediated moderation occurs when the interaction between two variables affects a mediator, which then affects a dependent variable. In this article, we describe the mediated moderation model and evaluate it with a statistical simulation using an adaptation of product-of-coefficients methods to assess mediation. We also demonstrate the use of this method with a substantive example from the adolescent tobacco literature. In the simulation, relative bias (RB) in point estimates and standard errors did not exceed problematic levels of +/- 10% although systematic variability in RB was accounted for by parameter size, sample size, and nonzero direct effects. Power to detect mediated moderation effects appears to be severely compromised under one particular combination of conditions: when the component variables that make up the interaction terms are correlated and partial mediated moderation exists. Implications for the estimation of mediated moderation effects in experimental and nonexperimental research are discussed.


Prior poliomyelitis-reduced capillary supply and metabolic enzyme content in hypertrophic slow-twitch (type I) muscle fibres.
Capillary supply and oxidative and glycolytic enzyme activities were determined in muscle biopsies from the tibialis anterior muscle in six prior polio patients and a control group. The polio patients, who had paresis and atrophy, but were able to walk normally by making maximal use of all remaining anterior tibial motor units, showed type I (slow-twitch) muscle fibre predominance with a mean (SD) of 98 (2%) type I fibres versus 81 (8)% in the controls (p less than 0.01) and muscle fibre hypertrophy, the average type I fibre cross-sectional area being 108% (p less than 0.005) larger than in the controls. The number of capillaries per muscle fibre was not significantly different from that in the control group, but with the increased muscle fibre area in the polio patients, the capillary density was significantly lower. The number of capillaries in contact with type I fibres relative to fibre area was 40% lower in the patients than in the controls (p less than 0.005). The levels of citrate synthase and phosphofructokinase were significantly lower (38% and 33%, respectively, p less than 0.05) in the patients than in the controls, indicating decreased oxidative and glycolytic potentials in the muscle fibres of the polio patients. It is proposed that the abnormal high-frequency activation of all remaining motor units during each step cycle recorded in these patients constitutes a stimulus for type I muscle fibre predominance and hypertrophy but that the overall low muscle usage results in a decreased stimulation of capillary proliferation and mitochondrial enzyme synthesis. The low capillary density and decreased oxidative and glycolytic enzyme potentials might be important factors for the development of muscle weakness, fatigue and muscle pain, which are commonly occurring symptoms in patients with prior poliomyelitis.


CONSISTENT SELECTION OF THE NUMBER OF CHANGE-POINTS VIA SAMPLE-SPLITTING.
In multiple change-point analysis, one of the major challenges is to estimate the number of change-points. Most existing approaches attempt to minimize a Schwarz information criterion which balances a term quantifying model fit with a penalization term accounting for model complexity that increases with the number of change-points and limits overfitting. However, different penalization terms are required to adapt to different contexts of multiple change-point problems and the optimal penalization magnitude usually varies from the model and error distribution. We propose a data-driven selection criterion that is applicable to most kinds of popular change-point detection methods, including binary segmentation and optimal partitioning algorithms. The key idea is to select the number of change-points that minimizes the squared prediction error, which measures the fit of a specified model for a new sample. We develop a cross-validation estimation scheme based on an order-preserved sample-splitting strategy, and establish its asymptotic selection consistency under some mild conditions. Effectiveness of the proposed selection criterion is demonstrated on a variety of numerical experiments and real-data examples.


A Phase I, randomized, open-label study to evaluate the safety and immunogenicity of an enterovirus 71 vaccine.
Large-scale outbreaks of enterovirus 71 (EV71) infections have occurred in Asia-Pacific regions. Severe complications include encephalitis and poliomyelitis-like paralysis, cardiopulmonary collapse, and death, necessitating an effective vaccine against EV71. In this randomized Phase I study, we evaluated the safety and immunogenicity of an inactivated alum-adjuvanted EV71 whole-virus vaccine produced on Vero cell cultures. Sixty healthy volunteers aged 20-60 years received two doses of vaccine, administered 21 days apart. Each dose contained either 5 μg of EV71 antigen with 150 μg of adjuvant (Group A05) or 10 μg of EV71 antigen with 300 μg of adjuvant (Group B10). Serologic analysis was performed at baseline, day 21, and day 42. There were no serious adverse events. Mild injection site pain and myalgia were the most common adverse events with either vaccine formulation. The immunogenicity data showed that 90% of vaccine recipients have a 4-fold or greater increase in neutralization antibody titers (NT) after the first dose, without a further increase in NT after the second dose. The seroconversion rates on day 21 and day 42 were 86.7% and 93.1% respectively, in Group A05, and 92.9% and 96.3%, respectively, in Group B10. Thus, 5 μg and 10 μg of the EV71 vaccine can induce a remarkable immune response in healthy adults after only the first vaccination. The 5 μg and 10 μg adjuvanted EV71 vaccines are generally safe and immunogenic in healthy adults. (ClinicalTrials.gov number, NCT01268787).


Reduced Myxobolus cerebralis actinospore production in a Colorado reservoir may be linked to changes in Tubifex tubifex population structure.
Elucidating the dynamics of a parasitic infection requiring two hosts in a natural ecosystem can be a daunting task. Myxobolus cerebralis (Mc), the myxozoan parasite that causes whirling disease in some salmonids, was detected in the Colorado River upstream of Windy Gap Reservoir (WGR) in 1988. Subsequently, whirling disease was implicated in the decline of wild Rainbow Trout Oncorhynchus mykiss in the river when WGR was identified as a point source of Mc triactinomyxons (TAMs). Between 1997 and 2004, numerous investigations began to elucidate the etiology of Mc in WGR. During this period, Mc TAM production in WGR declined more than 90%. Explanations for the decline have included differences in stream discharge between years, changes in the thermal regime of the lake, severe drought, changes in the fish population structure in WGR, and reductions in the prevalence and severity of Mc infection in salmonids in the Colorado and Fraser rivers upstream of WGR. All of these have been discredited as explanations for the reduced TAM production. In 2005, a new study was conducted to replicate the studies completed in 1998. In this paper, the results of a new real-time polymerase chain reaction assay utilized to quantify the mitochondrial 16S rDNA specific to each of four lineages of Tubifex tubifex in pooled samples of 50 oligochaetes are presented. These results suggest that compared with 1998, the densities of aquatic oligochaetes and T. tubifex have increased, TAM production has been greatly reduced, and the decline is congruent with the dominance of lineages I, V, and VI of T. tubifex-three lineages that are refractory or highly resistant to Mc infection-in the oligochaete population. While it is possible that the resistant lineages function as biofilters that deactivate Mc myxospores, the reason for the decline in TAM production in WGR remains an enigma.


IL-1 alpha or tumor necrosis factor-alpha stimulate release of three NAP-1/IL-8-related neutrophil chemotactic proteins in human dermal fibroblasts.
Human dermal fibroblasts in culture secrete three protein-like neutrophil chemotactic factors, when stimulated either with human rIL-1 alpha or IL-1 beta; not, however, after incubation with LPS. These three fibroblast-derived neutrophil-activating proteins (FINAP) could be purified by subsequently performed reversed phase and size exclusion HPLC. By high resolution SDS-PAGE, all the proteins were shown to migrate with an Mr of 6,700 (alpha-FINAP), 3,600 (beta-FINAP), and 5,300 (gamma-FINAP). All purified cytokine preparations were found to be chemotactic for human neutrophils. In addition, all FINAP induced release of lysosomal enzymes in neutrophils. Deactivation of chemotaxin-elicitable enzyme release showed cross-desensitization of all FINAP with NAP-1/IL-8. Western blot analysis of alpha-FINAP by using mAb against neutrophil-activating protein (NAP)-1/IL-8 reveals immunologic cross-reactivity with NAP-1/IL-8. By amino-terminal amino acid sequence analysis alpha-FINAP could be identified as the 77-residue extended form of NAP-1/IL-8 containing the 79-residue form as a minor contaminant. Whereas beta-FINAP has been found to be a truncation product of alpha-FINAP, gamma-FINAP shows identity with authentic melanoma growth stimulatory activity with respect to retention time upon reversed phase HPLC, high resolution SDS-PAGE, and biologic properties, as well as amino-terminal amino acid sequence. These data show that human dermal fibroblasts may actively participate in inflammatory reactions by secretion of proinflammatory cytokines.


Knowledge and practice of prechewing/prewarming food by HIV-infected women.
HIV transmission has been associated with offering a child food prechewed by an HIV-infected caregiver. We assessed awareness of prechewing and oral prewarming of food by an adult before offering it to a child among HIV-infected pregnant women and clinical investigators in 3 Latin American countries. HIV-infected pregnant women at 12 sites (Eunice Kennedy Shriver National Institute of Child Health and Human Development International Site Development Initiative Perinatal Longitudinal Study in Latin American Countries, a prospective cohort trial) in Argentina, Brazil, and Peru were administered a screening survey about prechewing/prewarming of infant foods and cautioned against these feeding practices. Survey responses were analyzed, overall, and stratified according to country. Of the 401 HIV-infected pregnant women interviewed, 34% had heard about prechewing (50% from Argentina, 32% from Brazil, and 36% from Peru), 23% knew someone who prechewed food for infants, and 4% had prechewed food in the past. Seventeen percent had heard about oral prewarming of food, 13% knew someone who prewarmed food for infants, and 3% had prewarmed food for an infant in the past. Women who reported knowing someone who prechewed were more likely to also know someone who prewarmed food (P < .0001). Few site investigators anticipated that their patients would be aware of these practices. Prechewing food, a potential risk factor for HIV transmission, and orally prewarming food, which has not been associated with HIV transmission but might expose a child to blood from an HIV-infected adult, are not uncommon practices in Latin America. Both practices should be further investigated. Site investigator responses underscore that health care providers could be missing information about cultural practices that patients may not report unless specifically asked.


First study of on-treatment volumetric imaging during respiratory gated VMAT.
To obtain on-treatment volumetric patient anatomy during respiratory gated volumetric modulated arc therapy (VMAT). On-board imaging device integrated with Linacs offers a viable tool for obtaining patient anatomy during radiation treatment delivery. In this study, the authors acquired beam-level kV images during gated VMAT treatments using a Varian TrueBeam™STx Linac. These kV projection images are triggered by a respiratory gating signal and can be acquired immediately before treatment MV beam on at every breathing cycle during delivery. Because the kV images are acquired with an on-board imaging device during a rotational arc therapy, they provide the patient anatomical information from many different angles or projection views (typically 20-40). To reconstruct the volumetric image representing patient anatomy during the VMAT treatment, the authors used a compressed sensing method with a fast first-order optimization algorithm. The conventional FDK reconstruction was also used for comparison purposes. The method was tested on a dynamic anthropomorphic physical phantom as well as a lung patient. The reconstructed volumetric images for a dynamic anthropomorphic physical phantom and a lung patient showed clearly visible soft-tissue target as well as other anatomical structures, with the proposed compressed sensing-based image reconstruction method. Compared with FDK, the compressed sensing method leads to a ≈ two and threefold increase in contrast-to-noise ratio around the target area in the phantom and patient case, respectively. The proposed technique provides on-treatment volumetric patient anatomy, with only a fraction (<10%) of the imaging dose used in conventional CBCT procedures. This anatomical information may be valuable for geometric verification and treatment guidance, and useful for verification of treatment dose delivery, accumulation, and adaptation in the future.


Non-invasive terahertz imaging of tissue water content for flap viability assessment.
Accurate and early prediction of tissue viability is the most significant determinant of tissue flap survival in reconstructive surgery. Perturbation in tissue water content (TWC) is a generic component of the tissue response to such surgeries, and, therefore, may be an important diagnostic target for assessing the extent of flap viability in vivo. We have previously shown that reflective terahertz (THz) imaging, a non-ionizing technique, can generate spatially resolved maps of TWC in superficial soft tissues, such as cornea and wounds, on the order of minutes. Herein, we report the first in vivo pilot study to investigate the utility of reflective THz TWC imaging for early assessment of skin flap viability. We obtained longitudinal visible and reflective THz imagery comparing 3 bipedicled flaps (i.e. survival model) and 3 fully excised flaps (i.e. failure model) in the dorsal skin of rats over a postoperative period of 7 days. While visual differences between both models manifested 48 hr after surgery, statistically significant (p < 0.05, independent t-test) local differences in TWC contrast were evident in THz flap image sets as early as 24 hr. Excised flaps, histologically confirmed as necrotic, demonstrated a significant, yet localized, reduction in TWC in the flap region compared to non-traumatized skin. In contrast, bipedicled flaps, histologically verified as viable, displayed mostly uniform, unperturbed TWC across the flap tissue. These results indicate the practical potential of THz TWC sensing to accurately predict flap failure 24 hours earlier than clinical examination.


Atypical clinical variants in New World cutaneous leishmaniasis: disseminated, erysipeloid, and recidiva cutis due to Leishmania (V.) panamensis.
In recent times, there has been an increase in the number of reports for new and rare variants of cutaneous leishmaniasis (CL). Here, we describe three unusual clinical forms of CL identified in Ecuadorian children. A total of 131 patients with CL were diagnosed over a 2-year period of active search. In 3 (2.29%), the lesions were very unusual; these included erysipeloid, recidiva cutis (LRC), and disseminated leishmaniasis (DL). The erysipeloid case is characterized by erythematous and indurated plaque seen on the face of a 5-year-old boy; the LRC one is differentiated by slowly progressing red-brown papules around large scars of healed sores in a 6-year-old girl, and the DL case is characterized by dozens of cutaneous ulcers distributed in the whole body of a 1-year-old girl. Leishmania parasites were isolated by lesion aspirate and analyzed by the technique multilocus enzyme electrophoresis (MLEE). All three isolates were identified as Leishmania (Viannia) panamensis. These distinct clinical variants rarely have been reported previously in the American cutaneous leishmaniasis, and for the first time L. (V.) panamensis was identified as the etiologic agent. Our cases extend the spectrum of clinical presentations in New World leishmaniasis.