Determination of sodium 3,4-diaminonaphthalene-1-sulfonate, a Congo Red derivative, in plasma and brain of hamsters by high-performance liquid chromatography after solid-phase extraction and ultraviolet absorbance.
In the search for compounds with similar or greater activity than Congo Red (CR) in protecting normal prion protein from being converted into the pathological form, we have synthesized various compounds which derive from CR. One of these is the sodium 3,4-diaminonaphthalene-1-sulfonate (RCA) which has an activity similar to CR in preliminary experiments. This study describes a method to determine RCA in plasma and in brain tissue by high-performance liquid chromatography (HPLC), using a solid-phase extraction and UV detection. RCA is an amphoteric molecule difficult to separate from biological matrices. Extraction was achieved by solid-phase extraction (ENV+ columns) together with the use of a counter ion. The resulting solid-phase extraction is efficient and rapid. RCA was separated on a Symmetry C18 250 x 4.6 mm I.D. 5 lm column at 1 ml/min using a 50 mM NaSO4 in 5 mM tetra-n-butylammoniumiodide (TEBA) in water-methanol (82:18, v/v) mobile phase. Retention times of RCA and I.S. were 21 and 24 min. The UV detector was set at 210 nm. The limit of quantitation was 0.5 microg/ml. The method has intra-assay and inter-assay accuracies higher than 95%, coefficients of variation ranging between 2.8 and 8.6%, and recovery rates between 74.3 and 80.1% in plasma and in brain tissue. A linear response to quantities of RCA from 0.5 to 100 microg/ml or 10 microg/g in plasma or brain was obtained. The present method allows the study of the pharmacokinetics of RCA in plasma after i.p. administration, and the distribution of the compound into the brain at the peak time.


Dementia and the law in Connecticut.
Laws pertain to almost every aspect of our lives. How a law applies to a person or one situation is dependent on many variables. One important variable is the capacity of a person to understand the ramifications of their actions. One of the most common reasons for permanent loss of decisional capacity is the development of dementia. Dementia is primarily a disease of old age. As the population of Connecticut ages and the prevalence of dementiaincreases, physicians will be presented with an increasing number of difficult decisions, where the interface between the law and medical practice will have an impact on their approach to the patient and their medical care. Familiarity with pertaining Connecticut laws and the appropriate procedures to follow as outlined by those laws will help physicians address these complex issues.


Model of 2,3-bisphosphoglycerate metabolism in the human erythrocyte based on detailed enzyme kinetic equations: in vivo kinetic characterization of 2,3-bisphosphoglycerate synthase/phosphatase using 13C and 31P NMR.
This is the first in a series of three papers [see also Mulquiney and Kuchel (1999) Biochem. J. 342, 579-594; Mulquiney and Kuchel (1999) Biochem. J. 342, 595-602] that present a detailed mathematical model of erythrocyte metabolism which explains the regulation and control of 2,3-bisphosphoglycerate (2,3-BPG) metabolism. 2,3-BPG is a modulator of haemoglobin oxygen affinity and hence plays an important role in blood oxygen transport and delivery. This paper presents an in vivo kinetic characterization of 2,3-BPG synthase/phosphatase (BPGS/P), the enzyme that catalyses both the synthesis and degradation of 2,3-BPG. Much previous work had indicated that the behaviour of this enzyme in vitro is markedly different from that in vivo. (13)C and (31)P NMR were used to monitor the time courses of selected metabolites when erythrocytes were incubated with or without [U-(13)C]glucose. Simulations of the experimental time courses were then made. By iteratively changing the parameters of the BPGS/P part of the model until a good match between the NMR-derived data and simulations were achieved, it was possible to characterize BPGS/P kinetically in vivo. This work revealed that: (1) the pH-dependence of the synthase activity results largely from a strong co-operative inhibition of the synthase activity by protons; (2) 3-phosphoglycerate and 2-phosphoglycerate are much weaker inhibitors of 2,3-BPG phosphatase in vivo than in vitro; (3) the K(m) of BPGS/P for 2,3-BPG is significantly higher than that measured in vitro; (4) the maximal activity of the phosphatase in vivo is approximately twice that in vitro, when P(i) is the sole activator (second substrate); and (5) 2-phosphoglycollate appears to play no role in the activation of the phosphatase in vivo. Using the newly determined kinetic parameters, the percentage of glycolytic carbon flux that passes through the 2, 3-BPG shunt in the normal in vivo steady state was estimated to be 19%.


The transcriptome of follicular cells: biological insights and clinical implications for the treatment of infertility.
Oocyte maturation is under strict regulatory control, not only from intrinsic cellular processes, but also extrinsic influences. While the oocyte is directly connected to the surrounding cumulus cells (CCs) via a network of gap junctions facilitating communication and exchange of molecules, it is also influenced by the greater follicular environment. In order to produce an oocyte capable of successfully transmitting the female genetic material and able to support the earliest stages of preimplantation development, cytoplasmic and nuclear maturation must be achieved. Granulosa and CCs play an essential role in the maturation and competence acquisition of the developing oocyte. The fact that these cells are closely associated with the oocyte, share the same microenvironment and can be easily collected during IVF procedures makes them attractive targets for basic research and the development of clinically relevant assays. Analysis of follicular cells is likely to reveal important information concerning the viability and genetic constitution of their associated oocyte, as well as increase our understanding of normal follicular processes and the impact of disorders or of medical interventions such as controlled ovarian stimulation (COS). This review summarizes results obtained during the investigation of granulosa and CCs, and considers the possibilities of using follicular cells as surrogate markers of stimulation response during IVF, oocyte/embryo competence and clinical outcome. In order to summarize the current knowledge obtained from the analysis of follicular cells, a thorough literature search was carried out. Relevant research articles published in English up to March 2013 were reviewed. Multiple groups of genes expressed in follicular cells have been identified as possible indicators of ovulation, oocyte maturity, fertilization, chromosome status, ability to generate embryos capable of reaching the blastocyst stage of development, embryo morphology and the establishment of a pregnancy. However, there is a general lack of uniformity concerning groups of gene biomarkers among different studies. Extensive investigation of genes and proteins of granulosa and CCs has provided a detailed insight into the follicular microenvironment surrounding oocytes. It was evident from the data reviewed that the gene expression of follicular cells influences and is influenced by the oocyte, affecting factors such as maturity, chromosomal constitution, viability and competence. However, a general lack of overlap among genes identified as potentially useful biomarkers suggests that the transcriptome of follicular cells could be affected by multiple intrinsic factors, having to do with the patient and possibly the aetiology of infertility, as well as extrinsic factors, such as hormonal stimulation. Further work is required in order to establish a universally applicable, non-invasive test for the determination of oocyte competence based upon follicular cell assessment.


Polyphosphate-accumulating bacterial community colonizing the calcium bodies of terrestrial isopod crustaceans Titanethes albus and Hyloniscus riparius.
Terrestrial isopods from the group Trichoniscidae accumulate calcium in specialized organs, known as the calcium bodies. These consist of two pairs of epithelial sacs located alongside the digestive system. These organs contain various forms of calcium and constantly present bacteria. To elucidate their origin and role, we analyzed the bacteria of the calcium bodies in the cave-dwelling isopod Titanethes albus and the epigean species Hyloniscus riparius, by microscopy, histochemistry, energy dispersive X-ray spectrometry, 16S rRNA analysis and in situ hybridization. The calcium bodies of both species comprise numerous and diverse bacterial communities consisting of known soil bacteria. Despite their diversity, these bacteria share the polyphosphate-accumulation ability. We present the model of phosphorous dynamics in the calcium bodies during the molting cycle and potentially beneficial utilization of the symbiotic phosphate by the host in cyclic regeneration of the cuticle. Although not fully understood, this unique symbiosis represents the first evidence of polyphosphate-accumulating bacterial symbionts in the tissue of a terrestrial animal.


Quaternary Centers by Nickel-Catalyzed Cross-Coupling of Tertiary Carboxylic Acids and (Hetero)Aryl Zinc Reagents.
This work bridges a gap in the cross-coupling of aliphatic redox-active esters with aryl zinc reagents. Previously limited to primary, secondary, and specialized tertiary centers, a new protocol has been devised to enable the coupling of general tertiary systems using nickel catalysis. The scope of this operationally simple method is broad, and it can be used to simplify the synthesis of medicinally relevant motifs bearing quaternary centers.


Function and mechanisms of memory destabilization and reconsolidation after retrieval.
Memory retrieval is not a passive process. When a memory is retrieved, the retrieved memory is destabilized, similar to short-term memory just after learning, and requires memory reconsolidation to re-stabilize the memory. Recent studies characterizing destabilization and reconsolidation showed that a retrieved memory is not always destabilized and that there are boundary conditions that determine the induction of destabilization and reconsolidation according to certain parameters, such as the duration of retrieval and the memory strength and age. Moreover, the reconsolidation of contextual fear memory is not independent of memory extinction; rather, these memory processes interact with each other. There is an increasing number of findings suggesting that destabilization following retrieval facilitates the modification, weakening, or strengthening of the original memory, and the resultant updated memory is stabilized through reconsolidation. Reconsolidation could be targeted therapeutically to improve emotional disorders such as post-traumatic stress disorder and phobia. Thus, this review summarizes recent findings to understand the mechanisms and function of reconsolidation.


Evaluating the Contextual Integrity of Australia's My Health Record.
My Health Record (MyHR) is Australia's national personally-controlled electronic health record. Initially established in 2012, it moved from an opt-in to an opt-out system in 2018. This paper considers the privacy aspects of MyHR shared health summary. Drawing on Nissenbaum's theory of privacy as contextual integrity, we argue that the shift in the event-specific nature of information sharing leads to MyHR breaching contextual integrity. As per Nissenbaum's decision heuristic for contextual integrity, we evaluate this breach through a reflection on the changing nature of health care, including patient empowerment, and the greater complexity of care. It is evident that more needs to be known about the benefits of shared health summaries, as well as the actual use of MyHR by clinicians and patients. Though we focus on MyHR, this evaluation has broader applicability to other national electronic health records and electronic shared health summaries.


Highly conserved influenza A sequences as T cell epitopes-based vaccine targets to address the viral variability.
Vaccines are the only proven effective method for prevention of human infectious diseases. Almost all traditional vaccines require activating immunological memory B cells to secrete neutralizing antibodies against invading pathogens. The complication with influenza viruses is the high viral mutation rate that results in immune escape through modification of the B cell epitopes. Studies of T-cell immunity to influenza infection provide an alternative vaccine strategy based on highly conserved T-cell epitopes. In this review, we discuss the importance of T cell-mediated immunity in influenza infection and the need for a targeted vaccine approach focused on highly conserved T-cell epitopes to mitigate immune escape. We propose 15 highly conserved pan-influenza sequences as possible T cell epitopes-based vaccine targets for broad protection and lasting immunity against variant influenza strains.


Long-Term Outcome of Patients with Perimembranous Ventricular Septal Defect: Results from the Belgian Registry on Adult Congenital Heart Disease.
Studies evaluating the long-term outcome of adults with ventricular septal defect (VSD) are important to inform patients about prognosis. This study investigated the long-term outcome of patients with perimembranous VSD (pmVSD) followed in the Belgian Registry on Adult Congenital Heart Disease. All pmVSD patients in the registry were analyzed. Two hundred and sixty-six patients were studied. Fifteen patients had Eisenmenger syndrome. One hundred and seventy-three had isolated pmVSD and 78 had pmVSD with concomitant lesions. Of the patients with isolated pmVSD, 52% were male, median age was 29 years (IQR 24-35 years) and median follow-up duration was 18 years (IQR 10-25 years). Fifty-three (31%) patients underwent VSD closure and 10 (19%) had a residual shunt. Most (93%) patients were in NYHA class I. No patients died. Two (4%) patients developed atrial arrhythmia and 2 (4%) required pacemaker implantation. Seven (14%) developed left ventricular outflow tract obstruction (LVOTO). In the unrepaired pmVSD group, 4 developed endocarditis. In the entire group, moderate or severe aortic regurgitation (AR) occurred in 9 (5%) patients. Long-term survival in patients with isolated pmVSD was not uneventful. Moderate or severe AR might develop and endocarditis occurred in patients without VSD repair. Complications after VSD closure included atrial arrhythmia, pacemaker implantation and LVOTO.


Persistent primitive trigeminal artery associated with a cavernous carotid aneurysm. Case report and literature review.
The persistent primitive trigeminal artery is the most common persistent carotid-vertebrobasilar anastomosis. Patients are usually asymptomatic and the persistent primitive trigeminal artery is commonly found incidentally on imaging. Rarely, they may present with symptoms of neurovascular conflict or cranial nerve compression syndromes as the artery may be intimately related to the cranial nerves. The basilar artery is often hypoplastic in this condition and blood supply to the posterior circulation is predominantly via the persistent primitive trigeminal artery. Recognizing the persistent primitive trigeminal artery is imperative as disease of the artery may result in ischemia of the posterior circulation. To date, there is no clear association between this artery and cerebral aneurysms. We present a rare case of a patient with a persistent primitive trigeminal artery and a concomitant cavernous carotid aneurysm together with a literature review.


Disruption of the thrombospondin-2 gene alters the lamellar morphology but does not permit vascularization of the adult mouse lumbar disc.
The biological basis for the avascular state of the intervertebral disc is not well understood. Previous work has suggested that the presence of thrombospondin-1 (TSP-1), a matricellular protein, in the outer annulus reflects a role for this protein in conferring an avascular status to the disc. In the present study we have examined thrombospondin-2 (TSP-2), a matricellular protein with recognized anti-angiogenic activity in vivo and in vitro. We examined both the location and expression of TSP-2 in the human disc, and its location in the disc and bordering soft tissues of 5-month-old normal wild-type (WT) mice and of mice with a targeted disruption of the TSP-2 gene. Immunohistochemistry and quantitative histology were utilized in this study. TSP-2 was found to be present in some, but not all, annulus cells of the human annulus and the mouse annulus. Although there was no difference in the number of disc cells in the annulus of TSP-2-null mice compared with that of WT animals, polarized light microscopy revealed a more irregular lamellar collagen structure in null mouse discs compared with WT mouse discs. Additionally, vascular beds at the margins of discs of TSP-2-null mice were substantially more irregular than those of WT animals. Counts of platelet endothelial cell adhesion molecule-1-positive blood vessels in the tissue margin bordering the ventral annulus showed a significantly larger vascular bed in the tissue bordering the disc of TSP-2-null mice compared with that of WT mice (P = 0.0002). There was, however, no vascular ingrowth into discs of the TSP-2-null mice. These data confirm a role for TSP-2 in the morphology of the disc and suggest the presence of other inhibitors of angiogenesis in the disc. We have shown that although an increase in vasculature was present in the TSP-2-null tissue in the margin of the disc, vascular ingrowth into the body of the disc did not occur. Our results point to the need for future research to understand the transition from the well-vascularized status of the fetal and young discs to the avascular state of the adult human disc or the small mammalian disc.


Three-Dimensional Spirothienoquinoline-Based Small Molecules for Organic Photovoltaic and Organic Resistive Memory Applications.
A new electron-rich spirothienoquinoline unit, tBuSAF-Th, has been developed via incorporation of a thienyl unit instead of a phenyl unit into the six-membered ring of the spiroacridine (SAF) and utilized for the first time as a building block for constructing small-molecule electron donors in organic solar cells (OSCs) and as active layers in organic resistive memory devices. The resulting three-dimensional spirothienoquinoline-containing 1-4 exhibit high-lying highest occupied molecular orbital (HOMO) energy levels. By the introduction of electron-deficient benzochalcogenodiazole linkers, with the chalcogen atoms being varied from O to S and Se, a progressively lower lowest unoccupied molecular orbital (LUMO) energy level has been achieved while keeping the HOMO energy levels similar. This strategy has allowed an enhanced light-harvesting ability without compromising open-circuit voltage (Voc) in vacuum-deposited bulk heterojunction OSCs using 1-4 as donors and C70 as the acceptor. Good photovoltaic performances with power conversion efficiencies (PCEs) of up to 3.86% and high short-circuit current densities (Jsc) of up to 10.84 mA cm-2 have been achieved. In addition, organic resistive memory devices fabricated with these donor-acceptor small molecules exhibit binary logic memory behaviors with long retention times and high on/off current ratios. This work indicates that the spirothienoquinoline moiety is a potential building block for constructing multifunctional organic electronic materials.


Pontibacter terrae sp. nov., isolated from soil.
A bacterial strain, designated 17SD1-15T, was isolated from soil. Cells of this strain were Gram-stain-negative and aerobic rods. The major fatty acids of strain 17SD1-15T were iso-C15 : 0 and summed feature 4 (anteiso-C17 : 1 B and/or iso-C17 : 1 I). The polar lipids were phosphatidylethanolamine, one phospholipid and five unidentified lipids. The G+C content of the genomic DNA of strain 17SD1-15T was 49.0 mol%. The 16S rRNA gene sequence analysis showed that strain 17SD1-15T was phylogenetically related to Pontibacter saemangeumensis GCM0142T, Pontibacter korlensis X14-1T, Pontibacter yuliensis H9XT, Pontibacter diazotrophicus H4XT and Pontibacter humi SWU8T (98.3, 96.4, 96.4, 96.4 and 96.0 % sequence similarity, respectively). DNA-DNA relatedness between 17SD1-15T and the most closely related type strain of Pontibacter species was 42.9±0.8 %. The low level of DNA-DNA relatedness identified strain 17SD1-15T as a member of a novel species in the genus Pontibacter. The results of genotypic and phenotypic data, including chemotaxonomic traits, showed that strain 17SD1-15T could be distinguished from its phylogenetically related species. Therefore, strain 17SD1-15T represents a novel species within the genus Pontibacter, for which the name Pontibacter terrae sp. nov. is proposed, with the type strain 17SD1-15T (=KCTC 52915T=NBRC 113057T).


Implementing evidence-based practice for patients with chronic fatigue syndrome.
The aim of our study was to explore whether community-based mental health care centres (MHCs) are able to implement and sustain cognitive behaviour therapy (CBT) for chronic fatigue syndrome (CFS) with the help of an implementation manual. We monitored the implementation process and treatment outcome data of three Dutch MHCs that implemented or sustained CBT for CFS, one in the context of a stepped care programme. We compared these data with findings of other treatment studies conducted in the context of CBT for CFS. All three MHCs included at least 40 patients with dropout rates between 15% and 35% from intention-to-treat to second assessment. Effect sizes ranged between 0.88 and 1.76 for changes in fatigue severity and 0.43 and 1.23 for changes in physical functioning. With one exception, these outcomes were within the range of our benchmark. Contrary to original expectations, we provided additional implementation support to the two MHCs new with CBT for CFS. We concluded that our implementation manual does not seem to substitute external support for team leaders and associated professions during initial implementation of CBT for CFS but may have the potential to make this assistance more efficient. Particular attention should be paid to challenges of implementing stepped care for CFS. Implementation of CBT for CFS in community-based MHCs was monitored. External support was provided in addition to an implementation manual during initial implementation of CBT for CFS. Participating MHCs were generally capable of successfully implementing and delivering CBT for CFS. Implementation of low-intensity interventions for CFS might better be postponed until therapists have sufficient experience with conventional CBT for CFS.


Clinical utility of neuronal cells directly converted from fibroblasts of patients for neuropsychiatric disorders: studies of lysosomal storage diseases and channelopathy.
Methodologies for generating functional neuronal cells directly from human fibroblasts [induced neuronal (iN) cells] have been recently developed, but the research so far has only focused on technical refinements or recapitulation of known pathological phenotypes. A critical question is whether this novel technology will contribute to elucidation of novel disease mechanisms or evaluation of therapeutic strategies. Here we have addressed this question by studying Tay-Sachs disease, a representative lysosomal storage disease, and Dravet syndrome, a form of severe myoclonic epilepsy in infancy, using human iN cells with feature of immature postmitotic glutamatergic neuronal cells. In Tay-Sachs disease, we have successfully characterized canonical neuronal pathology, massive accumulation of GM2 ganglioside, and demonstrated the suitability of this novel cell culture for future drug screening. In Dravet syndrome, we have identified a novel functional phenotype that was not suggested by studies of classical mouse models and human autopsied brains. Taken together, the present study demonstrates that human iN cells are useful for translational neuroscience research to explore novel disease mechanisms and evaluate therapeutic compounds. In the future, research using human iN cells with well-characterized genomic landscape can be integrated into multidisciplinary patient-oriented research on neuropsychiatric disorders to address novel disease mechanisms and evaluate therapeutic strategies.


QMLS: quaternion mutual learning strategy for multi-modal brain tumor segmentation.
Due to non-invasive imaging and the multimodality of Magnetic Resonance Imaging (MRI) images, MRI-based multi-modal brain tumor segmentation (MBTS) studies are attracting more and more attention in recent years. With the great success of convolutional neural networks (CNN) in various computer vision tasks, lots of MBTS models have been proposed to address the technical challenges of MBTS. However, the problem of limited data collection usually exists in MBTS tasks, making existing studies usually have difficulty in fully exploring the multi-modal MRI images to mine complementary information among different modalities.
Approach: We propose a novel Quaternion Mutual Learning Strategy (QMLS), which consists of a voxel-wise lesion knowledge mutual learning mechanism (VLKML mechanism) and a quaternion multimodal feature learning module (QMFL module). Specifically, VLKML mechanism allows the networks to converge to a robust minimum so that aggressive data augmentation techniques can be applied to fully expand the limited data. In particular, quaternion-valued QMFL module treats different modalities as components of quaternions to sufficiently learn complementary information among different modalities on the hypercomplex domain while significantly reduces the number of parameters by about 75\%.
Main results: Extensive experiments on the dataset BraTS 2020 and BraTS 2019 indicate that QMLS achieves superior results to current popular methods with less computational cost.
Significance: We propose a novel algorithm to brain tumor segmentation task and achieves better performance with fewer parameters, which helps the clinical application of automatic brain tumor segmentation.


Extrapulmonary radioactivity in lung permeability measurements.
The pulmonary clearance rate of aerosolized and deposited [99mTc]DTPA is used to assess pulmonary epithelial permeability to solutes. To evaluate whether it is necessary to correct these measurements for radioactivity in the chest wall and pulmonary vasculature five patients with no ventilation to one hemithorax were studied. After inhaling a submicronic aerosol of [99mTc]DTPA a gamma camera measured count rates over both hemithoraces for 20 min. The observed T1/2 for clearance from the normal hemithorax was 56 min (range 18-115 min), and when this was corrected for chest wall contribution (derived from the abnormal hemithorax) the average T1/2 was 52 min (range 17-107 min). To simulate infinitely permeable lungs we measured thoracic radioactivity in two adults and six children who were injected i.v. with a known amount of [99mTc]DTPA. The count rate over the thorax was only 8.1% (range 2.7%-11%) of that obtained when a similar amount of aerosolized [99mTc]DTPA was deposited in the lungs during a subsequent study. We conclude that it is not necessary to correct for nonpulmonary epithelial radioactivity during the measurement of [99mTc]DTPA clearance rate from the lungs.


BiEntropy, TriEntropy and Primality.
The order and disorder of binary representations of the natural numbers < 28 is measured using the BiEntropy function. Significant differences are detected between the primes and the non-primes. The BiEntropic prime density is shown to be quadratic with a very small Gaussian distributed error. The work is repeated in binary using a Monte Carlo simulation of a sample of natural numbers < 232 and in trinary for all natural numbers < 39 with similar but cubic results. We found a significant relationship between BiEntropy and TriEntropy such that we can discriminate between the primes and numbers divisible by six. We discuss the theoretical basis of these results and show how they generalise to give a tight bound on the variance of Pi(x)-Li(x) for all x. This bound is much tighter than the bound given by Von Koch in 1901 as an equivalence for proof of the Riemann Hypothesis. Since the primes are Gaussian due to a simple induction on the binary derivative, this implies that the twin primes conjecture is true. We also provide absolutely convergent asymptotes for the numbers of Fermat and Mersenne primes in the appendices.


A two-stage hepatectomy procedure combined with portal vein embolization to achieve curative resection for initially unresectable multiple and bilobar colorectal liver metastases.
To assess outcome after a 2-stage hepatectomy procedure (TSHP) combined with portal vein embolization (PVE) in the treatment of patients with unresectable multiple and bilobar colorectal liver metastases (MBCLM). Patients with MBCLM are often considered for palliative chemotherapy only, due to too small future remnant liver (FRL). Recently, right hepatectomy with simultaneous left liver wedge resections after previous right PVE has been reported in a curative intent. However, the growth of metastatic nodules in FRL after PVE can be more rapid than that of the nontumoral remnant hepatic parenchyma. Therefore, metastases located in the FRL should be ideally resected before PVE. Then, a right (or extended right) hepatectomy can be safely performed during a second-stage hepatectomy. Therefore, we analyzed our experience with the use of TSHP combined with PVE in treatment of MBCLM. Between December 1996 and April 2003, 33 patients with unresectable MBCLM were selected for a TSHP. A right or an extended right hepatectomy was planned after treatment of left FRL metastases to achieve a curative resection. The first-stage hepatectomy consisted in a clearance of the left hemiliver by resection or radiofrequency destruction of metastases of the left FRL. Subsequently, a right PVE was performed to induce atrophy of the right hemiliver and hypertrophy of the left hemiliver. Finally, a second-stage hepatectomy was planned to resect the right liver metastases. There was no operative mortality. Post-PVE morbidity was 18.1%; postoperative morbidity was 15.1% and 56.0% after first- and second-stage hepatectomy, respectively. TSHP could be achieved in 25 of 33 patients (75.7%). The 1- and 3-year survival rates were 70.0% and 54.4%, respectively, in the 25 patients in whom the TSHP was completed. In selected patients with initially unresectable MBCLM, a TSHP combined with PVE can be achieved safely with long-term survival similar to that observed in patients with initially resectable liver metastases.


A humanized mouse model identifies key amino acids for low immunogenicity of H7N9 vaccines.
Influenza vaccines of H7N9 subtype are consistently less immunogenic in humans than vaccines developed for other subtypes. Although prior immunoinformatic analysis identified T-cell epitopes in H7 hemagglutinin (HA) which potentially enhance regulatory T cell response due to conservation with the human genome, the links between the T-cell epitopes and low immunogenicity of H7 HA remains unknown due to the lack of animal models reproducing the response observed in humans. Here, we utilized a humanized mouse model to recapitulate the low immunogenicity of H7 HA. Our analysis demonstrated that modification of a single H7 epitope by changing 3 amino acids so that it is homologous with a known H3 immunogenic epitope sequence significantly improved the immunogenicity of the H7 HA in the humanized mouse model, leading to a greater than 4-fold increase in HA-binding IgG responses. Thus, we provide experimental evidence for the important contribution of this H7-specific T cell epitope in determining the immunogenicity of an influenza vaccine. Furthermore, this study delineates strategies that can be used for screening and selecting vaccine strains using immunoinformatics tools and a humanized mouse model.


Multiple confidence estimates as indices of eyewitness memory.
Eyewitness identification decisions are vulnerable to various influences on witnesses' decision criteria that contribute to false identifications of innocent suspects and failures to choose perpetrators. An alternative procedure using confidence estimates to assess the degree of match between novel and previously viewed faces was investigated. Classification algorithms were applied to participants' confidence data to determine when a confidence value or pattern of confidence values indicated a positive response. Experiment 1 compared confidence group classification accuracy with a binary decision control group's accuracy on a standard old-new face recognition task and found superior accuracy for the confidence group for target-absent trials but not for target-present trials. Experiment 2 used a face mini-lineup task and found reduced target-present accuracy offset by large gains in target-absent accuracy. Using a standard lineup paradigm, Experiments 3 and 4 also found improved classification accuracy for target-absent lineups and, with a more sophisticated algorithm, for target-present lineups. This demonstrates the accessibility of evidence for recognition memory decisions and points to a more sensitive index of memory quality than is afforded by binary decisions.


Role of wound instillation with bupivacaine through surgical drains for postoperative analgesia in modified radical mastectomy.
Modified Radical Mastectomy (MRM) is the commonly used surgical procedure for operable breast cancer, which involves extensive tissue dissection. Therefore, wound instillation with local anaesthetic may provide better postoperative analgesia than infiltration along the line of incision. We hypothesised that instillation of bupivacaine through chest and axillary drains into the wound may provide postoperative analgesia. In this prospective randomised controlled study 60 patients aged 45-60 years were divided into three groups. All patients were administered general anaesthesia. At the end of the surgical procedure, axillary and chest wall drains were placed before closure. Group C was the control with no instillation; Group S received 40 ml normal saline, 20 ml through each drain; and Group B received 40 ml of 0.25% bupivacaine and the drains were clamped for 10 min. After extubation, pain score for both static and dynamic pain was evaluated using visual analog scale and then 4(th) hourly till 24 h. Rescue analgesia was injection tramadol, if the pain score exceeds 4. Statistical analysis was performed using SPSS version 13. There was a significant difference in the cumulative analgesic requirement and the number of analgesic demands between the groups (P: 0.000). The mean duration of analgesia in the bupivacaine group was 14.6 h, 10.3 in the saline group and 4.3 h in the control group. Wound instillation with local anaesthetics is a simple and effective means of providing good analgesia without any major side-effects.


High intensity interval exercise increases the frequency of peripheral PD-1+ CD8+ central memory T-cells and soluble PD-L1 in humans.
Exercise can exert anti-inflammatory effects in an intensity-dependent manner; however, the mechanisms mediating these effects are continually being established. Programme Death Receptor-1 (PD-1) is a membrane bound receptor that maintains immune tolerance by dampening immune cell interactions, such as those mediated by cytotoxic T-cell lymphocytes (CD8+). The aim of this study was to characterise sub-populations of CD8+ T-cells with regards to their expression of PD-1 before and immediately after exercise. Interleukin (IL)-6, soluble PD-1 (sPD-1) and its ligand (sPD-L1) were also quantified in plasma. Eight individuals (mean ± SD: age 29 ± 5 years; BMI 24.2 ± 3.4 kg m2; V ˙ O2max 44.5 ± 6.4 ml kg-1·min-1) undertook two time and energy-matched cycling bouts in a counterbalanced study design: one of moderate intensity (MOD) and a bout of high intensity interval exercise (HIIE). Both MOD and HIIE increased the number, but not the proportion of circulating CD8+ PD-1+ cells, with no differences between trials. Within the CD8+ PD-1+ pool, the expression of PD-1 increased on central memory cells following HIIE only (fold change: MOD 1.0 vs HIIE +1.4), as well the concentration of CD8+PD-1+ memory cells within the circulation (cells/uL: MOD -0.4 vs HIIE +5.8). This response composed a very small part of the exercise-induced CD8+ lymphocytosis (Pre-Ex: 0.38% to Post-Ex: 0.69%; p > 0.05). sPD-L1 and IL-6 concentration increased in tandem following MOD and HIIE (r = 0.57; P = 0.021), with a reciprocal decline in sPD-1 observed. The current data demonstrate that PD-1+ CD8+ lymphocytes were mobilised following both MOD and HIIE. Both the number of central memory CD8+ T-cells expressing PD-1 and the expression level on these cells were increased following HIIE only. This intensity-dependent phenotypic response, in conjunction with increased circulatory sPD-L1 may represent an aspect of the anti-inflammatory response to exercise and warrants further investigation.


In Vitro Biomedical and Photo-Catalytic Application of Bio-Inspired Zingiber officinale Mediated Silver Nanoparticles.
To minimize the hazardous effect of physical and chemical synthesis of nanoparticles we focused on the green synthesis of nanoparticles. Nanotechnology is a research hotspot and catch great attention because of its versatile applications in medical, biosciences and engineering fields. Purpose of our recent study is to synthesize bio-inspired metallic silver NPs by root mediated Zingiber officianale extract. The synthesized Ag-NPs were further characterized by using UVVisible spectroscopy, XRD, EDX, SEM, TEM and DLS techniques. The extent of crystallites were confirmed by X-ray diffraction. SEM and TEM revealed the morphological features with size of nanoparticles between 17.3 and 41.2 nm. FTIR analysis confirmed the capping of nanoparticles by bio active constituents present in Zingiber officinale extract. Later EDX confirmed the elemental composition of nanoparticles. Zeta potential, PDI and hydrodynamic size of Ag-NPs were confirmed by DLS. The synthesize Ag-NPs possess eminent biological potency against bacterial and leishmanial strains. Moreover considerable anti-diabetic, anticancer, antioxidant and biocompatibility nature of Ag-NPs was elucidated. The highest antioxidant activity of 50.61± 1.12%, 38.22 ± 1.18% and 27.39 ± 0.92 at 200 g/mL for TAC, TRP DPPH and was observed respectively. Ag-NPs exhibit potent leishmanicidal activity of 80% ± 1.4 against promastigotes and 77% ± 1.6 against amastigotes cultures of L. tropica. Highest antidiabetic activity 30 ± 0.77% recorded at 200 μg/ml. Highest Brine shrimps cytotoxicity of Ag-NPs was 60 ± 1.18 at 200 g/ml. Maximum dye degradation for Ag-NPs was recorded as 94.1% at 140 minute. All UTI isolates were resistant to antibiotics not coated with Ag-NPs. By applying 1% of Ag-NPs highest activity was recorded as 25 ± 1.58 mm against K. pneumoniae. Maximum zone of inhibition for Ag-NPs coated with Imipenem antibiotics 26 ± 1.5 mm against K. pneumoniae and coated with Ciprofloxacin 26 ± 1.4 m against S. aureus were measured. Last but not least high biocompatible nature of Ag-NPs was observed against fresh RBCs making the ecofriendly biosynthesized silver NPs a multi-dimensional candidate in biomedical field.


Hereditary pancreatitis as the premalignant disease: a Japanese case of pancreatic cancer involving the SPINK1 gene mutation N34S.
Mutations in the cationic trypsinogen gene are acknowledged as a risk factor for pancreatic cancer in patients with hereditary pancreatitis. However, whether patients with mutations in other genes, such as the serine protease inhibitor Kazal type 1 (SPINK1) gene, are also at a higher risk of pancreatic cancer remains unknown. We report a case of pancreatic cancer associated with chronic calcifying pancreatitis in a patient with a homozygous N34S mutation in the SPINK1 gene. A 44-year-old woman was hospitalized due to obstructive jaundice. Preoperative examination showed a tumor in the head of the pancreas and multiple pancreatic stones; pancreatoduodenectomy revealed a solid tumor, 3.0 x 2.5 cm in size, in the head of the pancreas, and numerous pancreatic stones throughout the pancreas. Pathologic studies revealed moderately differentiated tubular adenocarcinoma. Mutational analyses of the SPINK1 and PRSS1 genes in members of the patient's family were carried out. The homozygous N34S mutation in the SPINK1 gene was found in the patient and her older sister, who was previously diagnosed with chronic calcific pancreatitis and had undergone the Frey operation. The patient's parents and brother were unaffected carriers of the N34S heterozygous mutation. No family members had any mutations in the cationic trypsinogen gene. To our knowledge, this is the first reported case of chronic pancreatitis accompanied by pancreatic cancer in a patient with the SPINK1 N34S mutation. Although this case does not meet the classic criteria of hereditary pancreatitis, it does suggest that the SPINK1 N34S mutation may be associated with cancer development in patients with hereditary pancreatitis. Further prospective, multicenter trials investigating secondary screening for pancreatic cancer in hereditary pancreatitis are necessary to clarify the role of SPINK1 mutations in the development of pancreatic cancer.


Disseminated and circulating tumor cells: Role in effective cancer management.
Dissemination of tumor cells from primary tumors in the circulatory system is an early event in carcinogenesis. The presence of these single disseminated tumor cells (DTC) in peripheral blood, bone marrow and distant organs is the rationale for adjuvant systemic treatment. Detection of DTC in bone marrow aspirates from breast cancer patients and other solid tumors at the primary diagnosis impacts the prognosis of disease. In peripheral blood these cells are termed as circulating tumor cells (CTC). Due to technical difficulties the clinical significance of CTC detection at early stages is less established. This review focuses on available techniques for detection of DTC and CTC, recent technical advances in development of more sensitive microfluidic methods for capture of DTC and CTC and possibilities for further detection and their potential molecular characterization. Not only the clinical significance of DTC but also the presence of cancer stem cells in dissemination clearly demonstrates the need for development of sensitive technologies allowing for definition of biomarkers and molecular targets on cells in dissemination, thus eventually leading to optimization of systemic therapies.


Three-Dimensional Mass Spectrometry Imaging Reveals Distributions of Lipids and the Drug Metabolite Associated with the Enhanced Growth of Colon Cancer Cell Spheroids Treated with Triclosan.
The application of mass spectrometry imaging (MSI) to explore the responses of cancer cell spheroids (CCS) after treatment of exogenous molecules has attracted growing attention. Increasing studies have utilized MSI to image the two-dimensional distributions of exogenous and endogenous molecules in planar CCS sections. However, because CCS are volumetric and heterogenous, maintaining their three-dimensional (3D) information is essential for acquiring a better understanding of the tumor microenvironment and mechanisms of action of exogenous molecules. Here, an established method of 3D MSI was applied to distinguish the distributions of triclosan sulfate and endogenous lipids in three microregions of colon CCS with an enhanced growth induced by the treatment of triclosan, a common antimicrobial agent. The results of 3D MSI showed that triclosan sulfate gradually accumulated from the periphery to the entire structure of CCS and finally localized in the core region. Spatial lipidomics analysis revealed that the upregulated phosphatidylethanolamine (fold change (FD) = 1.26, p = 0.0021), phosphatidylinositol (FD = 1.17, p = 0.0180), and phosphatidylcholine (FD = 1.22, p = 0.0178) species mainly distributed in the outer proliferative region, while the upregulated sphingomyelin (FD = 1.18, p = 0.024) species tended to distribute in the inner necrotic region. Our results suggest that a competitive mechanism between inhibiting and promoting CCS growth might be responsible for the proliferation of CCS treated with triclosan.


Surface Collective Modes in the Topological Insulators Bi_{2}Se_{3} and Bi_{0.5}Sb_{1.5}Te_{3-x}Se_{x}.
We used low-energy, momentum-resolved inelastic electron scattering to study surface collective modes of the three-dimensional topological insulators Bi_{2}Se_{3} and Bi_{0.5}Sb_{1.5}Te_{3-x}Se_{x}. Our goal was to identify the "spin plasmon" predicted by Raghu and co-workers [Phys. Rev. Lett. 104, 116401 (2010)]. Instead, we found that the primary collective mode is a surface plasmon arising from the bulk, free carriers in these materials. This excitation dominates the spectral weight in the bosonic function of the surface χ^{"}(q,ω) at THz energy scales, and is the most likely origin of a quasiparticle dispersion kink observed in previous photoemission experiments. Our study suggests that the spin plasmon may mix with this other surface mode, calling for a more nuanced understanding of optical experiments in which the spin plasmon is reported to play a role.


Effects of contrast and size on orientation discrimination.
Motivated by the recent physiological finding that a neuron's receptive field can increase in size by a factor of 2-4-fold at low contrast [Nat. Neurosci. 2 (1999) 733, Proc. Natl. Acad. Sci. USA 96 (1999) 12073], we sought to examine whether a psychophysical task might reflect the contrast dependent changes in the size/structure of a receptive field. We postulate that since spatial summation is not contrast invariant, a task that relies on the spatial structure of a receptive field, such as orientation discrimination, should also be affected by changes in contrast. Previously, orientation discrimination thresholds have been reported to be roughly independent of the contrast of a stimulus for most of the visible range of contrasts [i.e. J. Neurophysiol. 57 (1987) 773, J. Opt. Soc. Am. 6 (1989) 713, Vis. Res. 30 (1990) 449, Vis. Res. 39 (1999) 1631]. Here, we found large improvements in orientation discrimination with contrast that were dependent on stimulus area. Furthermore, the apparent constancy of orientation discrimination for large area stimuli is possibly a result of a floor effect on the threshold. Therefore we conclude that there is not strong evidence for contrast invariant orientation discrimination. We interpret these results in the context of recent neurophysiological results about the expansion of cortical cells' receptive fields at low contrast.


Chronic cough: an approach to management.
Management of chronic cough is complex and warrants careful evaluation. Some patients cough for years without help because of the indiscriminate use of antitussive medications. All patients should be evaluated in a specific manner. The cause of cough can be found and effectively treated in almost all patients. Antitussive therapy should only be used as adjuvant therapy or when a cause cannot be found and the patient is not harmed by decreasing the cough. When used, the safest, least expensive antitussive drug should be instituted for a limited time pending re-evaluation of the patient's clinical course.


Using two self-developed InDel panels to explore forensic feature and population genetic structure in the Hui group.
To address the challenges faced by forensic examiners in degraded DNA analysis, we have developed two different panels for various forensic applications, encompassing the AIM-InDel panel for ancestry inference and the Multi-InDel panel for individual identification, respectively. Herein, the efficiencies of these two panels were tested in the Chinese Hui group. By calculating forensic parameters and simulating family relationships, we verified that the Multi-InDel panel could be an effective tool for individual identification, paternity testing, and could assist in kinship identification in the Hui group. For full siblings, the accuracy of kinship discrimination was 98.895%. The cumulative probability of matching as well as cumulative probability of exclusion was 3.8117 × 10-26 and 0.999999722, respectively. Meanwhile, we found that the AIM-InDel panel was effective for bio-geographic ancestry inference, with the vast majority of loci contributing significantly to distinguish East Asian, African, and European populations. By studying the population structure of the Hui ethnic minority, the genetic distance to the Beijing Han population was the closest among the 26 reference populations, which was similar to previous reports. In summary, we have developed two panels that can be effectively applied to the Hui group for individual identification, parentage testing and bio-geographic ancestry inference.


Evaluation of the CAM treatment for amblyopia: a controlled study.
Single letter and linear acuity (near and distance) and contrast sensitivity were measured in 15 amblyopes (ages 5 to 12) before, during, and after four weekly 7 min sessions of CAM treatment. Six of the children, however, played games over a homogeneous grey disc having the same space-averaged luminance as that of the striped stimuli. Experimental and controls results were indistinguishable. In a few subjects from both groups, contrast sensitivity and slight linear acuity improvement was observed. We conclude that these vision changes can be attributed to the short-term occlusion experienced by all subjects during treatment and that grating stimulation did not contribute to this improvement.


[Ultrasonography in urinary tract infection in infancy].
In a prospective study 77 infants (35 boys) with a mean age of 5.23 months were studied to determine the value of sonography for detection of renal parenchymal involvement in urinary tract infection (UTI). Sonography was performed during UTI and about one month later. UTI was classified as upper and lower UTI according to the clinical and laboratory findings; radiological investigations (voiding cystoureterography = MCU) were performed in all infants. 40 infants were classified to have upper UTI. There was a high sensitivity (80%) and specificity (97%) for detection of renal involvement by sonography. Incidence for vesicoureteral reflux (VUR) was significantly higher in infants with repeated pathological findings on sonography. In contrast, no VUR was detected on MCU in all 12 infants with normal findings in both sonographic examinations. Yet, sonography without catheterization could not detect VUR in all infants with radiologically confirmed reflux. Our results show, that sonography is of definite value in infants with UTI, but cannot replace radiological work up.


Reduction of neuromuscular activity is required for the rescue of motoneurons from naturally occurring cell death by nicotinic-blocking agents.
Spinal motoneurons (MNs) in the chick embryo undergo programmed cell death coincident with the establishment of nerve-muscle connections and the onset of synaptic transmission at the neuromuscular junction. Chronic treatment of embryos during this period with nicotinic acetylcholine receptor (nAChR)-blocking agents [e.g., curare or alpha-bungarotoxin (alpha-BTX)] prevents the death of MNs. Although this rescue effect has been attributed previously to a peripheral site of action of the nAChR-blocking agents at the neuromuscular junction (NMJ), because nAChRs are expressed in both muscle and spinal cord, it has been suggested that the rescue effect may, in fact, be mediated by a direct central action of nAChR antagonists. By using a variety of different nAChR-blocking agents that target specific muscle or neuronal nAChR subunits, we find that only those agents that act on muscle-type receptors block neuromuscular activity and rescue MNs. However, paralytic, muscular dysgenic mutant chick embryos also exhibit significant increases in MN survival that can be further enhanced by treatment with curare or alpha-BTX, suggesting that muscle paralysis may not be the sole factor involved in MN survival. Taken together, the data presented here support the argument that, in vivo, nAChR antagonists promote the survival of spinal MNs primarily by acting peripherally at the NMJ to inhibit synaptic transmission and reduce or block muscle activity. Although a central action of these agents involving direct perturbations of MN activity may also play a contributory role, further studies are needed to determine more precisely the relative roles of central versus peripheral sites of action in MN rescue.


Petroleum: tar quantities floating in the northwestern atlantic taken with a new quantitative neuston net.
The neuston net has been modified to obtain quantitative samples of surface zooplankton. Petroleum lumps are commonly taken with these nets, and quantities of tar up to almost 0.1 gram (wet weight) per cubic meter of filtered surface water have been taken in the northwestern Atlantic. This information is used to estimate the quantity of tar lumps present in the North Atlantic and to indicate the probable limits of the degree of existing oil pollution in this region. It is suggested that previous estimates of ocean oil pollution may be too low.


Studies on thymus function. I. Cooperative effect of thymic function and lymphohemopoietic cells in restoration of neonatally thymectomized mice.
Immunological restoration of 45-day old, neonatally thymectomized C3Hf mice by treatment with humoral thymic function (thymoma grafts, thymus or thymoma in diffusion chambers) ranges from 0 to 12% and is difficult to acheive. When small numbers (5-20 x 10(6)) of young adult lymphohemopoietic cells, ineffective by themselves, are given in association with humoral thymic function, a cooperative effect is observed and restoration ranges from 30 to 60%. With a particular cell dosage (20 x 10(6)), effectivity for cooperation with thymic function was the following in decreasing order: spleen, lymph nodes, thoracic duct cells, bone marrow, blood leukocytes, thymus, and Peyer's patch cells. Comparable results were obtained using spleen, thymus, and hemopoietic liver from newborn donors in association with thymic function. For similar cell dosages, newborn thymus cells were more effective than adult thymus in their cooperative effect with thymic function. Dispersed thymus cells in association with young adult bone marrow or newborn hemopoietic liver cells showed no synergism for the cooperative effect with thymic function in the present model. Using hemiallogeneic cells (F(1) hybrid into parent) it was possible to show that restoration was mediated by proliferative expansion of the injected cells. This was indicated by specific tolerance to tissues of the other parental strain and by cellular chimerism, especially of lymphoid tissues, as indicated by chromosome markers and absence of significant numbers of immunocompetent cells of host origin. A population of paritally differentiated cells of hemopoietic origin, termed postthymic, sensitive to humoral activity of the thymus and present in the lymphohemopoietic tissues of adult and newborn mice is postulated to explain our results. These cells are postthymic and thymus dependent in the sense that they already received thymic influence, probably through traffic, and are incapable of self-renewal in absence of the thymus. Sensitivity to humoral activity of the thymus is characterized by proliferative expansion and/or a differentiative process eventually leading to larger numbers of competent cells.


Joint hypermobility, growing pain and obesity are mutually exclusive as causes of musculoskeletal pain in schoolchildren.
Chronic musculoskeletal pain (MSP) is common in children and can be due to several non-inflammatory conditions such as the benign joint hypermobility syndrome (BJHS), and growing pains (GP). We evaluated frequency, risk factors and causes of MSP in a large cohort of healthy schoolchildren. We conducted a cross sectional study in a cohort of healthy schoolchildren, aged 8-13 years, by collecting information and performing a physical examination. The anamnesis was focused on family history for MSP, presence and sites of MSP interfering with the regular daily activities during the previous 6 months and presence of GP. Physical examination included body mass index, pubertal stage and musculoskeletal examination focused on the presence of hypermobility according to the Beighton criteria. Two hundred and eighty-nine schoolchildren, 143 females and 146 males, participated in the study. Chronic MSP occurred in 30.4% of subjects, BJHS occurred in 13.2%. GJH was more frequent in symptomatic subjects than in asymptomatic ones (p=0.054). Symptomatic subjects were more frequently pre-pubertal than pubertal (p=0.006). In general, GP, BJHS and obesity (OB) were mutually exclusive as causes of MSP as, among 88 symptomatic subjects, 52.3% had GP, 40.9% presented BJHS, 4.5% were OB and only two (2.3%) presented both BJHS and OB. After puberty, GP persisted in 66.7%, BJHS in 26.7% and in association with OB in 6.7%. Approximately one third of schoolchildren suffer from MSP. BJHS, GP and OB are mutually exclusive as causes of MSP in schoolchildren. Pubertal stage plays an important role in the physiopathology of this condition.


Molecular approaches for neuropathic pain treatment.
Neuropathic pain is initiated or caused by a primary lesion or dysfunction in the nervous system. It is estimated that 75-150 million people in the United States have a chronic pain disorder. Neuropathic pain has a great impact on the quality of life. It is debilitating and often has an associated degree of depression that contributes to decreasing human wellbeing. Moreover, the management of chronic pain is costly to the health care system. The United States Congress has declared the present decade (2001-2010) as the "Decade of Pain Control and Research", making pain a national healthcare priority. In Europe, statistics provided by the International Association on the Study of Pain (IASP) and the European Federation of the IASP Chapters (EFIC) indicate that one in five people suffer from moderate to severe chronic pain, and that one in three are unable or less able to maintain an independent lifestyle due to their pain. Between one-half and two-thirds of people with chronic pain are less able or unable to exercise, enjoy normal sleep, perform household chores, attend social activities, drive a car, walk or have sexual relations. The effect of pain means that one in four reports that relationships with family and friends are strained or broken, according to the IASP/EFIC data. Neuropathic pain treatment is extremely difficult. Neuropathic pain is a very complex disease, involving several molecular pathways. Excitatory or inhibitory pathways controlling neuropathic pain development show altered gene expression, caused by peripheral nerve injury. Current available drugs are usually not acting on the several mechanisms underlying the generation and propagation of pain. Nowadays, pain research is directing on new molecular methods, such as gene therapy, stem cell therapy and viral vectors for delivery of biologic antinociceptive molecules. These methods could provide a new therapeutic approach to neuropathic pain relief.


The NRF2‑PGC‑1β pathway activates kynurenine aminotransferase 4 via attenuation of an E3 ubiquitin ligase, synoviolin, in a cecal ligation/perforation‑induced septic mouse model.
Sepsis‑associated encephalopathy (SAE) is a systemic inflammatory response syndrome of which the precise associated mechanisms remain unclear. Synoviolin (Syvn1) is an E3 ubiquitin ligase involved in conditions associated with chronic inflammation, including rheumatoid arthritis, obesity, fibrosis and liver cirrhosis. However, the role of Syvn1 in acute inflammation is not clear. The aim of the present study was to investigate the role of Syvn1 in a septic mouse model induced by cecal ligation/perforation (CLP). Metabolome analysis revealed that kynurenine (KYN), a key factor for the development of neuroinflammation, was increased in CLP‑induced septic mice. Notably, KYN was not detected in CLP‑induced septic Syvn1‑deficient mice. KYN is converted to kynurenic acid (KYNA) by kynurenine aminotransferases (KATs), which has a neuroprotective effect. The expression of KAT4 was significantly increased in Syvn1‑deficient mice compared to that in wild‑type mice. Promoter analysis demonstrated that Syvn1 knockdown induced the KAT4 promoter activity, as assessed by luciferase reporter activity, whereas Syvn1 overexpression repressed this activity in a dose‑dependent manner. Furthermore, the KAT4 promoter was significantly activated by the transcriptional factors, NF‑E2‑related factor 2 and peroxisome proliferator‑activated receptor coactivator 1β, which are targets of Syvn1‑induced degradation. In conclusion, the results of the current study demonstrates that the repression of Syvn1 expression induces the conversion of neurotoxic KYN to neuroprotective KYNA in a CLP‑induced mouse model of sepsis, and that Syvn1 is a potential novel target for the treatment of SAE.


NOD1 contributes to mouse host defense against Helicobacter pylori via induction of type I IFN and activation of the ISGF3 signaling pathway.
Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular epithelial cell protein known to play a role in host defense at mucosal surfaces. Here we show that a ligand specific for NOD1, a peptide derived from peptidoglycan, initiates an unexpected signaling pathway in human epithelial cell lines that results in the production of type I IFN. Detailed analysis revealed the components of the signaling pathway. NOD1 binding to its ligand triggered activation of the serine-threonine kinase RICK, which was then able to bind TNF receptor-associated factor 3 (TRAF3). This in turn led to activation of TANK-binding kinase 1 (TBK1) and IkappaB kinase epsilon (IKKepsilon) and the subsequent activation of IFN regulatory factor 7 (IRF7). IRF7 induced IFN-beta production, which led to activation of a heterotrimeric transcription factor complex known as IFN-stimulated gene factor 3 (ISGF3) and the subsequent production of CXCL10 and additional type I IFN. In vivo studies showed that mice lacking the receptor for IFN-beta or subjected to gene silencing of the ISGF3 component Stat1 exhibited decreased CXCL10 responses and increased susceptibility to Helicobacter pylori infection, phenotypes observed in NOD1-deficient mice. These studies thus establish that NOD1 can activate the ISGF3 signaling pathway that is usually associated with protection against viral infection to provide mice with robust type I IFN-mediated protection from H. pylori and possibly other mucosal infections.


Release of endogenous amino acids from the striatum from developing and adult mice in ischemia.
In most other studies the release of amino acid neurotransmitters and modulators in vitro has been studied mostly using labeled preloaded compounds. For several reasons the estimated release may not reliably reflect the release of endogenous compounds. The magnitudes of the release cannot thus be quite correctly estimated using radioactive labels. The basal and K(+)-evoked release of the neuroactive endogenous amino acids γ-aminobutyrate (GABA), glycine, taurine, glutamate and aspartate was now studied in slices from the striatum from 7-day-old to 3-month-old mice under control (normoxic) and ischemic conditions. The release of alanine, threonine and serine was assessed as control. GABA and glutamate release was much greater in 3-month-old than in 7-day-old mice, whereas with taurine the situation was the opposite. Ischemia markedly enhanced the release of all these three amino acids. The release of aspartate and glycine was markedly enhanced as well whereas no effects were discernible in the release of glutamine, alanine, serine and threonine. K(+) stimulation (50 mM) enhanced the release of GABA, glutamate, taurine, aspartate and glycine in most cases, except with taurine in 3-month-old mice under the ischemic conditions and with aspartate in 7-day-old mice under the control conditions. K(+) stimulation did not affect the release of glutamine, alanine, serine or threonine. The results on endogenous amino acids are qualitatively similar to those obtained in our earlier experiments with labeled preloaded amino acids. In conclusion, in developing mice only inhibitory taurine is released in such amounts that may counteract the harmful effects of excitatory amino acids in ischemia.


Maternal 25(OH)D concentrations ≥40 ng/mL associated with 60% lower preterm birth risk among general obstetrical patients at an urban medical center.
Given the high rate of preterm birth (PTB) nationwide and data from RCTs demonstrating risk reduction with vitamin D supplementation, the Medical University of South Carolina (MUSC) implemented a new standard of care for pregnant women to receive vitamin D testing and supplementation. To determine if the reported inverse relationship between maternal 25(OH)D and PTB risk could be replicated at MUSC, an urban medical center treating a large, diverse population. Medical record data were obtained for pregnant patients aged 18-45 years between September 2015 and December 2016. During this time, a protocol that included 25(OH)D testing at first prenatal visit with recommended follow-up testing was initiated. Free vitamin D supplements were offered and the treatment goal was ≥40 ng/mL. PTB rates (<37 weeks) were calculated, and logistic regression and locally weighted regression (LOESS) were used to explore the association between 25(OH)D and PTB. Subgroup analyses were also conducted. Among women with a live, singleton birth and at least one 25(OH)D test during pregnancy (N = 1,064), the overall PTB rate was 13%. The LOESS curve showed gestational age rising with increasing 25(OH)D. Women with 25(OH)D ≥40 ng/mL had a 62% lower risk of PTB compared to those <20 ng/mL (p<0.0001). After adjusting for socioeconomic variables, this lower risk remained (OR = 0.41, p = 0.002). Similar decreases in PTB risk were observed for PTB subtypes (spontaneous: 58%, p = 0.02; indicated: 61%, p = 0.006), by race/ethnicity (white: 65%, p = 0.03; non-white: 68%, p = 0.008), and among women with a prior PTB (80%, p = 0.02). Among women with initial 25(OH)D <40 ng/mL, PTB rates were 60% lower for those with ≥40 vs. <40 ng/mL on a follow-up test (p = 0.006); 38% for whites (p = 0.33) and 78% for non-whites (p = 0.01). Maternal 25(OH)D concentrations ≥40 ng/mL were associated with substantial reduction in PTB risk in a large, diverse population of women.


Risk-adjusted resource allocation: using Taiwan's National Health Insurance as an example.
To determine if access to medical services differed by regions and to demonstrate the extent of the differences of adopting a claims-based risk-adjustment system versus a demographic model for regional resource allocation. The claims of a 1% random sample of Taiwan's National Health Insurance enrollees (N = 173 175) in 2002 was used. The number of visits and morbidity-adjusted resource consumption were calculated individually then collapsed regionally. Regional expected resource allocation was compared with actual consumption. After controlling for diagnosis-based health measures, the average numbers of visits were stable across regions. Two models were consistent in showing over- or underutilization; the overall difference between two models in resource allocation was 5.8% at the district level. We observed strong urban overutilization and rural underutilization. Access to medical services is similar across regions. The adoption of a diagnosis-based model over a demographic-adjusted budgeting method would affect resource allocation considerably.


Induction of a passive cutaneous anaphylaxis inhibitory factor in mice.
The administration of a purified protein from Dactylis glomerata pollen, named Dactylis inhibitory protein (DIP), to Balb/C mice results in the production of a heat-resistant seric factor that blocks the passive cutaneous anaphylaxis (PCA) reaction in rat skin. This PCA inhibitory factor (PCA-IF) was purified following different purification procedures and analyzed in sodium dodecyl sulfate polyacrylamide gel. Amongst the array of bands detected it was possible to ascribe the inhibitory activity to a protein band of 76,000 daltons but only when it was associated either with another protein band of 69,000 daltons (obtained after a one-step purification procedure) or two other protein bands of 55,000 and 26,000 daltons (obtained after a three-step purification procedure). The inhibitory activity of the PCA-IF is present at a low level in normal Balb/C mice sera and is enhanced after DIP treatment of the mice.


Optical properties of alumina titanium carbide sliders used in rigid disk drives.
A common material for read-write sliders is a composite of alumina (Al(2)O(3)) and titanium carbide (TiC), with a grain size of the order of 1 mum. I derive the effective complex reflectivity of this material, using scalar diffraction theory and the known indices of refraction of Al(2)O(3) and TiC. The effective reflectivity is a function of the relative surface area of the exposed TiC grains as well as of the numerical aperture of the collection optics. The theory resolves several known discrepancies between ellipsometry and reflectometry of Al(2)O(3)-TiC. The theory also predicts a systematic error in the phase shift on reflection calculation. These results are of considerable interest for surface shape metrology of the slider as well as for optical flying-height testing and control of pole-tip recession.


Enkephalinase activity is modified and correlates with fatty acids in frontal cortex depending on fish, olive or coconut oil used in the diet.
Enkephalins are neuropeptides involved in functions such as pain modulation and/ or cognitive processes. It has been reported that dietary fat modifies enkephalins in the brain. Since enkephalins are hydrolyzed by enkephalinases, the study of the influence of dietary fats, differing in their degree of saturation, on brain fatty acids content and enkephalinase activity is important to understand its regulatory role on neuropeptides under different type of diets. We analyzed enkephalinase activity, assayed with alanine-β-naphthylamide as sub-strate, in frontal cortex of adult male rats fed diets supplemented with fish oil, olive oil or coconut oil, which markedly differed in the saturation of their fatty acids. Rats fed a diet enriched with coconut oil had lower soluble enkephalinase activity than the group fed olive oil (p<0.01) and fish oil (p<0.05) whereas rats fed a diet enriched with fish oil had lower membrane-bound enkephalinase activity than the group fed with olive (p<0.001) or coconut oil (p<0.05). Significant negative correlations were observed between certain fatty acids and enkephalinase activities in the groups fed with olive and coconut oils. No correlations were observed in the group fed with fish oil. Dietary fat modifies enkephalinase activity in the frontal cortex depending on the degree of saturation of the used oil. It is postulated that the functions, in which enkephalins are involved, such as pain modulation or cognitive functions, may also be affected according to the type of oil used in the diet.


Enantioselective radical conjugate additions driven by a photoactive intramolecular iminium-ion-based EDA complex.
The photochemical activity of electron donor-acceptor (EDA) complexes provides a way to generate radicals under mild conditions. This strategy has found application in chemical synthesis and recently in enantioselective catalysis. Reported methods classically relied on the formation of intermolecular EDA complexes, generated upon aggregation of two suitable reagents. Herein, we further expand the synthetic utility of this strategy demonstrating that an intramolecular EDA complex can trigger a photochemical catalytic enantioselective radical process. This approach enables radical conjugate additions to β-substituted cyclic enones to form quaternary carbon stereocenters with high stereocontrol using visible light irradiation. Crucial for success is the use of an amine catalyst, adorned with a carbazole moiety, which generates, upon condensation with enones, chiral iminium ions that show a broad absorption band in the visible region. This optical property originates from an intramolecular charge transfer π-π interaction between the electron-rich carbazole nucleus and the electron-deficient iminium double bond.


Carbohydrates-Key Players in Tobacco Aroma Formation and Quality Determination.
Carbohydrates are important compounds in natural products where they primarily serve as a source of energy, but they have important secondary roles as precursors of aroma or bioactive compounds. They are present in fresh and dried (cured) tobacco leaves as well. The sugar content of tobacco depends on the tobacco variety, harvesting, and primarily on the curing conditions (temperature, time and moisture). If the process of curing employs high temperatures (flue-curing and sun-curing), final sugar content is high. In contrast, when air curing has a lower temperature, at the end of the process, sugar level is low. Beside simple sugars, other carbohydrates reported in tobacco are oligosaccharides, cellulose, starch, and pectin. Degradation of polysaccharides results in a higher yield of simple sugars, but at the same time reduces sugars oxidization and transfer into carbon dioxide and water. Loss of sugar producers will compensate with added sugars, to cover undesirable aroma properties and achieve a better, pleasant taste during smoking. However, tobacco carbohydrates can be precursors for many harmful compounds, including formaldehyde and 5-hydroxymethylfurfural. Keeping in mind that added sugars in tobacco production are unavoidable, it is important to understand all changes in carbohydrates from harvesting to consuming in order to achieve better product properties and avoid the formation of harmful compounds. This review summarizes current knowledge about tobacco carbohydrates, including changes during processing with special focus on carbohydrates as precursors of harmful compounds during smoking.


May sediment contamination be xenoestrogenic to benthic fish? A case study with Solea senegalensis.
Within an environmental risk assessment framework of a moderately contaminated estuary (the Sado, SW Portugal), the present work intended to detect endocrine disruption in a flatfish, Solea senegalensis Kaup, 1858, and its potential relationship to organic toxicants. Animals were collected from two distinct areas in the estuary (industrial and rural) and from an external reference area. Hepatic vitellogenin (VTG) levels, cytochrome P450 (CYP1A) induction, ethoxyresorufin-O-deethylase (EROD) activity plus gonad histology were analysed. Males and females were sexually immature and showed no significant evidence of degenerative pathologies. However, hepatic VTG concentrations in males from the industrial area were higher than Reference, even reaching levels comparable to females, indicating low but measurable oestrogenic effects caused by the complex contaminant mixture in estuarine sediments. These individuals also presented elevated CYP1A induction and EROD activity, which is consistent with contamination by organic toxicants such as PAHs and other aryl hydrocarbon receptor (Ahr) -mediated toxicants.


Effect of asymmetric stress relaxation on the polarization-dependent transmission characteristics of a CO2 laser-written long-period fiber grating.
The effect of stress-induced birefringence on polarization-dependent transmission characteristics was thoroughly investigated for a long-period fiber grating (LPFG) that was fabricated by use of a stress relaxation method with a CO2 laser. A series of two-dimensional axial stress profiles for one complete period of a LPFG was measured with an optical tomographic measurement technique. We found that the asymmetry in the stress distribution of the cladding was much larger than in the core of the LPFG. The splitting of polarization-dependent loss peaks in the optical transmission spectrum was calculated based on the measured asymmetric stress profiles and was compared with an experimental result.


A Soft Tooling Process Chain for Injection Molding of a 3D Component with Micro Pillars.
The purpose of this paper is to present the method of a soft tooling process chain employing Additive Manufacturing (AM) for fabrication of injection molding inserts with micro surface features. The Soft Tooling inserts are manufactured by Digital Light Processing (vat photo polymerization) using a photopolymer that can withstand relatively high temperaturea. The part manufactured here has four tines with an angle of 60°. Micro pillars (Ø200 µm, aspect ratio of 1) are arranged on the surfaces by two rows. Polyethylene (PE) injection molding with the soft tooling inserts is used to fabricate the final parts. This method demonstrates that it is feasible to obtain injection-molded parts with microstructures on complex geometry by additive manufactured inserts. The machining time and cost is reduced significantly compared to conventional tooling processes based on computer numerical control (CNC) machining. The dimensions of the micro features are influenced by the applied additive manufacturing process. The lifetime of the inserts determines that this process is more suitable for pilot production. The precision of the inserts production is limited by the additive manufacturing process as well.


Adult attention-deficit/hyperactivity disorder and nicotine use: a qualitative study of patient perceptions.
Adult Attention-Deficit/Hyperactivity Disorder (ADHD) is associated with high rates of comorbid substance use disorders, and cigarette smoking has a particularly high prevalence in this population. However, there is an ongoing debate as to whether this tobacco use is an attempt at "self-medication" or due to behavioral disinhibition. There is a surprising lack of qualitative studies that investigate the subjective perceptions of adults with ADHD regarding cigarette smoking. The present study was designed to fill this gap in the literature. We recruited twelve adult patients with ADHD and comorbid tobacco use from our ADHD consultation service, an outpatient facility of the Zurich University Psychiatric Hospital. Subjects were interviewed using qualitative methodology, and Mayring's qualitative content analysis was used to evaluate findings. We identified two explanatory models linking ADHD and tobacco use: smoking as an attempt at self-medication and "smoking as a social behavior". On one hand, subjects considered tobacco a therapeutic aid, reporting positive effects on "inner tension" and cognitive function, and noted possible antidepressant properties as well. On the other hand, subjects considered smoking to enhance social functioning and to have a positive impact on interpersonal relationships. The majority believed that stimulant medications offered only a transient decrease in patterns of tobacco use because their ability to reduce nicotine cravings wore off quickly. Others believed that stimulants had no effect or even reinforced cigarette use. Participants had different views about the link between cigarette smoking and ADHD. While the majority thought of nicotine as a sort of therapy, viewing smoking as a way to self-medicate symptoms of ADHD, motivations for nicotine use were also related to self-image, desire to belong to a peer-group, and a drive to undermine perceived social norms. Ultimately, these findings can be used by clinicians to improve treatment alliance and collaboration.


Total Disc Arthroplasty Versus Anterior Interbody Fusion in the Lumbar Spine Have Relatively a Few Differences in Readmission and Short-term Adverse Events.
Retrospective matched cohort study of prospectively collected data. To compare rates of adverse events and readmission between lumbar total disc arthroplasty (TDA) and anterior lumbar interbody fusion (ALIF) using the American College of Surgeons National Surgical Quality Improvement Program database. TDA and ALIF may be considered for similar degenerative indications. However, there have been a few large-cohort comparison studies of short-term clinical outcomes for these procedures. The 2011-2015 NSQIP databases were retrospectively queried to identify patients who underwent elective stand-alone ALIF and TDA. After propensity matching, the association of procedure type with adverse events and readmission was determined using McNemar's test. Operative time and postoperative length of stay (LOS) were compared using multivariate linear regression. Risk factors for adverse events were determined using multivariate Poisson regression. In total, 1801 ALIF and 255 TDA patients were identified. After matching with propensity scores, there were no significant differences in the rates of any adverse event, serious adverse events, individual adverse events, or readmission other than blood transfusion, which occurred more frequently in the ALIF cohort (3.92% vs. 0.39%, P = 0.007). Operative time was not significantly different between the two cohorts, but postoperative LOS was significantly longer for ALIF cases (+0.28 days, P < 0.001). When evaluating 10 preoperative variables as potential risk factors for adverse events and readmission after TDA and ALIF, the majority of results were similar. The only identified differences in perioperative outcomes between TDA and ALIF were a 3.53% higher incidence of blood transfusion and 0.28-day longer LOS for the ALIF group. These results suggest overall similar short-term general-health outcomes between the two groups, and that the choice between the two procedures, for the appropriately selected patient, should be based on longer-term functional outcomes. 3.


[A mathematical model of the growth of a population of Legionella pneumophila in the presence of Tetrahymena pyriformis protozoa].
The mathematical model describing the dynamics of the growth of L. pneumophila in aqueous environment in the presence of protozoa has been worked out. The model has demonstrated considerable heterogeneity of the initial population of virulent L. pneumophila strains. The number of bacteria capable of multiplication in Infusoria is no more than 0.1% of the initial population. The time of the generation of the infective agent inside Tetrahymena pyriformis is 2.8 hours.


The relationship between released soluble FceRI-alpha and its cell surface density on human basophils.
The IgE-mediated activation of mast cells and basophils results in the secretion of many substances, including the release of FceRI-alpha subunit. This released alpha subunit can bind IgE and it may act as a down-regulator of subsequent IgE-dependent reactions. However, previous studies do not observe loss of the mass of FceRI-alpha associated with the cells, at least not for human basophils. This study was designed to understand the basis for the discordant observations. Purified human basophils were stimulated with multiple activating secretagogues and supernatants were examined for histamine and released FceRI-alpha. In addition, cell surface IgE densities (occupied and unoccupied) were measured by flow cytometry and total cellular content of mature and immature FceRI-alpha determined with Western blots. Released FceRI-alpha, on average, represented 7% of the total surface FceRI before the reaction. The molecular weight of the soluble FceRI-alpha was approximately 54 kD, larger than immature subunit and somewhat smaller than surface subunit. In addition, 1) release ceased long before internalized FceRI-alpha was processed, 2) release was insensitive to Bafilomycin A, 3) release was independent of the starting density of FceRI and 4) release occurred more effectively with non-IgE-dependent stimuli, FMLP or C5a. There appears to be relatively constant amount of nearly mature FceRI-alpha that is susceptible to secretion events induced by any form of stimulation. The amount, on average, represents about 7% of the mature form of FceRI-alpha.


[Abortion in women living in the outskirts of São Paulo: experience and socioeconomic aspects].
To compare and analyze socioeconomic aspects and the emotional experience of women with spontaneous or induced abortion and in women living in the outskirts of São Paulo. A prospective case-control study carried out from July 2008 to March 2010, involving semi-structured interviews with women who presented a previous diagnosis of abortion and who had been admitted to two public hospitals in the outskirts of São Paulo. The study included 100 women with diagnosis of abortion and were hospitalized for curettage. Eleven women who reported induced abortion (11%) represented the case group. The control group (n=22) was selected at a 2:1 ratio according to the following procedure: for every case of induced abortion, the next two cases of spontaneous abortion at the same hospital. A semistructured interview was conducted with questions regarding emotional aspects and family, social and economic context. The women with induced abortion compared to the group with spontaneous abortion had lower educational level, with more frequent elementary level (82 versus 36%, p=0.04), lower income (median, R$ 1,000.00 versus R$ 1,400.00, p=0.04), lower personal income (median, R$ 200.00 versus R$ 333.00, p=0.04), higher frequency of negative feelings upon suspicion (82 versus 22%, p=0.004) and confirmation (72 versus 22%, p=0.03) of pregnancy. Among women looking for health care in hospitals in the outskirts of São Paulo, induced abortion is related to unfavorable socioeconomic conditions, which affects the emotional experiences of suspicion and confirmation of pregnancy.


Growth and development of children of mothers with leprosy and healthy controls.
In the pre-sulphone and early sulphone years children of leprous parents had been followed in a few prospective studies to observe the development of leprosy. No studies were made of the growth and development of these children. A prospective, open-ended, cohort study began in 1975 with follow-up of both mothers and their children until 2003. 156 pregnancies were studied consisting of 36 non-leprous (NL), 25 tuberculoid and borderline tuberculoid leprosy (TT&BT) (released-from-treatment), 18 with TT&BT (active), 42 borderline lepromatous leprosy (BL) and 35 lepromatous leprosy (LL). Babies of mothers with leprosy had lower birth weight, smaller placentae, grew more slowly, had more infections and higher infant mortality than those of non-leprous mothers. The findings were most marked in babies of LL mothers. Growth in childhood was uneventful, infants of LL mothers catching up by age 3.6 years. Childhood infections were common in all groups but more serious for children of lepromatous mothers. The puberty skeletal growth spurt, and, for the girls, menarche was delayed for children studied compared with a new healthy control group, with catch-up by late teens. These findings were most marked in children of lepromatous, especially LL, mothers. Impaired growth in utero and infancy is probably due to immunological factors but we could find no explanation for the delayed growth in adolescent children of LL mothers.


Development of the PSORIQoL, a psoriasis-specific measure of quality of life designed for use in clinical practice and trials.
Patients with psoriasis have significant impairment in their quality of life (QoL). Several patient-completed instruments are available to measure outcome in dermatological conditions but these primarily focus on severity of disease rather than on QoL. To develop a new instrument specifically designed to measure QoL in psoriasis-the Psoriasis Index of Quality of Life (PSORIQoL). The content of the instrument was derived from qualitative interviews with 62 psoriasis patients in the U.K., Italy and the Netherlands. Content analysis of the interview transcripts from the three countries identified potential items for the questionnaire. All further stages of the project were conducted in the U.K. only. Face and content validity were determined by means of a focus group held with seven psoriasis patients and face-to-face interviews with a further 21 patients. A new draft version of the PSORIQoL, together with the Dermatology Life Quality Index (DLQI) and the General Well-Being Index (GWBI), were completed by a new sample of psoriasis patients contacted by mail, in order to determine construct validity. A subsample of the respondents completed a similar package 2 weeks later, to assess reproducibility (reliability). The first version of the PSORIQoL consisted of 61 items covering the needs identified in the interviews as having been affected by psoriasis or its treatment. These included fear of negative reactions from others, self-consciousness and poor self-confidence, problems with socialization, physical contact and intimacy, limitations on personal freedom and impaired relaxation, sleep and emotional stability. Following the focus group and field-test interviews, a new draft measure consisting of 45 items was completed by 148 patients, 88 of whom completed and returned a similar package 2 weeks later. Application of Rasch analysis identified a final 25-item version of the PSORIQoL. This version had a test-retest reliability coefficient of 0.89, indicating good reproducibility. The levels of association with the DLQI and PGWB indicated that the PSORIQoL measures a related but distinct construct. The PSORIQoL appears to be a practical, reliable and valid instrument for measuring the impact of psoriasis on QoL. It remains necessary to establish the instrument's responsiveness to changes in QoL associated with treatment.


Biological factors and therapeutic modulation in prostate cancer radiotherapy.
Biologic factors affect the ability of radiation to effectively treat all patients with prostate cancer. The use of prognostic and genetic markers (12 lipoxygenase, p53, bc1-2 genes, ploidy) may aid in the development of treatments for these patients. Particularly, several studies have shown that p53 tumor suppressor gene mutations are infrequent in prostate cancer and are associated with advanced disease. Recent efforts have been directed toward novel therapeutic modalities, especially in combination with standard irradiation of prostate carcinoma. These modalities are based on an improved knowledge of these biological factors involved in the progression and diffusion of the tumor, especially p53. Several authors evaluated the predictive and prognostic role of p53 in patients with prostatic cancer treated with radiotherapy. An extensive review of international reports on the subject is provided.


The social conditions for successful peer education: a comparison of two HIV prevention programs run by sex workers in India and South Africa.
Peer education is a community-based intervention being implemented worldwide as an approach to HIV prevention. However, its results are inconsistent, with little consensus on why some projects succeed while others fail. Considering peer education as an 'intervention-in-context', we systematically compare the context and the implementation of two peer education interventions run by sex workers, one in India and one in South Africa, which produced contrasting outcomes. In so doing, we aim to identify key factors in the projects' successes or failures that may inform future peer education efforts. The Indian project's relative success was facilitated (1) by a more stable and supportive social, material and political context, and (2) by a community development ethos which devoted significant resources to sex workers' involvement, ownership and empowerment, as opposed to a biomedical approach which marginalised sex workers' concerns. We conclude with lessons learned and implications for current trends in peer education.


Reversing Ribot: does regression hold in language of prodromal Alzheimer's disease?
We consider the regression or retrogenesis hypothesis, which argues that order of acquisition in development is reversed in neurodegeneration or pathology. Originally proposed as a regression hypothesis for the study of memory disorders, specifically retrograde amnesia, by Ribot (1881), it has been extended to the study of brain aging and pathology and to language. We investigate this hypothesis in a new study of language development, aging, and pathology. Through interuniversity collaboration using a matched experimental design and task, we compare production of complex sentences containing relative clauses by normal monolingual children during normal development, healthy young adults, healthy aging adults, and aging adults diagnosed with mild cognitive impairment, a recognized potential harbinger of Alzheimer's disease. Our results refute the regression hypothesis in this area and lead to potential syntactic markers for prodromal Alzheimer's disease and predictions for future brain imaging analyses.


Phosphorothioate 2' deoxyribose oligomers as microbicides that inhibit human immunodeficiency virus type 1 (HIV-1) infection and block Toll-like receptor 7 (TLR7) and TLR9 triggering by HIV-1.
Topical microbicides may prove to be an important strategy for preventing human immunodeficiency virus type 1 (HIV-1) transmission. We examined the safety and efficacy of sequence-nonspecific phosphorothioate 2' deoxyribose oligomers as potential novel microbicides. A short, 13-mer poly(T) phosphorothioate oligodeoxynucleotide (OPB-T) significantly inhibited infection of primary peripheral blood mononuclear cells (PBMC) by high-titer HIV-1(Ba-L) and simian immunodeficiency virus mac251 (SIV(mac251)). Continuous exposure of human vaginal and foreskin tissue explants to OPB-T showed no toxicity. An abasic 14-mer phosphorothioate 2' deoxyribose backbone (PDB) demonstrated enhanced anti-HIV-1 activity relative to OPB-T and other homo-oligodeoxynucleotide analogs. When PDB was used to pretreat HIV-1, PDB was effective against R5 and X4 isolates at a half-maximal inhibitory concentration (IC(50)) of <1 μM in both PBMC and P4-R5 MAGI cell infections. PDB also reduced HIV-1 infectivity following the binding of virus to target cells. This novel topical microbicide candidate exhibited an excellent in vitro safety profile in human PBMC and endocervical epithelial cells. PDB also retained activity in hydroxyethylcellulose gel at pH 4.4 and after transition to a neutral pH and was stable in this formulation for 30 days at room temperature. Furthermore, the compound displayed potent antiviral activity following incubation with a Lactobacillus strain derived from normal vaginal flora. Most importantly, PDB can inhibit HIV-1-induced alpha interferon production. Phosphorothioate 2' deoxyribose oligomers may therefore be promising microbicide candidates that inhibit HIV-1 infection and also dampen the inflammation which is critical for the initial spread of the virus.