A comparison of rapid (opioid) detoxification with clonidine-assisted detoxification for heroin-dependent persons.
This study compares two methods of detoxification available to heroin users in Western Australia: clonidine-assisted detoxification (CD) or clonidine-naloxone precipitated withdrawal under sedation (rapid opioid detoxification [ROD]). Oral naltrexone was made available to all participants following detoxification. Eighty heroin-dependent persons were randomly assigned to either ROD or CD. Most undertaking ROD commenced and completed this treatment. Less than one-third undertaking CD completed this treatment. There was no significant difference in those treated by CD or ROD in subjective assessment of degree or duration of pain, severity of withdrawal and craving, nor was there an increase in the withdrawal sequelae after treatment. Induction of oral naltrexone following ROD was greater, but oral naltrexone compliance levels and abstinence from heroin four weeks following detoxification were similar between ROD and CD groups. The level of patient satisfaction between the two treatments was also similar. The authors discuss why ROD is considered more effective than CD.


Effective approaches to study the plant-root knot nematode interaction.
Plant-parasitic nematodes cause major agricultural losses worldwide. Examining the molecular mechanisms underlying plant-nematode interactions and how plants respond to different invading pathogens is attracting major attention to reduce the expanding gap between agricultural production and the needs of the growing world population. This review summarizes the most recent developments in plant-nematode interactions and the diverse approaches used to improve plant resistance against root knot nematode (RKN). We will emphasize the recent rapid advances in genome sequencing technologies, small interfering RNA techniques (RNAi) and targeted genome editing which are contributing to the significant progress in understanding the plant-nematode interaction mechanisms. Also, molecular approaches to improve plant resistance against nematodes are considered.


Type VII collagen is required for Ras-driven human epidermal tumorigenesis.
Type VII collagen defects cause recessive dystrophic epidermolysis bullosa (RDEB), a blistering skin disorder often accompanied by epidermal cancers. To study the role of collagen VII in these cancers, we examined Ras-driven tumorigenesis in RDEB keratinocytes. Cells devoid of collagen VII did not form tumors in mice, whereas those retaining a specific collagen VII fragment (the amino-terminal noncollagenous domain NC1) were tumorigenic. Forced NC1 expression restored tumorigenicity to collagen VII-null epidermis in a non-cell-autonomous fashion. Fibronectin-like sequences within NC1 (FNC1) promoted tumor cell invasion in a laminin 5-dependent manner and were required for tumorigenesis. Tumor-stroma interactions mediated by collagen VII thus promote neoplasia, and retention of NC1 sequences in a subset of RDEB patients may contribute to their increased susceptibility to squamous cell carcinoma.


Quantifying Neuromuscular Fatigue Induced by an Intense Training Session in Rugby Sevens.
To compare the sensitivity of a sprint vs a countermovement-jump (CMJ) test after an intense training session in international rugby sevens players, as well as analyze the effects of fatigue on sprint acceleration. Thirteen international rugby sevens players completed two 30-m sprints and a set of 4 repetitions of CMJ before and after a highly demanding rugby sevens training session. Change in CMJ height was unclear (-3.6%; ±90% confidence limits 11.9%. Chances of a true positive/trivial/negative change: 24/10/66%), while a very likely small increase in 30-m sprint time was observed (1.0%; ±0.7%, 96/3/1%). A very likely small decrease in the maximum horizontal theoretical velocity (V0) (-2.4; ±1.8%, 1/4/95%) was observed. A very large correlation (r = -.79 ± .23) between the variations of V0 and 30-m-sprint performance was also observed. Changes in 30-m sprint time were negatively and very largely correlated with the distance covered above the maximal aerobic speed (r = -.71 ± .32). The CMJ test appears to be less sensitive than the sprint test, which casts doubts on the usefulness of a vertical-jump test in sports such as rugby that mainly involve horizontal motions. The decline in sprint performance relates more to a decrease in velocity than in force capability and is correlated with the distance covered at high intensity.


Prenatal alcohol exposure and infant behavior: immediate effects and implications for later development.
Infants exposed to alcohol prenatally, even when they do not suffer from fetal alcohol syndrome (FAS), may be at high risk for many of the negative outcomes typically found among children of alcoholics including hyperactivity and other behavioral and learning problems. A series of studies are described designed to investigate the incidence and persistence of central nervous system (CNS) related behavioral alterations in three groups of infants born to low SES black women: (1) those who never drank in pregnancy; (2) those who drank at an average of 12 ounces of absolute alcohol (AA) per week throughout pregnancy; and (3) those who drank an equivalent amount but stopped by the second trimester of pregnancy. Only healthy, full-term infants were examined for the physical dysmorphic features associated with FAS and for behavioral alterations that could be assessed using the Brazelton Neonatal Behavioral Assessment Scale. One hundred and three neonates were examined at three days; those who had been exposed to alcohol were found to be less optimal in neurobehavioral responses. Infants whose mothers continued to drink were significantly lower on their orientation toward auditory and visual stimuli, motor performance, and autonomic regulation than the nonexposed infants. Although a second study found that some of these effects were related to neonatal withdrawal syndrome, a follow-up to 30 days of age in a subsample of the original group found that there were persistent behavioral alterations. Infants in the stopped-drinking group showed more recovery over the first month than did those in the continued-drinking group in reflexive behavior and autonomic control. A reassessment at six months of 60 of the infants who had been tested at three days indicated that differences in orientation, motor performance, reflexive behavior and autonomic control were predictive of mental and motor performance on the Bayley Scales of Infant Development. This series of studies supports the contention that the negative effects on infant behavior of prenatal alcohol exposure are both immediate and persistent.


Erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B in primary cultured human erythroid precursors.
We examined signaling by erythropoietin in highly purified human colony forming unit-erythroid cells, generated in vitro from CD34(+) cells. We found that erythropoietin induces tyrosine phosphorylation of Jak2, STAT5A, and STAT5B. Tyrosine phosphorylation of Jak2 reaches a peak around 10 minutes after stimulation and is maximum at 5 U/mL of erythropoietin. Tyrosine phosphorylation of STAT5 is accompanied by the translocation of activated STAT5 to the nucleus as shown by electrophoretic mobility shift assay (EMSA) using 32Pi-labeled STAT5 binding site in the beta-casein promoter. Tyrosine phosphorylation STAT1 or STAT3 was not detected in human erythroid precursors after stimulation with erythropoietin. Crkl, an SH2/SH3 adapter protein, becomes coimmunoprecipitated specifically with STAT5 from erythropoietin-stimulated erythroid cells; although it was shown to become associated with c-Cbl in the studies using cell lines. Thus, human erythroid precursors can be expanded in vitro in sufficient numbers and purity to allow its usage in signal transduction studies. This report sets a basis for further studies on signaling in primary cultured human erythroid precursors, which in turn contribute to our better understanding in the differentiation processes of erythrocytes and their precursors.


Describing and predicting frequent callers to an ambulance service: analysis of 1 year call data.
Ambulance services in England receive around 8 million calls a year, and no known studies have explored characteristics of frequent callers. This study aimed to identify the characteristics of the most frequent callers to Yorkshire Ambulance Service (YAS) between April 2010 and March 2011. Top 100 frequent callers to YAS were analysed using population comparison, case control and multiple regression methods. 7808 calls were made by the frequent callers, and data were analysed to predict total number of calls made, and explore characteristics of frequent callers. Six call codes were associated with a higher number of calls. Frequent callers were assigned slower response levels, or often no call code. Calls increased during the times of 4:00-9:00, 16:00-20:00 and 22:00-2:00, and in the months of December, January and February. Men and patients with all but the very highest conveyance rates had a higher number of different reasons for calling. Patients with a medical diagnosis were more likely to be conveyed, while patients with a psychiatric classification had a higher number of different reasons for calling, were older and were more likely to call for 'assault/sexual assault' or 'haemorrhage/laceration'. Frequent callers to YAS were a heterogeneous group that differed from the overall population served, resulting in numerous implications for the delivery of services for this group of patients. Further research is required to determine if and how frequent callers differ from frequent attenders at emergency departments.


Multiscale energy reallocation during low-frequency steady-state brain response.
Traditional task-evoked brain activations are based on detection and estimation of signal change from the mean signal. By contrast, the low-frequency steady-state brain response (lfSSBR) reflects frequency-tagging activity at the fundamental frequency of the task presentation and its harmonics. Compared to the activity at these resonant frequencies, brain responses at nonresonant frequencies are largely unknown. Additionally, because the lfSSBR is defined by power change, we hypothesize using Parseval's theorem that the power change reflects brain signal variability rather than the change of mean signal. Using a face recognition task, we observed power increase at the fundamental frequency (0.05 Hz) and two harmonics (0.1 and 0.15 Hz) and power decrease within the infra-slow frequency band (<0.1 Hz), suggesting a multifrequency energy reallocation. The consistency of power and variability was demonstrated by the high correlation (r > .955) of their spatial distribution and brain-behavior relationship at all frequency bands. Additionally, the reallocation of finite energy was observed across various brain regions and frequency bands, forming a particular spatiotemporal pattern. Overall, results from this study strongly suggest that frequency-specific power and variability may measure the same underlying brain activity and that these results may shed light on different mechanisms between lfSSBR and brain activation, and spatiotemporal characteristics of energy reallocation induced by cognitive tasks.


2016 SOSORT guidelines: orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth.
The International Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) produced its first guidelines in 2005 and renewed them in 2011. Recently published high-quality clinical trials on the effect of conservative treatment approaches (braces and exercises) for idiopathic scoliosis prompted us to update the last guidelines' version. The objective was to align the guidelines with the new scientific evidence to assure faster knowledge transfer into clinical practice of conservative treatment for idiopathic scoliosis (CTIS). Physicians, researchers and allied health practitioners working in the area of CTIS were involved in the development of the 2016 guidelines. Multiple literature reviews reviewing the evidence on CTIS (assessment, bracing, physiotherapy, physiotherapeutic scoliosis-specific exercises (PSSE) and other CTIS) were conducted. Documents, recommendations and practical approach flow charts were developed using a Delphi procedure. The process was completed with the Consensus Session held during the first combined SOSORT/IRSSD Meeting held in Banff, Canada, in May 2016. The contents of the new 2016 guidelines include the following: background on idiopathic scoliosis, description of CTIS approaches for various populations with flow-charts for clinical practice, as well as literature reviews and recommendations on assessment, bracing, PSSE and other CTIS. The present guidelines include a total of 68 recommendations divided into following topics: bracing (n = 25), PSSE to prevent scoliosis progression during growth (n = 12), PSSE during brace treatment and surgical therapy (n = 6), other conservative treatments (n = 2), respiratory function and exercises (n = 3), general sport activities (n = 6); and assessment (n = 14). According to the agreed strength and level of evidence rating scale, there were 2 recommendations on bracing and 1 recommendation on PSSE that reached level of recommendation "I" and level of evidence "II". Three recommendations reached strength of recommendation A based on the level of evidence I (2 for bracing and one for assessment); 39 recommendations reached strength of recommendation B (20 for bracing, 13 for PSSE, and 6 for assessment).The number of paper for each level of evidence for each treatment is shown in Table 8. The 2016 SOSORT guidelines were developed based on the current evidence on CTIS. Over the last 5 years, high-quality evidence has started to emerge, particularly in the areas of efficacy of bracing (one large multicentre trial) and PSSE (three single-centre randomized controlled trials). Several grade A recommendations were presented. Despite the growing high-quality evidence, the heterogeneity of the study protocols limits generalizability of the recommendations. There is a need for standardization of research methods of conservative treatment effectiveness, as recognized by SOSORT and the Scoliosis Research Society (SRS) non-operative management Committee.


Regulation of SMN protein stability.
Spinal muscular atrophy (SMA) is caused by mutations of the survival of motor neuron (SMN1) gene and deficiency of full-length SMN protein (FL-SMN). All SMA patients retain one or more copies of the SMN2 gene, but the principal protein product of SMN2 lacks exon 7 (SMNDelta7) and is unable to compensate for a deficiency of FL-SMN. SMN is known to oligomerize and form a multimeric protein complex; however, the mechanisms regulating stability and degradation of FL-SMN and SMNDelta7 proteins have been largely unexplored. Using pulse-chase analysis, we characterized SMN protein turnover and confirmed that SMN was ubiquitinated and degraded by the ubiquitin proteasome system (UPS). The SMNDelta7 protein had a twofold shorter half-life than FL-SMN in cells despite similar intrinsic rates of turnover by the UPS in a cell-free assay. Mutations that inhibited SMN oligomerization and complex formation reduced the FL-SMN half-life. Furthermore, recruitment of SMN into large macromolecular complexes as well as increased association with several Gemin proteins was regulated in part by protein kinase A. Together, our data indicate that SMN protein stability is modulated by complex formation. Promotion of the SMN complex formation may be an important novel therapeutic strategy for SMA.


Multispectral size-averaged incoherent spatial filtering.
A method of 2-D size-averaged incoherent recognition filtering is described. White light input illumination is used to multiplex chromatically a continuum of inputs differing in their spatial Fourier spectral magnifications. A two-grating dichromated-gelatin lateral-dispersion compensating device is inserted to correct chromatic dispersion introduced by a computer-generated hologram filter. The resulting registered recognition patterns are added to form a single effective filter size-averaged recognition peak. Using high efficiency compensating gratings and a bleached binary hologram allow the use of a relatively low-power light source.


Feeding guild of non-host community members affects host-foraging efficiency of a parasitic wasp.
Interactions between predator and prey, or parasitoid and host, are shaped by trait- and density-mediated processes involving other community members. Parasitoids that lay their eggs in herbivorous insects locate their hosts through infochemicals such as herbivore-induced plant volatiles (HIPVs) and host-produced kairomones. Hosts are frequently accompanied by non-host herbivores that are unsuitable for the parasitoid. These non-hosts may interfere with host location primarily through trait-mediated processes, by their own infochemicals, and their induction of the emission of plant volatiles. Although it is known that single non-hosts can interfere with parasitoid host location, it is still unknown whether the observed effects are due to species specific characteristics or to the feeding habits of the non-host herbivores. Here we addressed whether the feeding guild of non-host herbivores differentially affects foraging of the parasitoid Cotesia glomerata for its common host, caterpillars of Pieris brassicae feeding on Brassica oleracea plants. We used different phloem-feeding and leaf-chewing non-hosts to study their effects on host location by the parasitoid when searching for host-infested plants based on HIPVs and when searching for hosts on the plant using infochemicals. To evaluate the ultimate effect of these two phases in host location, we studied parasitism efficiency of parasitoids in small plant communities under field-tent conditions. We show that leaf-chewing non-hosts primarily affected host location through trait-mediated effects via plant volatiles, whereas phloem-feeding non-hosts exerted trait-mediated effects by affecting foraging efficiency of the parasitoid on the plant. These trait-mediated effects resulted in associational susceptibility of hosts in environments with phloem feeders and associational resistance in environments with non-host leaf chewers.


Identification of signal transduction pathways involved in constitutive NF-kappaB activation in breast cancer cells.
Nuclear factor-kappaB (NF-kappaB) is usually maintained in an inactive form in the cytoplasm through its association with inhibitor of kappaB (IkappaB) proteins, and is activated upon stimulation of cells with a variety of signals. However, constitutive activation of NF-kappaB is observed in a number of cancers including breast cancer. The signaling pathways that are involved in constitutive NF-kappaB activation remain largely unknown. Using breast cancer cell lines derived from transgenic mice that overexpress specific oncogene/growth factors in the mammary gland, we show that heregulin but not her2/neu, c-Myc or v-Ha-ras plays a major role in constitutive NF-kappaB activation. Her2/neu potentiated tumor necrosis factor alpha (TNFalpha)-inducible NF-kappaB activation whereas c-Myc potentiated 12-o-tetracecanyolphorbol-13-acetate (TPA)-induced NF-kappaB activation. Heregulin-mediated NF-kappaB activation correlated with phosphorylation of epidermal growth factor receptor (EGFR) and ErbB3 but not her2/neu. Tryphostin AG1517, which inhibits heregulin-mediated phosphorylation of EGFR, her2/neu and ErbB3 reduced NF-kappaB activation. In contrast, emodin, which blocks phosphorylation of her2/neu by heregulin, failed to reduce NF-kappaB activation. These results suggest that heregulin induces NF-kappaB independent of her2/neu. PI3 kinase/AKT, protein kinase A (PKA) and IkappaB kinase appear to be downstream signaling molecules involved in NF-kappaB activation as specific inhibitors of these kinases but not inhibitors of ERK/MAP kinase or protein kinase C reduced heregulin-mediated NF-kappaB activation. Based on these results, we propose that heregulin increases the expression of pro-invasive, pro-metastatic and anti-apoptotic genes in cancer cells through autocrine activation of NF-kappaB, which leads to invasive and drug-resistant growth of breast cancer.


Pulse oximetry correction for smoking exposure.
Pulse oximetry oxygen saturation (SpO2) does not distinguish carboxyhemoglobin (COHb) from oxyhemoglobin (O2Hb), giving a false impression of the apparent degree of oxyhemoglobin saturation in smokers who have elevated levels of COHb. We questioned whether accounting for smoking exposure history could improve description of pulse oximetry by correcting for COHb levels. We evaluated smoking history and %SpO2 as predictors of %O2Hb and %COHb by CO-oximetry of arterial blood in 18 actively smoking and 18 age-matched nonsmoking patients in a clinical pilot study. The difference between %SpO2 and %O2Hb was significantly greater (p < 0.001) in the smokers (5.6 +/- 3.1) than the nonsmokers (2.1 +/- 2.1). This difference correlated with %COHb (rp = 0.789; p < 0.001) and the smoking exposure score (SES, rp = 0.621; p < 0.001), a six-point index we developed based on whether patients were active smokers, refrained from smoking prior to testing, or were exposed to passive smoking in the home or workplace. The following formula summarizes the correction: %O2Hb = 0.882[%SpO2] - 0.968[SES] + 9.245 (rp = 0.841; SES = 2.478; p < 0.001). This pilot study suggests that smoking exposure history correlates with COHb levels and that correction for smoking exposure improves the accuracy of pulse oximetry.


New gene for bacterial blight resistance in rice located on chromosome 12 identified from minghui 63, an elite restorer line.
ABSTRACT Bacterial blight, caused by Xanthomonas oryzae pv. oryzae, is a serious disease of rice worldwide. A new dominant gene for bacterial blight resistance in rice, Xa25(t), was identified from Minghui 63, a restorer line for a number of rice hybrids that are widely cultivated in China. This gene conferred resistance to Philippine race 9 (PXO339) of X. oryzae pv. oryzae in both seedling and adult stages. It was mapped to the centromeric region of chromosome 12, 2.5 cM from a disease resistance gene-homologous sequence, NBS109, and 7.3 cM from a restriction fragment length polymorphism marker, G1314. The genomic location of this gene is similar to the previously identified blast resistance genes, Pi-ta and Pi-ta2.


Polymorphism of cytochrome p450, glutathione-s-transferase and N-acetyltransferases: influence on lung cancer susceptibility.
Lung cancer remains a major health challenge in the world. It is the commonest cause of cancer mortality in men, it has been suggested that genetic susceptibility may contribute to the major risk factor, with increasing prevalence of smoking. Lung cancer has reached epidemic proportions in India. Recently indoor air pollution and dietary factors have been implicated in the causation of lung Cancer development. Accumulating evidences have highlighted that several polymorphisms involve the metabolic activation or detoxification of carcinogens derived from cigarette smoke have been found to be associated with lung cancer risk. Many studies have focused on the relation between the distribution of polymorphic variants of different forms of the metabolic enzymes and lung cancer susceptibility, Few of human biotransformating enzymes (Phase I enzyme: Cytochrome p450 enzymes, and Phase II enzymes: Glutathione-s-transferases, N-acetyltransferases) have been implicated in the formation and scavenging of ultimate reactive metabolites. These enzyme families are known to catalyze detoxification of electrophilic compounds including carcinogens. The treatment and prevention of lung cancer are major unmet needs that can probably be improved by a better understanding of the molecular origins and evolution of the disease. This review will focus on major recent advances in the molecular study of the origins and biology of lung cancer.


The animal body plan, the prototypic body segment, and eye evolution.
Developmental genetics of Drosophila continue to have a great impact on our understanding of evolution. The specification of the body plan involves four conceptual steps: 1) Localization of maternal mRNAs in the egg cytoplasm. 2) Translation of these RNAs and formation of morphogen gradients. 3) Subdivision of the antero-posterior gradient into a repetitive pattern of body segments. 4) Assignment of a specific identity to each segment by the Hox genes. The discovery of the Hox genes has uncovered a universal principle shared by all bilaterians; they serve as master control genes specifying organization along the antero-posterior axis. The ancestral arthropods presumably consisted of a series of more or less identical segments, which may be represented by recently discovered precambrian Lobopodia which have a pair of legs and a pair of eyes in each segment. The progressive divergence of Hox genes has led to progressive cephalization and caudalization. From the amino acid sequences of the clustered homeodomains we can deduce that the mesothoracic segment represents the prototype from the more anterior and the more posterior segments evolved. Pax6 has been identified as a master control gene for eye development in all bilaterians. Since Pax6 is involved in eye development in all bilaterian phyla, this argues strongly for a monophyletic origin of the metazoan eye. With the same tool box of transcription factors all the different eye-types can be constructed.


Characterisation of G418-induced metabolic load in recombinant CHO and BHK cells: effect on the activity and expression of central metabolic enzymes.
In a previous article (Yallop and Svendsen 2001), recombinant CHO and BHK cell lines, expressing the human glucagon receptor and the gastric inhibitory peptide receptor, respectively, showed reduced growth rates and altered nutrient utilisation when grown with increasing concentrations of G418. This response was associated with an increased expression of the neo (r) protein, while expression of the recombinant membrane receptors remained unaltered. The metabolic response was characterised in both cell lines by an increase in the specific rate of glutamine utilisation and in CHO cells by a decrease in the yield of lactate from glucose, suggesting a change in the flux of glucose through central metabolism. The aim of this study was to further elucidate these metabolic changes by determining the activity and relative expression of key enzymes involved in glucose and glutamine metabolism. For both CHO and BHK cells, there was an increase in the activity of glutaminase, glutamate dehydrogenase and glutamine synthetase, suggesting an increased flux through the glutaminolysis pathway. The activity of glucose-6-phosphate dehydrogenase and pyruvate carboxylase in CHO cells was also increased whilst lactate dehydrogenase activity remained unaltered, suggesting an increased flux to the pentose phosphate pathway and TCA cycle, respectively. The activity of these enzymes in BHK cells was unchanged. Quantitative RT-PCR showed that expression levels of glutaminase and pyruvate carboxylase were the same with and without G418, indicating that the differences in activities were likely due to post-translational modifications.


Extracting the hydrodynamic resistance of droplets from their behavior in microchannel networks.
The overall traffic of droplets in a network of microfluidic channels is strongly influenced by the liquid properties of the moving droplets. In particular, the effective hydrodynamic resistance of individual droplets plays a key role in their global behavior. Here we propose two simple and low-cost experimental methods for measuring this parameter by analyzing the dynamics of a regular sequence of droplets injected into an "asymmetric loop" network. The choice of a droplet taking either route through the loop is influenced by the presence of previous droplets that modulate the hydrodynamic resistance of the branches they are sitting in. We propose to extract the effective resistance of a droplet from easily observable time series, namely, from the choices the droplets make at junctions and from the interdroplet distances. This becomes possible when utilizing a recently proposed theoretical model based on a number of simplifying assumptions. Here we present several sets of measurements of the hydrodynamic resistance of droplets, expressed in terms of a "resistance length." The aim is twofold: (1) to reveal its dependence on a number of parameters, such as the viscosity, the volume of droplets, their velocity as well as the spacing between them. At the same time (2), by using a standard measurement technique, we compare the limitations of the proposed methods. As an important result of this comparison, we obtain the range of validity of the simplifying assumptions made in the theoretical model.


Fecal microbiota transplantation for Clostridium difficile infection in patients with ileal pouches.
Background:Clostridium difficile infection (CDI) in patients with ileal pouch-anal anastomosis (IPAA) has been increasingly recognized. The aim of this study was to evaluate the outcome of fecal microbiota transplantation (FMT) in patients with pouch and CDI. Methods: All consecutive patients that underwent FMT for CDI from 2012 to 2016 were extracted from our IRB-approved, prospectively maintained Registry of Pouch Disorders. The primary outcome was negative stool tests for Clostridium difficile after FMT and the secondary outcomes were symptomatic and endoscopic responses. Results: A total of 13 patients were included in this study, with 10 being Caucasian males (76.9%). All patients had underlying ulcerative colitis for J pouch surgery. After a mean of 2.8±0.8 courses of antibiotic treatments was given and failed, 22 sessions of FMT were administered with an average of 1.7±1.1 sessions each. Within the 22 sessions, 16 were given via pouchoscopy, 4 via esophagogastroduodenoscopy and 2 via enemas. All patients tested negative on C. difficile polymerase chain reaction (PCR) after the initial FMT with a total of 7/12 (58.3%) documented patients showed symptomatic improvements and 3/11 (27.3%) patients showed endoscopic improvement according to the modified Pouchitis Disease Activity Index. During the follow-up of 1.2±1.1 years, there were a total of five patients (38.5%) that had recurrence after the successful initial treatment and four of them were successfully treated again with FMT. Conclusions: FMT appeared to be effective in eradication of CDI in patients with ileal pouches. However, FMT had a modest impact on endoscopic inflammation and recurrence after FMT and recurrence was common.


Highly luminescent, heteroatom-doped carbon quantum dots for ultrasensitive sensing of glucosamine and targeted imaging of liver cancer cells.
A novel fluorescent boronate nanoprobe has been synthesized by judiciously doping boron, nitrogen, and sulphur in carbon quantum dots (BNSCQD). Specifically, the synergistic presence of nitrogen and sulphur along with boronic acid provides excellent luminescence properties and offers recognition sites for specific sensing of glucosamine. Fluorescence intensity enhances in the presence of glucosamine because of agglomeration of luminescent centers, and thus restricts nonradiative emission channels. The detection limit of this turn on fluorescence for glucosamine is 0.7 nM in PBS. Following this protocol, for the first time, a paper based sensor strip has been prepared for naked eye detection of glucosamine with an LOD of 2.5 μM. The developed nanoprobe shows very low cytotoxicity. More interestingly, boronic acid located on the surface of BNSCQD offers molecular recognition sites for the sialyl Lewisa receptor, which is overexpressed on the surface of liver cancer cells (HepG2). The selective uptake of the BNSCQD nanoprobe in HepG2 cells compared to L929, 3T3 and PC3 cells shows its cell targeting capability.


Nafamostat mesylate, a serine protease inhibitor, demonstrates novel antimicrobial properties and effectiveness in Chlamydia-induced arthritis.
Effective treatment of reactive arthritis would ideally achieve both control of inflammation and eradication of persisting arthritogenic pathogens. We use a model of experimental Chlamydia trachomatis-induced arthritis (CtIA) to evaluate the effectiveness of nafamostat mesilate (NM), a serine protease inhibitor with complement-modifying effects and anticoagulant properties. To date clinical use of NM has largely been in Asia and has been primarily confined to inflammatory states such as pancreatitis. In vitro studies examined inhibition of Chlamydia proliferation using fibroblast cell lines as targets and phase contrast microscopy. In vivo studies used an established protocol, experimental CtIA, induced in Lewis rats by injection of synoviocyte-packaged C. trachomatis. NM was dissolved in water and administered by daily intraperitoneal injection at a dose of 10 mg/kg beginning the day prior to the administration of Chlamydia. Readouts in vivo included (i) joint swelling, (ii) histopathology scoring of severity of arthritis, (iii) host clearance of the pathogen (by ELISA, the IDEIA PCE Chlamydia). NM exerted a dose-dependent inhibition of chlamydial proliferation in vitro. Without NM, the mean number of inclusion bodies (IB) per well was 17,886 (± 1415). At 5 μg/mL NM, there were 8,490 (± 756) IB, at 25 μg/mL NM there were 35 IB and at 50 μg/mL NM no IB was observed. Chlamydial antigens in each well along the concentration gradient were assayed by ELISA, demonstrating that at 25 μg/mL NM inhibition of Chlamydia was almost complete. In the experimental arthritis model, joint swelling was significantly reduced with NM treatment: average joint width for the NM-treated animals was 8.55 mm (s.d. ± 0.6578, n = 10) versus 11.18 mm (s.d. ± 0.5672, n = 10) in controls (P < 0.001). Histopathology scoring indicated that NM resulted in a marked attenuation of the inflammatory infiltration and joint damage: mean pathology score in NM-treated animals was 10.9 (± 2.45, n = 11) versus 15.9 (± 1.45, n = 10) in controls (P < 0.0001). With respect to persistence of Chlamydia within the synovial tissues, NM treatment was accompanied by a reduction in the microbial load in the joint: mean optical density (O.D.) for ELISA with NM treatment was 0.05 (± 0.02, n = 4) versus 0.18 (± 0.05, n = 4) in controls (P < 0.001). NM is a protease inhibitor not previously recognized to possess antimicrobial properties. The present study demonstrates for the first time that NM exerts significant impact on C. trachomatis-induced arthritis and suggests that such approaches may prove clinically useful in chronic reactive arthritis.


Pneumocystis pneumonia in a non-HIV patient on chronic corticosteroid therapy: a question of prophylaxis.
A man in his late 50s with a history of membranoproliferative glomerulonephritis presented with fever and mild dyspnoea. He was HIV-negative and had been on corticosteroids as immunosuppression for 6 months prior to tapering them off 1 week before presentation. He was not taking prophylaxis for Pneumocystis jirovecii pneumonia. After unsuccessful treatment for community-acquired pneumonia, his condition worsened and he required intubation and mechanical ventilation. Full respiratory workup including bronchoscopy revealed P jirovecii as a source for the patient's infection. He was treated successfully with a 21-day course of trimethoprim-sulfamethoxazole and eventually weaned off the ventilator. He has had no complications to date. In our review of this case and the existing literature, we believe that proper utilisation of prophylaxis for pneumocystis pneumonia may have prevented our patient's transfer to intensive care unit. In our article, we discuss this issue and explore current evidence for prophylaxis.


Purification of native p94, a muscle-specific calpain, and characterization of its autolysis.
p94, a skeletal muscle-specific calpain, has attracted much attention because its gene is responsible for limb-girdle muscular dystrophy type 2A. p94, however, has not been characterized at the protein and enzyme levels, owing to its very rapid autolysis. In the present study, a purification procedure for p94 was first established by using a recombinant inactive p94 expressed in COS cells in which the active site cysteine residue was changed to serine [p94(C129S)]. The isolation of native p94 from rabbit skeletal muscle by the established method with conventional procedures was extremely difficult because p94 became highly unstable in a crude extract on the addition of NaCl for separation. Purification of native p94 was possible with an antibody-affinity column but only as an inactive enzyme; p94(C129S) was purified as a homodimer. Characterization of p94, especially autolysis, was performed with partly purified native p94 and p94(C129S). The autolysis of p94, which consisted at least partly of an intermolecular reaction, proceeded in three consecutive steps; 60 and 58 kDa fragments were produced as intermediates before a stable 55 kDa fragment appeared. Autolysis of p94 was regarded as a degradative step rather than for the activation of the enzyme. All the autolysis cleavage sites were located in the p94-specific insertion sequence 1 region, which explains why p94 is unstable compared with the other calpains. The autolysis sites in p94 clearly showed a different specificity relative to the autolytic and proteolytic cleavage sites of the ubiquitous mu- and m-calpains, in its preference for residues at the P3 to P1' sites, indicating a distinct substrate specificity and function for the muscle enzyme.


Tackling Halogenated Species with PBSA: Effect of Emulating the σ-Hole.
To model halogen-bond phenomena using classical force fields, an extra point (EP) of charge is frequently introduced at a given distance from the halogen (X) to emulate the σ-hole. The resulting molecular dynamics (MD) trajectories can be used in subsequent molecular mechanics (MM) combined with Poisson-Boltzmann and surface area calculations (PBSA) to estimate protein-ligand binding free energies (Δ Gbind). While EP addition improves the MM/MD description of halogen-containing systems, its effect on the calculation of solvation free energies (Δ Gsolv) using the PBSA approach is yet to be assessed. As the PBSA calculations depend, among other parameters, on the empirical assignment of radii (PB radii), a problematic issue arises, since standard halogen radii are smaller than the typical X···EP distances, thus placing the EP within the solvent dielectric. Herein, we took a common literature EP parametrization scheme, which uses X···EP = Rmin and RESP charges in the context of GAFF, and performed a comprehensive study on the performance of PBSA (using three different setups) in the calculation of Δ Gsolv values for 142 halogenated compounds (bearing Cl, Br, or I) for which the experimental values are known. By conducting an optimization (minimizing the error against experimental values), we provide a new optimized set of halogen PB radii, for each PBSA setup, that should be used in the context of the aforementioned scenario. A simultaneous optimization of PB radii and X···EP distances shows that a wide range of distance/radius pairs can be used without significant loss of accuracy, therefore laying the basis for expanding this halogen radii optimization strategy to other force fields and EP implementations. As ligand Δ Gsolv estimation is an important term in the determination of protein-ligand Δ Gbind, this work is particularly relevant in the framework of structure-based virtual screening and related computer-aided drug design routines.


Late sodium current in the pathophysiology of cardiovascular disease: consequences of sodium-calcium overload.
Late sodium current in cardiac cells is very small compared with the fast component, but as it flows throughout the action potential it may make a substantial contribution to sodium loading during each cardiac cycle. Late sodium current may contribute to triggering arrhythmia in two ways: by causing repolarisation failure (early after depolarisations); and by triggering late after depolarisations attributable to calcium oscillations in sodium-calcium overload conditions. Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as ischaemia in which sodium-calcium overload is a major feature.


Pharmacologic prophylaxis of postoperative atrial fibrillation in patients undergoing cardiac surgery: beyond beta-blockers.
Postoperative atrial fibrillation (POAF) is a frequent complication of cardiac surgery that increases patient morbidity, length of stay, and hospital costs. A substantial body of evidence exists evaluating various pharmacologic and nonpharmacologic methods to decrease the occurrence of POAF in an effort to decrease its burden on the health care system. Evidence-based guidelines support the use of beta-blockers as standard prophylaxis of POAF in patients undergoing cardiac surgery. Traditional prophylactic therapy for POAF targets the sympathetic nervous system, refractory period, and atrial conduction. However, associations between the development of POAF and the inflammatory process, oxidative stress, and atrial remodeling have prompted the investigation of novel therapies targeting these processes. To evaluate the role of pharmacologic strategies beyond beta-blockers in the prevention of POAF, we conducted a search of the PubMed database to identify studies published from 1950-February 2009. Emphasis was placed on how these therapies could be used in patients intolerant to beta-blockers or as additive therapy in high-risk patients. We found that sufficient evidence exists to recommend the use of amiodarone, sotalol, and possibly magnesium as monotherapy in patients unable to take beta-blockers or as add-on therapy for the prevention of POAF. Currently, available evidence does not support the use of propafenone, procainamide, digoxin, thiazolidinediones, triiodothyronine, or calcium channel blockers in the prevention of POAF. Preliminary evidence suggests that dofetilide, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), nonsteroidal antiinflammatory drugs, corticosteroids, omega-3 fatty acids, ascorbic acid, N-acetylcysteine, and sodium nitroprusside may be effective in preventing POAF. Additional large-scale, adequately powered clinical studies are needed to determine the benefit of these agents before they can be considered for routine use.


Evaluation of trends in hospital antimicrobial use in the Lao PDR using repeated point-prevalence surveys-evidence to improve treatment guideline use.
Antimicrobial use (AMU) is a key driver of antimicrobial resistance (AMR). There are few data on AMU, to inform optimizing antibiotic stewardship, in the Lao PDR (Laos). Point prevalence surveys (PPS) of AMU were conducted at four-month intervals in six general hospitals across Laos from 2017 to 2020, using modified Global-PPS data collection tools. The surveys focused on AMU amongst hospitalized inpatients. The overall prevalence of inpatient AMU was 71% (4,377/6,188), varying by hospital and survey round from 50·4% (135/268) to 88·4% (61/69). Of 4,377 patients, 44% received >one antimicrobial. The total number of prescriptions assessed was 6,555. Ceftriaxone was the most commonly used (39·6%) antimicrobial, followed by metronidazole (17%) and gentamicin (10%). Pneumonia was the most common diagnosis among those prescribed antimicrobials in both children aged ≤5 years (29% among aged ≤1 year and 27% among aged >1 to ≤5years) and adults aged ≥15 years at 9%. The percentage of antimicrobial use compliant with local treatment guidelines was 26%; inappropriate use was mainly found for surgical prophylaxis (99%). Adult patients received ACCESS group antimicrobials less commonly than children (47% vs 63%, p-value<0·0001). Most WATCH group prescriptions (99%) were without a microbiological indication. AMU among hospitalized patients in Laos is high with frequent inappropriate use of antimicrobials, especially as surgical prophylaxis. Continued monitoring and enhanced antimicrobial stewardship interventions are needed in Lao hospitals. The Wellcome Trust [Grant numbers 220211/Z/20/Z and 214207/Z/18/Z] and bioMérieux.


Bridging gaps in everyday life - a free-listing approach to explore the variety of activities performed by physiotherapists in specialized palliative care.
A growing body of studies indicate benefits of physiotherapy for patients in palliative care, for symptom relief and wellbeing. Though physiotherapists are increasingly acknowledged as important members of palliative care teams, they are still an underutilized source and not fully recognized. The aim of this study was to explore the variety of activities described by physiotherapists in addressing the needs and problems of patients and their families in specialized palliative care settings. Using a free-listing approach, ten physiotherapists working in eight specialized palliative care settings in Sweden described as precisely and in as much detail as possible different activities in which patients and their families were included (directly or indirectly) during 10 days. The statements were entered into NVivo and analysed using qualitative content analysis. Statements containing more than one activity were categorized per activity. In total, 264 statements, containing 504 varied activities, were coded into seven categories: Counteracting a declining physical function; Informing, guiding and educating; Observing, assessing and evaluating; Attending to signs and symptoms; Listening, talking with and understanding; Caring for basic needs; and Organizing, planning and coordinating. In practice, however, the activities were intrinsically interwoven. The activities showed how physiotherapists aimed, through care for the body, to address patients' physical, psychological, social and existential needs, counteracting the decline in a patient's physical function and wellbeing. The activities also revealed a great variation, in relation not only to what they did, but also to their holistic and inseparable nature with regard to why, how, when, where, with whom and for whom the activities were carried out, which points towards a well-adopted person-centred palliative care approach. The study provides hands-on descriptions of how person-centred palliative care is integrated in physiotherapists' everyday activities. Physiotherapists in specialized palliative care help patients and families to bridge the gap between their real and ideal everyday life with the aim to maximize security, autonomy and wellbeing. The concrete examples included can be used in understanding the contribution of physiotherapists to the palliative care team and inform future research interventions and outcomes.


The role of ammonites in the Mesozoic marine food web revealed by jaw preservation.
Ammonites are prominent in macroevolutionary studies because of their abundance and diversity in the fossil record, but their paleobiology and position in the marine food web are not well understood due to the lack of preserved soft tissue. We present three-dimensional reconstructions of the buccal apparatus in the Mesozoic ammonite Baculites with the use of synchrotron x-ray microtomography. Buccal mass morphology, combined with the coexistence of food remains found in the buccal mass, suggests that these ammonites fed on plankton. This diet may have extended to all aptychophoran ammonites, which share the same buccal mass morphology. Understanding the role of these ammonites in the Mesozoic food web provides insights into their radiation in the Early Jurassic, as well as their extinction at the end of the Cretaceous/early Paleogene.


Impaired permeability and antimicrobial barriers in type 2 diabetes skin are linked to increased serum levels of advanced glycation end-product.
The incidence of type 2 diabetes mellitus (DM) has been increasing rapidly, and the disease has become a serious sociomedical problem. Many skin problems, such as xerosis, pruritus, skin infections and delayed wound healing, that might be related to chronic impairment of skin barrier function decrease the quality of life in patients with DM. However, the status of the permeability and antimicrobial barrier of the skin in DM remains unknown. This study aimed to elucidate skin barrier impairment in patients with type 2 DM and its pathomechanisms using classic animal models of type 2 DM. Functional studies of the skin barrier and an analysis of stratum corneum (SC) lipids were compared between patients with type 2 DM and age- and sex-matched non-diabetes controls. Also, functional studies on the skin barrier, epidermal lipid analyses, and electron microscopy and biomolecular studies were performed using type 2 DM animal models, db/db and ob/ob mice. Patients with type 2 DM presented with epidermal barrier impairments, including SC hydration, which was influenced by blood glucose control (HbA1c level). In the lipid analysis of SC, ceramides, fatty acids and cholesterol were significantly decreased in patients with type 2 DM compared with controls. Type 2 DM murine models presented with severe hyperglycaemia, impairment of skin barrier homeostasis, decreases in epidermal proliferation and epidermal lipid synthesis, decreases in lamellar body (LB) and epidermal antimicrobial peptides (AMPs), an increase in receptors for advanced glycation end-product (AGE) in the epidermis and an increase in serum AGE. Impairment of the skin barrier was observed in type 2 DM, which results in part from a decrease in epidermal proliferation. Serum AGE and its epidermal receptors were increased in type 2 diabetic mice which display impaired skin barrier parameters such as epidermal lipid synthesis, LB production, epidermal AMP and SC lipids.


Sequential induction of heme pathway enzymes during erythroid differentiation of mouse Friend leukemia virus-infected cells.
The process of erythroid differentiation in mouse Friend leukemia virus transformed cells (T3-C1-2) was examined by following changes in several enzyme activities of the heme biosynthetic pathway and in heme concentration while the cells were undergoing erythroid differentiation after treatment with dimethylsulfoxide. Untreated cells on the one hand, have a limited capacity for spontaneous differentiation. On the other hand, dimethylsulfoxide(DMSO)-treated cells showed an increase in the activities of delta-aminolevulinic acid (ALA) synthetase, ALA dehydratase, uroporphyrinogen-I synthetase, ferrochelatase, and heme concentration by days 1, 1.5, 2, and 4, respectively. The increase of the heme pathway enzymes and heme concentration followed the order of these enzymes or products as they are arranged in the heme biosynthetic pathway. These changes induced by DMSO were effectively inhibited by treatment with actinomycin D, suggesting that continued RNA synthesis is required for the differentiation process. 5-bromo-2'-deoxyuridine (BrdU) (10(-5) M) inhibited the DMSO-induced changes of the heme pathway enzymes. BrdU was most effective when it was present during the first 2 days of cell culture. It gradually lost its inhibitory effect when added after the 3rd day or later. The BrdU-mediated inhibition was completely overcome by the addition of thymidine (7 x 10(-5) M), but not by uridine (7 x 10(-5) M). All these data suggest that a sequential induction of the heme pathway enzyme takes place during erythroid differentiation of Friend leukemia cells, and that the sequential induction of the enzymes may be due to a sequential activation of genes coding for these enzyme activities.


Public attitudes towards opt-out testing for HIV in primary care: a qualitative study.
BACKGROUND; The rate of new HIV infections in the UK continues to rise, with one-quarter of cases undiagnosed. Opt-out HIV testing - in which tests are routinely offered to all patients, with the offer to decline - have proved effective in antenatal care. Pilot studies of HIV opt-out testing at GP registration and acute medical admission to hospital have described service-level issues and the clinician's perspective, but not the views of the general public. To further understand the public's perspective on opt-out testing for HIV in England. Focus groups (n = 9) with a total of 54 participants in Brighton, England, where HIV prevalence is high. Quota sampling on sexual orientation, age, sex, and testing experience was applied to groups with high and low HIV prevalences, and analysed using framework analysis. Opt-out testing for HIV was acceptable. Testing on GP registration was regarded as a more appropriate setting than acute medical admission. Participants from groups in which HIV has a higher prevalence felt HIV testing required consideration that may not be possible during acute hospital admission. However, there was concern that screening would still be targeted at groups in which HIV prevalence is higher, based on clinicians' judgement of patients' behaviours, sexuality, or ethnicity. The opt-out method of testing for HIV must be routinely offered to all who are eligible, to increase test uptake and to prevent communities feeling targeted. Any pressure to test is likely to be poorly received. Inaccurate concerns about medical records being shared with financial services are a disincentive to test. Primary care should be an active setting for opt-out HIV testing.


Expression of aquaporin water channels in human urothelial carcinoma: correlation of AQP3 expression with tumour grade and stage.
To study the expression, localization and potential clinical significance of aquaporin water channels both in well-established urothelial cancer (UC) cell lines and in human bladder carcinoma specimens of different stages and grades and to discuss the clinical relevance of the findings. AQP transcript and protein expression by RT4, RT112 and T24 UC cell lines was investigated using reverse transcriptase polymerase chain reaction and immunofluorescence labelling. Immunohistochemistry (IHC) was used to assess AQP protein expression in 94 UC specimens of various grades and stages. AQP3 and 9 transcripts were expressed in low-grade RT4 and RT112, but not in high-grade T24 cells. By contrast, AQP4 mRNA was absent in RT4, but expressed by RT112 and T24. Transcripts for AQP7 and 11 were detected in all three UC cell lines. Immunofluorescence microscopy confirmed the expression of AQP3, 4 and 7 at the protein level. By IHC, AQP3 was shown to be intensely expressed by 86 %, 66 % and 33 % of specimens of stage pTa, pT1 and pT2 tumours, respectively (p < 0.001). Whereas 100 % of G1 tumours were positive, only 73 % and 55 % of G2 and G3 tumours were found to express AQP3 (p = 0.004). This is the first study to demonstrate that several AQPs are expressed in UC. Our results indicate that there is a correlation between AQP3 protein expression and tumour stage and grade, with AQP3 expression being reduced or lost in tumours of higher grade and stage. Taken together with the available evidence from other studies, we conclude that AQPs may play a role in the progression of UC and, in particular, that this could be of prognostic value.


Fetal lamb cerebral blood flow (CBF) and oxygen tensions during hypoxia: a comparison of laser Doppler and microsphere measurements of CBF.
This study was undertaken to compare microsphere and laser Doppler flowmetry techniques for the measurement of cerebral blood flow, to assess the effect of probe implantation at the tip of the sensing probe and to measure brain tissue P(O2) (tP(O2)) in response to acute hypoxia. Fetal sheep of ~131 days gestation (n = 8) were chronically instrumented with bilateral laser Doppler probes in the parietal cortices and catheters for injection of fluorescent microspheres. Five days after surgery fetuses were subjected to 1 h periods of baseline control breathing, hypoxia and recovery. Microspheres were injected 10 min prior to and 10, 30, 50 and 120 min after initiation of hypoxia. Microspheres were counted in four 12 mm(3) tissue samples from each hemisphere, the tip of the laser Doppler probe being positioned in the centre of one of the cubes. The cube containing the probe tip was also subdivided into 4 mm(3) pieces of tissue. In response to hypoxia, fetal arterial P(O2) declined from 21 +/- 2 to 12 +/- 1 Torr and brain tissue P(O2) fell from 10 +/- 1 to a nadir of 1 +/- 1 Torr. Each method detected a significant increase in CBF that reached a maximum after 30-45 min, although the increase of flow measured by laser Doppler flowmetry was less than that measured by spheres after 10 and 30 min (P < 0.05). Microspheres did not detect altered flow at the probe tip or heterogeneity of flow in surrounding volumes of cortical tissue. In summary, laser Doppler flowmetry is a useful measure of continuous relative changes of CBF in the chronically instrumented fetal sheep. Flow compensations in acute hypoxia are not adequate to sustain O(2) delivery, and other compensations, including reduced metabolic rate, are possible.


Salivary immunoglobulin free light chains: reference ranges and responses to exercise in young and older adults.
Free light chains (FLCs) have a range of biological functions and may act as a broad marker of immunesuppression and activation and inflammation. Measurement of salivary FLCs may provide practical advantages in a range of clinical populations. The aim of the present study was to develop normal reference ranges of FLCs in saliva and assess the effects of acute exercise on FLC levels in younger and older adults. Saliva FLC concentrations and secretion rates were measuredin young (n = 88, aged 18-36) and older (n = 53, aged 60-80) adults. To assess FLC changes in response to acute exercise, young adults completed a constant work-rate cycling exercise trial at 60% VO2max (n = 18) or a 1 h cycling time trial (TT) (n = 10) and older adults completed an incremental submaximal treadmill walking exercise test to 75% HRmax (n = 53). Serum FLCs were measured at baseline and in response to exercise. Older adults demonstrated significantly higher levels of salivary FLC parameters compared with young adults. Median (5-95th percentile) concentrationswere 0.45 (0.004- 3.45) mg/L for kappa and 0.30 (0.08-1.54) mg/L for lambda in young adults; 3.91 (0.75-19.65) mg/L for kappa and 1.00 (0.02-4.50) mg/L for lambda in older ad ults. Overall median concentrations of salivary kappa and lambda FLCs were 10-fold and 20-fold lower than serum, respectively. Reductions in salivary FLC concentrations and secretion rates were observed immediately post- and at 1 h post exercise, but were only significant for the older cohort; FLCs began to recover between post and 1 h post-exercise. No changes in serum FLCs were observed in response to exercise.


Pattern of BOLD signal in auditory cortex relates acoustic response to perceptual streaming.
Segregating auditory scenes into distinct objects or streams is one of our brain's greatest perceptual challenges. Streaming has classically been studied with bistable sound stimuli, perceived alternately as a single group or two separate groups. Throughout the last decade different methodologies have yielded inconsistent evidence about the role of auditory cortex in the maintenance of streams. In particular, studies using functional magnetic resonance imaging (fMRI) have been unable to show persistent activity within auditory cortex (AC) that distinguishes between perceptual states. We use bistable stimuli, an explicit perceptual categorization task, and a focused region of interest (ROI) analysis to demonstrate an effect of perceptual state within AC. We find that AC has more activity when listeners perceive the split percept rather than the grouped percept. In addition, within this ROI the pattern of acoustic response across voxels is significantly correlated with the pattern of perceptual modulation. In a whole-brain exploratory test, we corroborate previous work showing an effect of perceptual state in the intraparietal sulcus. Our results show that the maintenance of auditory streams is reflected in AC activity, directly relating sound responses to perception, and that perceptual state is further represented in multiple, higher level cortical regions.


Dietary adherence and weight loss success among overweight women: results from the A TO Z weight loss study.
Dietary adherence has been implicated as an important factor in the success of dieting strategies; however, studies assessing and investigating its association with weight loss success are scarce. We aimed to document the level of dietary adherence using measured diet data and to examine its association with weight loss success. Secondary analysis was performed using data from 181 free-living overweight/obese women (mean+/-s.d. age=43+/-5 years, body mass index=31+/-4 kg m(-2)) participating in a 1-year randomized clinical trial (the A TO Z study) comparing popular weight loss diets (Atkins, Zone and Ornish). Participants' dietary adherence was assessed as the difference between their respective assigned diet's recommended macronutrient goals and their self-reported intake. Association between dietary adherence and 12-month weight change was computed using Spearman's correlations. Differences in baseline characteristics and macronutrient intake between the most and least adherent tertiles for diet groups were compared using t-tests. Within each diet group, adherence score was significantly correlated with 12-month weight change (Atkins, r(s)=0.42, P=0.0003; Zone, r(s)=0.34, P=0.009 and Ornish, r(s)=0.38, P=0.004). Twelve-month weight change in the most vs least adherent tertiles, respectively, was -8.3+/-5.6 vs -1.9+/-5.8 kg, P=0.0006 (Atkins); -3.7+/-6.3 vs -0.4+/-6.8 kg, P=0.12 (Zone) and -6.5+/-6.8 vs -1.7+/-7.9 kg, P=0.06 (Ornish). Regardless of assigned diet groups, 12-month weight change was greater in the most adherent compared to the least adherent tertiles. These results suggest that strategies to increase adherence may deserve more emphasis than the specific macronutrient composition of the weight loss diet itself in supporting successful weight loss.


Infant temperament, maternal feeding behaviours and the timing of solid food introduction.
Despite guidance from the World Health Organization and the U.K. Department of Health, many mothers introduce solid food before their infant is 6 months old. The current study aimed to investigate relationships between maternal feeding behaviours (preintroduction and postintroduction to solids), infant temperament, and the timing of introduction to solid food. Eighty-one women were recruited on low-risk maternity units and were contacted at 1 week, 3, and 6 months postpartum. Mothers of infants (45 males, 36 females, mean birth weight 3.52 kg [SD 0.39]) completed the behaviours component of the Infant Feeding Style Questionnaire via telephone interview at 3 months. At 6 months, they were observed feeding their infant solid food at home and reported infant temperament using the Infant Behaviour Questionnaire-Revised (short form). Partial correlations (covariates: birth weight, maternal age, breastfeeding duration, and postnatal depression) revealed negative associations between age of introduction to solid food and temperament (smiling and laughter) and laissez-faire milk feeding behaviours; and positive associations between age of introduction to solid food and restrictive milk feeding behaviours and verbal involvement during an observed mealtime. Hierarchical multiple regression analysis revealed that an infant's birth weight and the degree to which their mothers perceive them to smile and laugh are key predictors of when they will be introduced to solid food, over and above other variables of interest (e.g., maternal milk feeding behaviours, breastfeeding duration, and postnatal depression).


CD8 epitope escape and reversion in acute HCV infection.
In the setting of acute hepatitis C virus (HCV) infection, robust HCV-specific CD8+ cytotoxic T lymphocyte (CTL) responses are associated with initial control of viremia. Despite these responses, 70-80% of individuals develop persistent infection. Although viral escape from CD8 responses has been illustrated in the chimpanzee model of HCV infection, the effect of CD8 selection pressure on viral evolution and containment in acute HCV infection in humans remains unclear. Here, we examined viral evolution in an immunodominant human histocompatibility leukocyte antigen (HLA)-B8-restricted NS3 epitope in subjects with acute HCV infection. Development of mutations within the epitope coincided with loss of strong ex vivo tetramer and interferon gamma enzyme-linked immunospot responses, and endogenous expression of variant NS3 sequences suggested that the selected mutations altered processing and presentation of the variant epitope. Analysis of NS3 sequences from 30 additional chronic HCV-infected subjects revealed a strong association between sequence variation within this region and expression of HLA-B8, supporting reproducible allele-specific selection pressures at the population level. Interestingly, transmission of an HLA-B8-associated escape mutation to an HLA-B8 negative subject resulted in rapid reversion of the mutation. Together, these data indicate that viral escape from CD8+ T cell responses occurs during human HCV infection and that acute immune selection pressure is of sufficient magnitude to influence HCV evolution.


High-resolution characterization of labile phosphorus, iron, and manganese in sediments of different trophic waters in Lake Taihu, China.
High-resolution combined ZrO-Chelex diffusive gradients in thin film (DGT) probes were arranged to synchronously monitor the characteristics of labile phosphorus (P), iron (Fe), and manganese (Mn) in sediments from regions of varying trophic levels in Lake Taihu, China. Results showed that P release was closely related to the lake region's trophic level. Labile P in sediments and the apparent diffusion flux (Fd) of P were higher in hyper-eutrophic algae-dominated regions than those in macrophyte-algae-dominated and macrophyte-dominated regions, indicating that P released from sediments may be facilitated in eutrophic environments. A positive correlation observed between DGT-labile P and Fe or Mn, which had similar regional spatial distributions to P, showed that reductive dissolution of Fe-Mn (oxyhydr)oxides (FeOOH-MnOOH) in sediments was responsible for internal P release, which was strengthened in eutrophic environments. Ratios of labile Fe or Mn/labile P (LFe/LP and LMn/LP) in sediments in algae-dominated regions showed lower values than those in macrophyte-algae-dominated and macrophyte-dominated regions, further confirming that FeOOH-MnOOH in algae-dominated regions were less able to fix P, which brought higher pollution risks for the overlying water. LFe/LP or LMn/LP also had a significantly positive correlation with Fd, further testament that labile Fe or Mn was much more relevant to the sediment P cycle.


Subclinical thyroid dysfunction and fracture risk: a meta-analysis.
Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.


Reduced Expression of Histone Methyltransferases KMT2C and KMT2D Correlates with Improved Outcome in Pancreatic Ductal Adenocarcinoma.
Genes encoding the histone H3 lysine 4 methyltransferases KMT2C and KMT2D are subject to deletion and mutation in pancreatic ductal adenocarcinoma (PDAC), where these lesions identify a group of patients with a more favorable prognosis. In this study, we demonstrate that low KMT2C and KMT2D expression in biopsies also defines better outcome groups, with median survivals of 15.9 versus 9.2 months (P = 0.029) and 19.9 versus 11.8 months (P = 0.001), respectively. Experiments with eight human pancreatic cell lines showed attenuated cell proliferation when these methyltransferases were depleted, suggesting that this improved outcome may reflect a cell-cycle block with diminished progression from G0-G1 RNA-seq analysis of PDAC cell lines following KMT2C or KMT2D knockdown identified 31 and 124 differentially expressed genes, respectively, with 19 genes in common. Gene-set enrichment analysis revealed significant downregulation of genes related to cell-cycle and growth. These data were corroborated independently by examining KMT2C/D signatures extracted from the International Cancer Genome Consortium and The Cancer Genome Atlas datasets. Furthermore, these experiments highlighted a potential role for NCAPD3, a condensin II complex subunit, as an outcome predictor in PDAC using existing gene expression series. Kmt2d depletion in KC/KPC cell lines also led to an increased response to the nucleoside analogue 5-fluorouracil, suggesting that lower levels of this methyltransferase may mediate the sensitivity of PDAC to particular treatments. Therefore, it may also be therapeutically beneficial to target these methyltransferases in PDAC, especially in those patients demonstrating higher KTM2C/D expression. Cancer Res; 76(16); 4861-71. ©2016 AACR.


Breast ultrasound: recommendations for information to women and referring physicians by the European Society of Breast Imaging.
This article summarises the information that should be provided to women and referring physicians about breast ultrasound (US). After explaining the physical principles, technical procedure and safety of US, information is given about its ability to make a correct diagnosis, depending on the setting in which it is applied. The following definite indications for breast US in female subjects are proposed: palpable lump; axillary adenopathy; first diagnostic approach for clinical abnormalities under 40 and in pregnant or lactating women; suspicious abnormalities at mammography or magnetic resonance imaging (MRI); suspicious nipple discharge; recent nipple inversion; skin retraction; breast inflammation; abnormalities in the area of the surgical scar after breast conserving surgery or mastectomy; abnormalities in the presence of breast implants; screening high-risk women, especially when MRI is not performed; loco-regional staging of a known breast cancer, when MRI is not performed; guidance for percutaneous interventions (needle biopsy, pre-surgical localisation, fluid collection drainage); monitoring patients with breast cancer receiving neo-adjuvant therapy, when MRI is not performed. Possible indications such as supplemental screening after mammography for women aged 40-74 with dense breasts are also listed. Moreover, inappropriate indications include screening for breast cancer as a stand-alone alternative to mammography. The structure and organisation of the breast US report and of classification systems such as the BI-RADS and consequent management recommendations are illustrated. Information about additional or new US technologies (colour-Doppler, elastography, and automated whole breast US) is also provided. Finally, five frequently asked questions are answered. • US is an established tool for suspected cancers at all ages and also the method of choice under 40. • For US-visible suspicious lesions, US-guided biopsy is preferred, even for palpable findings. • High-risk women can be screened with US, especially when MRI cannot be performed. • Supplemental US increases cancer detection but also false positives, biopsy rate and follow-up exams. • Breast US is inappropriate as a stand-alone screening method.


Prevalence and severity of hypertension in a dental hygiene clinic.
The purpose of this study was to assess the prevalence and severity of hypertension in a dental hygiene clinic and evaluate factors related to the disease. Records of 615 patients, treated by dental hygiene students during 2003, were reviewed. Data collected included systolic and diastolic blood pressure, presence of diabetes and renal disease, non-modifiers (race, gender, and age), and modifiers (marital status, smoking habits, and occupation). According to the Seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) classification, 154 (25%) of the subjects had normal blood pressure readings, 374 (60.8%) had prehypertension, and 87 (14.1%) had stage 1 hypertension. Statistical analysis showed a significant difference in the JNC7 classification between groups when considering the non-modifiers' race (p=.02) and the modifiers' smoking habits (p=.03) and occupation (p=.01). A statistically significant difference in the JNC7 classification existed between groups with diabetes (p=.00). The majority of patients had blood pressure readings in the prehypertension stage. Based on these results, the researchers recommend clinical policy modifications which include: additional documentation for blood pressure readings in the prehypertension stage, lowering the systolic reading from 160 mmHg to 140 mmHg when adding hypertension alert labels, and noting prehypertension/hypertension on the dental hygiene care plan with the appropriate interventions.


Yoga for Substance Use Disorder in Women: A Systematic Review.
It has been suggested that yoga may be an effective adjunct intervention in the management of substance use disorders (SUD). Additionally, women with SUD require different treatment approaches than men. The objective of this study was to critically evaluate the evidence for the effectiveness of yoga, specifically for women, as part of treatment for SUD. Nine electronic databases were searched from inception to January 2020. Randomized controlled trials (RCT) that evaluated any type of yoga, including yoga as a component of mindfulness-based treatment, against any type of control in individuals with any type of addiction were eligible. Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Checklist and Statement, methodological quality was appraised using Physiotherapy Evidence Database (PE Dro) criteria. Ten RC Ts (eight mixed-gender and two female-focused) met the eligibility criteria. Most of these RCTs were small to medium-sized, with various methodological and analytical flaws and deficits. The types of addictions included in these studies were alcohol, drug, and nicotine addiction. Most RCTs suggested that various types of yoga, primarily Hatha Yoga and its components, led to favorable or equivalent results for SUD as an adjunct to control or treatment-as-usual interventions. There are limited results on the impact of yoga for SUD specifically focused on women and their unique needs. Although the results of mixed-gender articles are encouraging, large RCTs with gender-specific subanalyses are required to better determine the benefits specific to women incorporating yoga for SUD.


Organization of actin cytoskeleton during early endothelial regeneration in vitro.
The pattern of early cell movement after an experimental 'wound' and the organization of actin in stationary and moving cultured endothelial cells have been studied by means of: time-lapse photography; indirect immunofluorescence using anti-actin antibodies with and without pretreatment with the actin destabilizing factor present in human plasma; and differential centrifugation and densitometric analysis of stained sodium dodecylsulphate/polyacrylamide gels in order to evaluate the total and relative amounts of G and F-actin. Up to 5 h after a single scratch, movement consists of a coordinate spreading and translocation of a band of about 10 cells from the wound edge. Compared to stationary cells, moving endothelial cells show: no significant changes in the intensity and distribution of immunofluorescent staining with anti-actin antibodies, but an increased sensitivity of cytoplasmic actin, including stress fibres, to the actin-destabilizing factor purified from human plasma; and no significant change in the total amount of actin, but a decreased relative amount of F-actin and a corresponding increased relative amount of G-actin. We conclude that endothelial cell movement in vitro is accompanied by a rapid change in the state of actin organization characterized by an overall decrease in cytoplasmic F-actin.


Reclassification of some species of Thiobacillus to the newly designated genera Acidithiobacillus gen. nov., Halothiobacillus gen. nov. and Thermithiobacillus gen. nov.
The species of the genus 'Thiobacillus' fall into the alpha-, beta- and gamma-subclasses of the Proteobacteria, the type species Thiobacillus thioparus being located in the beta-subclass. 'Thiobacillus' species exhibit almost as much diversity in DNA composition and physiology as is found collectively in all other proteobacterial groups. On the basis of physiological characters and 16S rRNA gene sequence comparisons, eight of the existing Thiobacillus species are proposed for reassignment to three newly designated genera within the gamma-subclass of the Proteobacteria, namely Acidithiobacillus, Halothiobacillus and Thermithiobacillus.


Visualizing Association of the Retroviral Gag Protein with Unspliced Viral RNA in the Nucleus.
Packaging of genomic RNA (gRNA) by retroviruses is essential for infectivity, yet the subcellular site of the initial interaction between the Gag polyprotein and gRNA remains poorly defined. Because retroviral particles are released from the plasma membrane, it was previously thought that Gag proteins initially bound to gRNA in the cytoplasm or at the plasma membrane. However, the Gag protein of the avian retrovirus Rous sarcoma virus (RSV) undergoes active nuclear trafficking, which is required for efficient gRNA encapsidation (L. Z. Scheifele, R. A. Garbitt, J. D. Rhoads, and L. J. Parent, Proc Natl Acad Sci U S A 99:3944-3949, 2002, https://doi.org/10.1073/pnas.062652199; R. Garbitt-Hirst, S. P. Kenney, and L. J. Parent, J Virol 83:6790-6797, 2009, https://doi.org/10.1128/JVI.00101-09). These results raise the intriguing possibility that the primary contact between Gag and gRNA might occur in the nucleus. To examine this possibility, we created a RSV proviral construct that includes 24 tandem repeats of MS2 RNA stem-loops, making it possible to track RSV viral RNA (vRNA) in live cells in which a fluorophore-conjugated MS2 coat protein is coexpressed. Using confocal microscopy, we observed that both wild-type Gag and a nuclear export mutant (Gag.L219A) colocalized with vRNA in the nucleus. In live-cell time-lapse images, the wild-type Gag protein trafficked together with vRNA as a single ribonucleoprotein (RNP) complex in the nucleoplasm near the nuclear periphery, appearing to traverse the nuclear envelope into the cytoplasm. Furthermore, biophysical imaging methods suggest that Gag and the unspliced vRNA physically interact in the nucleus. Taken together, these data suggest that RSV Gag binds unspliced vRNA to export it from the nucleus, possibly for packaging into virions as the viral genome.IMPORTANCE Retroviruses cause severe diseases in animals and humans, including cancer and acquired immunodeficiency syndromes. To propagate infection, retroviruses assemble new virus particles that contain viral proteins and unspliced vRNA to use as gRNA. Despite the critical requirement for gRNA packaging, the molecular mechanisms governing the identification and selection of gRNA by the Gag protein remain poorly understood. In this report, we demonstrate that the Rous sarcoma virus (RSV) Gag protein colocalizes with unspliced vRNA in the nucleus in the interchromatin space. Using live-cell confocal imaging, RSV Gag and unspliced vRNA were observed to move together from inside the nucleus across the nuclear envelope, suggesting that the Gag-gRNA complex initially forms in the nucleus and undergoes nuclear export into the cytoplasm as a viral ribonucleoprotein (vRNP) complex.


Low energy excited state vibrations revealed in conjugated copolymer PCDTBT.
Low energy vibrations in the excited state have been hypothesized to play an important role in quickly and efficiently generating free charges in bulk heterojunctions of some conjugated polymer systems. While time-resolved vibrational spectroscopies seemingly are well poised to address the relationship between kinetics and vibrational motions after initial photoexcitation, uncertainty in the measurement arises due to overlapping signals and difficulties in assigning observed oscillatory signals to the molecular response. Here, we demonstrate a high sensitivity strategy to distinguish between signal oscillations originating from lab noise and those molecular in origin in order to isolate the low energy excited-state vibrations in the model conjugated copolymer PCDTBT. Furthermore, to distinguish modes that may be implicated in different kinetic pathways, coherent signal oscillations extracted from 2-dimensional electronic spectroscopy (2DES) are compared for the polymer in two solvents with different polarities resulting in different kinetics. We observe that the change in solvent affects dynamics on the >2 ps scale but not on the time scale required for free charge generation in heterojunctions (∼200 fs time scale). By the same token, the excited state vibrational modes that appear and disappear based on solvent polarity may also be associated with the slower kinetic process. The observation of low energy vibrational motions coupled to the excited state manifold that persists through the solvent change and thus can be associated with the fast kinetic process supports the hypothesis that direct polaron formation, rather than exciton formation and diffusion followed by interfacial charge separation, is a more likely route toward free charges in organic heterostructures.


A tiny tick can cause a big health problem.
Ticks are tiny crawling bugs in the spider family that feed by sucking blood from animals. They are second only to mosquitoes as vectors of human disease, both infectious and toxic. Infected ticks spread over a hundred diseases, some of which are fatal if undetected. They spread the spirochete (which multiplies in the insect's gut) with a subsequent bite to the next host. We describe the only reported cases of peri ocular tick bite from India that presented to us within a span of 3 days and its management. Due suspicion and magnification of the lesions revealed the ticks which otherwise masqueraded as small skin tags/moles on gross examination. The ticks were firmly latched on to the skin and careful removal prevented incarceration of the mouth parts. Rickettsial diseases that were believed to have disappeared from India are reemerging and their presence has recently been documented in at least 11 states in the country. Among vector borne diseases, the most common, Lyme disease, also known as the great mimicker, can present with rheumatoid arthritis, fibromyalgia, depression, attention deficit hyperactivity disorder, multiple sclerosis, chronic fatigue syndrome, cardiac manifestations, encephalitis, and mental illness, to name some of the many associations. Common ocular symptoms and signs include conjunctivitis, keratitis, uveitis, and retinitis. Early detection and treatment of tick borne diseases is important to prevent multi system complications that can develop later in life.


Topiramate treatment for SSRI-induced weight gain in anxiety disorders.
Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), have been associated with significant weight gain, a problem that frequently leads to noncompliance and premature discontinuation of treatment. Topiramate is a novel anticonvulsant that has also been used as a mood stabilizer and augmentation agent in mood disorders. Topiramate has been observed to have an interesting side effect of weight loss in some individuals. In this study, topiramate was added to the treatment regimen of patients with a primary DSM-IV anxiety disorder who had experienced substantial SSRI-induced weight gain, in an attempt to induce weight loss. Topiramate was added to SSRI treatment in 15 anxiety disorder patients, starting at a dose of 50 mg/day and titrating up to a target daily dose of 100 mg/day, with a maximum dose of 250 mg/day. Subjects' weight was measured at baseline and after 5 and 10 weeks of treatment. Before topiramate treatment, SSRI-treated subjects in this sample had gained a mean of 13.0 +/- 8.4 kg (28.6 +/- 18.5 lb). After the addition of a mean dose of 135.0 +/- 44.1 mg/day of topiramate for approximately 10 weeks, subjects lost a mean of 4.2 +/- 6.0 kg (9.3 +/- 13.3 lb). Topiramate may have a role in managing SSRI-induced weight gain in anxiety disorder patients.


Cancer classification using the Immunoscore: a worldwide task force.
Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage. The current classification provides limited prognostic information, and does not predict response to therapy. Recent literature has alluded to the importance of the host immune system in controlling tumor progression. Thus, evidence supports the notion to include immunological biomarkers, implemented as a tool for the prediction of prognosis and response to therapy. Accumulating data, collected from large cohorts of human cancers, has demonstrated the impact of immune-classification, which has a prognostic value that may add to the significance of the AJCC/UICC TNM-classification. It is therefore imperative to begin to incorporate the 'Immunoscore' into traditional classification, thus providing an essential prognostic and potentially predictive tool. Introduction of this parameter as a biomarker to classify cancers, as part of routine diagnostic and prognostic assessment of tumors, will facilitate clinical decision-making including rational stratification of patient treatment. Equally, the inherent complexity of quantitative immunohistochemistry, in conjunction with protocol variation across laboratories, analysis of different immune cell types, inconsistent region selection criteria, and variable ways to quantify immune infiltration, all underline the urgent requirement to reach assay harmonization. In an effort to promote the Immunoscore in routine clinical settings, an international task force was initiated. This review represents a follow-up of the announcement of this initiative, and of the J Transl Med. editorial from January 2012. Immunophenotyping of tumors may provide crucial novel prognostic information. The results of this international validation may result in the implementation of the Immunoscore as a new component for the classification of cancer, designated TNM-I (TNM-Immune).


Dynamical theory of the inverted cheerios effect.
Recent experiments have shown that liquid drops on highly deformable substrates exhibit mutual interactions. This is similar to the Cheerios effect, the capillary interaction of solid particles at a liquid interface, but now the roles of solid and liquid are reversed. Here we present a dynamical theory for this inverted Cheerios effect, taking into account elasticity, capillarity and the viscoelastic rheology of the substrate. We compute the velocity at which droplets attract, or repel, as a function of their separation. The theory is compared to a simplified model in which the viscoelastic dissipation is treated as a localized force at the contact line. It is found that the two models differ only at small separation between the droplets, and both of them accurately describe experimental observations.


A theory of phase singularities for image representation and its applications to object tracking and image matching.
This paper studies phase singularities (PSs) for image representation. We show that PSs calculated with Laguerre-Gauss filters contain important information and provide a useful tool for image analysis. PSs are invariant to image translation and rotation. We introduce several invariant features to characterize the core structures around PSs and analyze the stability of PSs to noise addition and scale change. We also study the characteristics of PSs in a scale space, which lead to a method to select key scales along phase singularity curves. We demonstrate two applications of PSs: object tracking and image matching. In object tracking, we use the iterative closest point algorithm to determine the correspondences of PSs between two adjacent frames. The use of PSs allows us to precisely determine the motions of tracked objects. In image matching, we combine PSs and scale-invariant feature transform (SIFT) descriptor to deal with the variations between two images and examine the proposed method on a benchmark database. The results indicate that our method can find more correct matching pairs with higher repeatability rates than some well-known methods.


Laws for the dynamics of regulatory networks.
We start our analysis from historical but too seldom quoted papers by Delbrück, Noveck & Weiner, Cohn & Horibata and Monod & Jacob. We try to show how it became possible to draw a line coupling cell differentiation to the physical concept of multistationarity, and the latter to the concept of positive feedback circuits. Two laws give the minimal logical ingredients required for differentiative and homeostatic regulations. It is briefly shown how they can be used to treat such complex dynamics as deterministaic chaos, which, admittedly, does not yet belong to the corpus of developmental biology. It was taken as a challenge to express our ideas here in purely verbal terms, avoiding any formal treatment.


Landslides on Ceres: Diversity and Geologic Context.
Landslides are among the most widespread geologic features on Ceres. Using data from Dawn's Framing Camera, landslides were previously classified based upon geomorphologic characteristics into one of three archetypal categories, Type 1(T1), Type 2 (T2), and Type 3 (T3). Due to their geologic context, variation in age, and physical characteristics, most landslides on Ceres are, however, intermediate in their morphology and physical properties between the archetypes of each landslide class. Here we describe the varied morphology of individual intermediate landslides, identify geologic controls that contribute to this variation, and provide first-order quantification of the physical properties of the continuum of Ceres's surface flows. These intermediate flows appear in varied settings and show a range of characteristics, including those found at contacts between craters, those having multiple trunks or lobes; showing characteristics of both T2 and T3 landslides; material slumping on crater rims; very small, ejecta-like flows; and those appearing inside of catenae. We suggest that while their morphologies can vary, the distribution and mechanical properties of intermediate landslides do not differ significantly from that of archetypal landslides, confirming a link between landslides and subsurface ice. We also find that most intermediate landslides are similar to Type 2 landslides and formed by shallow failure. Clusters of these features suggest ice enhancement near Juling, Kupalo and Urvara craters. Since the majority of Ceres's landslides fall in the intermediate landslide category, placing their attributes in context contributes to a better understanding of Ceres's shallow subsurface and the nature of ground ice.


Favorable prognostic impact in loss of TP53 and PIK3CA mutations after neoadjuvant chemotherapy in breast cancer.
We investigated the loss of somatic mutations in TP53 and PIK3CA in breast cancer tissue after neoadjuvant chemotherapy (NCT) and the clinical relevance of the observed mutation profiles. Samples were derived from three cohorts: Cohort 1 consisting of 206 patients undergoing NCT with matched pre- and postchemotherapy tumor tissues; Cohort 2 consisting of 158 additional patients undergoing NCT; and Cohort 3, consisting of 81 patients undergoing chemotherapy with prechemotherapy tumor tissues. In the first cohort, somatic mutations in TP53 or PIK3CA were identified in 24.8% of the pre-NCT tumor samples but in only 12.1% of the post-NCT tumor samples (P < 0.001). Patients with initial TP53 and PIK3CA mutations who became negative for the mutations after NCT had a higher Miller-Payne score (P = 0.008), improved disease-free survival, and improved overall survival than those with no change or the opposite change. The association of loss of mutations in TP53 and PIK3CA and improved survival was successfully validated in the second cohort. In addition, 28.4% of the tumors showed intratumoral heterogeneity of somatic mutations in TP53 or PIK3CA, whereas 71.6% were homogeneous, either with or without the mutations. Our data reveal the novel concept that chemotherapy may reduce mutation frequency in patients with breast cancer. Furthermore, the loss of somatic mutations in TP53 and PIK3CA may be translated to biomarkers for prognosis via further verification, which may optimize the choice of sequential therapy and improve patient survival.


Surgical treatment of endometrioid endometrial carcinoma - laparotomy versus laparoscopy
Recent publications have raised doubts about the oncological safety of a laparoscopic approach in the treatment of endometrial cancer. The aim of this study was to investigate the beneficial aspects of laparoscopy versus laparotomy in patients with endometrial cancer, and present oncological outcomes. A retrospective study of patients who underwent surgery for the treatment of endometrioid endometrial cancer was performed. Surgical outcomes and complications in patients who were treated by laparoscopy or open surgery were compared. The patients were followed for 5-years. Patients' characteristics, tumor stage, complications rate and oncologic outcome were analyzed. A total of 151 patients were included. The laparoscopy (n=80) and laparotomy (n=71) groups were homogeneous in regards of demographic data and tumor stage. Median average blood loss (1.31 vs. 1.92 g/dL), the mean duration of hospitalization (5.73 vs. 12.25 days), intraoperative (0 vs. 6%), and severe postoperative complications (5.1 vs. 14.3%) were significantly lower in the laparoscopy group. The numbers of pelvic or para-aortic lymph nodes removed during systematic lymphadenectomy were similar in both groups. Women who underwent laparoscopy and those who underwent laparotomy had similar five-year recurrence-free survival rates (88.7% vs. 91.5%, p=0.864), as well as similar overall five-year survival rates (91.2% vs. 97.2%, p=0.094). The oncological outcome of laparoscopy was similar to that of laparotomy in the treatment of patients with endometrial cancer. However, surgical outcomes and morbidity rates were significantly better in patients treated by laparoscopy. Clinical trials are essential to evaluate the oncological efficacy of laparoscopy in patients with endometrial cancer.