The impact of lesion side on bilateral upper limb coordination after stroke.
A stroke frequently results in impaired performance of activities of daily life. Many of these are highly dependent on effective coordination between the two arms. In the context of bimanual movements, cyclic rhythmical bilateral arm coordination patterns can be classified into two fundamental modes: in-phase (bilateral homologous muscles contract simultaneously) and anti-phase (bilateral muscles contract alternately) movements. We aimed to investigate how patients with left (LHS) and right (RHS) hemispheric stroke are differentially affected in both individual-limb control and inter-limb coordination during bilateral movements. We used kinematic measurements to assess bilateral coordination abilities of 18 chronic hemiparetic stroke patients (9 LHS; 9 RHS) and 18 age- and sex-matched controls. Using KINARM upper-limb exoskeleton system, we examined individual-limb control by quantifying trajectory variability in each hand and inter-limb coordination by computing the phase synchronization between hands during anti- and in-phase movements. RHS patients exhibited greater impairment in individual- and inter-limb control during anti-phase movements, whilst LHS patients showed greater impairment in individual-limb control during in-phase movements alone. However, LHS patients further showed a swap in hand dominance during in-phase movements. The current study used individual-limb and inter-limb kinematic profiles and showed that bilateral movements are differently impaired in patients with left vs. right hemispheric strokes. Our results demonstrate that both fundamental bilateral coordination modes are differently controlled in both hemispheres using a lesion model approach. From a clinical perspective, we suggest that lesion side should be taken into account for more individually targeted bilateral coordination training strategies. the current experiment is not a health care intervention study.


Rho-dependent contractile responses in the neuronal growth cone are independent of classical peripheral retrograde actin flow.
Rho family GTPases have been implicated in neuronal growth cone guidance; however, the underlying cytoskeletal mechanisms are unclear. We have used multimode fluorescent speckle microscopy (FSM) to directly address this problem. We report that actin arcs that form in the transition zone are incorporated into central actin bundles in the C domain. These actin structures are Rho/Rho Kinase (ROCK) effectors. Specifically, LPA mediates growth cone retraction by ROCK-dependent increases in actin arc and central actin bundle contractility and stability. In addition, these treatments had marked effects on MT organization as a consequence of strong MT-actin arc interactions. In contrast, LPA or constitutively active Rho had no effect on P domain retrograde actin flow or filopodium bundle number. This study reveals a novel mechanism for domain-specific spatial control of actin-based motility in the growth cone with implications for understanding chemorepellant growth cone responses and nerve regeneration.


Novel migrating mouse neural crest cell assay system utilizing P0-Cre/EGFP fluorescent time-lapse imaging.
Neural crest cells (NCCs) are embryonic, multipotent stem cells. Their long-range and precision-guided migration is one of their most striking characteristics. We previously reported that P0-Cre/CAG-CAT-lacZ double-transgenic mice showed significant lacZ expression in tissues derived from NCCs. In this study, by embedding a P0-Cre/CAG-CAT-EGFP embryo at E9.5 in collagen gel inside a culture glass slide, we were able to keep the embryo developing ex vivo for more than 24 hours; this development was with enough NCC fluorescent signal intensity to enable single-cell resolution analysis, with the accompanying NCC migration potential intact and with the appropriate NCC response to the extracellular signal maintained. By implantation of beads with absorbed platelet-derived growth factor-AA (PDGF-AA), we demonstrated that PDGF-AA acts as an NCC-attractant in embryos.We also performed assays with NCCs isolated from P0-Cre/CAG-CAT-EGFP embryos on culture plates. The neuromediator 5-hydroxytryptamine (5-HT) has been known to regulate NCC migration. We newly demonstrated that dopamine, in addition to 5-HT, stimulated NCC migration in vitro. Two NCC populations, with different axial levels of origins, showed unique distribution patterns regarding migration velocity and different dose-response patterns to both 5-HT and dopamine. Although avian species predominated over the other species in the NCC study, our novel system should enable us to use mice to assay many different aspects of NCCs in embryos or on culture plates, such as migration, division, differentiation, and apoptosis.


A systematic overview of radiation therapy effects in cervical cancer (cervix uteri).
A systematic review of radiation therapy trials in several tumour types was performed by The Swedish Council of Technology Assessment in Health Care (SBU). The procedures for evaluation of the scientific literature are described separately (Acta Oncol 2003; 42: 357-365). This synthesis of the literature on radiation therapy for cervical cancer is based on data from 1 meta-analysis and 34 randomized trials. In total, 35 scientific articles are included, involving 7 952 patients. The results were compared with those of a similar overview from 1996 including 34 024 patients. The conclusions reached can be summarized in these points: There are limited scientific data supporting that postoperative pelvic radiotherapy improves disease-free survival in early cervical cancer. No firm conclusion can be drawn. There is moderate scientific evidence that external beam radiotherapy combined with brachytherapy gives a similar disease-free and overall survival rate as radical hysterectomy in early cervical cancer. There is strong scientific evidence that concomitant radiochemotherapy improves disease-free and overall survival compared to radiotherapy alone in early cervical cancer. The NCI has recently published an announcement stating that cisplatin-based chemotherapy should be used concomitantly with radiotherapy in cervical cancer. No solid documentation for this statement can be found concerning locally advanced stages ( >IIB). There is a strong scientific evidence that cisplatin-based chemotherapy given concomitantly with radiotherapy is superior to concomitant chemotherapy with hydroxyurea. There is no scientific evidence to show that neoadjuvant chemotherapy followed by radiotherapy improves disease-free or overall survival compared to radiotherapy alone in patients with localized cervical cancer. There is moderate scientific evidence that high-dose-rate brachytherapy gives the same local control rate as low-dose-rate brachytherapy but with fewer rectal complications.


Phytochemical Composition and Detection of Novel Bioactives in Anther Callus of Catharanthus roseus L.
Catharanthus roseus L. (G.) Don is the most widely studied plant because of its high pharmacological value. In vitro culture uses various plant parts such as leaves, nodes, internodes and roots for inducing callus and subsequent plant regeneration in C. roseus. However, till now, little work has been conducted on anther tissue using plant tissue culture techniques. Therefore, the aim of this work is to establish a protocol for in vitro induction of callus by utilizing anthers as explants in MS (Murashige and Skoog) medium fortified with different concentrations and combinations of PGRs. The best callusing medium contains high α-naphthalene acetic acid (NAA) and low kinetin (Kn) concentrations showing a callusing frequency of 86.6%. SEM-EDX analysis was carried out to compare the elemental distribution on the surfaces of anther and anther-derived calli, and the two were noted to be nearly identical in their elemental composition. Gas chromatography-mass spectrometry (GC-MS) analysis of methanol extracts of anther and anther-derived calli was conducted, which revealed the presence of a wide range of phytocompounds. Some of them are ajmalicine, vindolinine, coronaridine, squalene, pleiocarpamine, stigmasterol, etc. More importantly, about 17 compounds are exclusively present in anther-derived callus (not in anther) of Catharanthus. The ploidy status of anther-derived callus was examined via flow cytometry (FCM), and it was estimated to be 0.76 pg, showing the haploid nature of callus. The present work therefore represents an efficient way to produce high-value medicinal compounds from anther callus in a lesser period of time on a larger scale.


Self-efficacy for Coping Moderates the Effects of Distress on Quality of Life in Palliative Cancer Care.
Recent aggressive chemotherapeutic and combined treatments have resulted in increased survivorship for advanced stage breast cancer. In some patients, treatment produces an actual abatement of their cancer, while in others treatment mitigates the progression of cancer bringing those patients into palliative care where their chronic disease requires continuous management. There is also evidence that the majority of palliative-care cancer patients have a deteriorating quality of life that only precipitously declines in the final few weeks of life. The new paradigm of patient-centered care for palliative patients is resulting in a new model of treatment in which the self-efficacy seems to play an important role. The present study represents an extension of the role of self-efficacy for coping to palliative care. Using a stress-coping model, the primary aim of this study was to evaluate a process model, in which self-efficacy for coping with cancer is a moderator between stress and the quality of life in a sample of breast cancer patients in palliative care. The secondary aim was to validate a specific domain coping self-efficacy scale, the Cancer Behavior Inventory. The current study confirmed the role of self-efficacy for coping with cancer as moderator of the relationship between stress and quality of life of a sample of breast cancer patients in palliative care. In addition, this study confirmed the structure, reliability and validity of the scale.


Discriminating Seebeck sensing of molecules.
One of the fundamental challenges in molecular-scale sensors is the junction to junction variability leading to variations in their electrical conductance by up to a few orders of magnitude. In contrast, thermal voltage measurements of single and many molecule junctions show that this variation in the Seebeck coefficient is smaller. Particularly, the sign of the Seebeck coefficient is often resilient against conformational changes. In this paper, we demonstrate that this robust molecular feature can be utilised in an entirely new direction of discriminating molecular sensing of gas and bio-molecules. We show that the positive sign of the Seebeck coefficient in the presence of cytosine nucleobases changes to a negative one when cancerous cytosine nucleobases were absorbed on the molecular wire formed by metalloporphyrins. Furthermore, the sign of the Seebeck coefficient changes when chlorine gas interacts with the Mn-porphyrin molecular wire. The change in the sign of Seebeck coefficient is due to the formation of spin driven bound states with energies close to the Fermi energy of electrodes. Seebeck sensing is a generic concept and opens new avenues for molecular sensing with huge potential applications in the years ahead.


Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation.
Although autosomal forms of nonsyndromic mental retardation account for the majority of cases of mental retardation, the genes that are involved remain largely unknown. We sequenced the autosomal gene SYNGAP1, which encodes a ras GTPase-activating protein that is critical for cognition and synapse function, in 94 patients with nonsyndromic mental retardation. We identified de novo truncating mutations (K138X, R579X, and L813RfsX22) in three of these patients. In contrast, we observed no de novo or truncating mutations in SYNGAP1 in samples from 142 subjects with autism spectrum disorders, 143 subjects with schizophrenia, and 190 control subjects. These results indicate that SYNGAP1 disruption is a cause of autosomal dominant nonsyndromic mental retardation.


Expectant versus aggressive management in severe preeclampsia remote from term.
Our study aims to compare neonatal and maternal outcomes between expectant (or conservative) and aggressive (or immediate) management in cases with severe preclampsia remote from term. This is a comparative study conducted at Al-Batool Teaching Hospital in Mosul City, Iraq, from April 2003 to August 2004. A total of 74 singleton pregnancies complicated by severe preeclampsia with gestational age of 24-34 weeks were studied during this period. The criteria used for the diagnosis of severe preeclampsia were in accordance with the guidelines of the American College of Obstetricians and Gynaecologists. All the patients were counselled for expectant management. 39 patients were delivered immediately due to refusal of expectant management either by the patient or the attending physician. The other 35 patients were managed expectantly; this group was followed-up and carefully monitored for a period ranging from 72 hours to 18 days. Neonatal parameters, neonatal outcome and maternal outcome were compared between the two groups. The mean value of pregnancy prolongation was 9.2 days. Median gestational age for the first group was 29 weeks, and for the second group, it was 30 weeks. Regarding neonatal parameters, the expectantly-managed group had a higher Apgar score at one minute (3.56 +/- 1.72 vs. 5.05 +/- 1.77, p-value equals 0.001), lower mean days of hospitalisation in the neonatal intensive care unit (6.83 +/- 5.38 vs. 4.50 +/- 3.46, p-value equals 0.03), with a lower incidence of neonatal and maternal complications. Expectant management is recommended in patients with severe preeclampsia remote from term, after proper selection of patients and careful monitoring.


Simulated resistance training, but not alendronate, increases cortical bone formation and suppresses sclerostin during disuse.
Mechanical loading modulates the osteocyte-derived protein sclerostin, a potent inhibitor of bone formation. We hypothesized that simulated resistance training (SRT), combined with alendronate (ALEN) treatment, during hindlimb unloading (HU) would most effectively mitigate disuse-induced decrements in cortical bone geometry and formation rate (BFR). Sixty male, Sprague-Dawley rats (6-mo-old) were randomly assigned to either cage control (CC), HU, HU plus either ALEN (HU+ALEN), or SRT (HU+SRT), or combined ALEN and SRT (HU+SRT/ALEN) for 28 days. Computed tomography scans on days -1 and 28 were taken at the middiaphyseal tibia. HU+SRT and HU+SRT/ALEN rats were subjected to muscle contractions once every 3 days during HU (4 sets of 5 repetitions; 1,000 ms isometric + 1,000 ms eccentric). The HU+ALEN and HU+SRT/ALEN rats received 10 μg/kg ALEN 3 times/wk. Compared with the CC animals, HU suppressed the normal slow growth-induced increases of cortical bone mineral content, cortical bone area, and polar cross-sectional moment of inertia; however, SRT during HU restored cortical bone growth. HU suppressed middiaphyseal tibia periosteal BFR by 56% vs. CC (P < 0.05). However, SRT during HU restored BFR at both periosteal (to 2.6-fold higher than CC) and endocortical (14-fold higher than CC) surfaces (P < 0.01). ALEN attenuated the SRT-induced BFR gains during HU. The proportion of sclerostin-positive osteocytes in cortical bone was significantly higher (+121% vs. CC) in the HU group; SRT during HU effectively suppressed the higher proportion of sclerostin-positive osteocytes. In conclusion, a minimum number of high-intensity muscle contractions, performed during disuse, restores cortical BFR and suppress unloading-induced increases in sclerostin-positive osteocytes.


Knockdown of FOXO6 Inhibits Glycolysis and Reduces Cell Resistance to Paclitaxel in HCC Cells via PI3K/Akt Signaling Pathway.
Previous studies have reported that FOXO6 is highly expressed in hepatocellular carcinoma (HCC) tissues and is associated with the prognosis of HCC patients. However, little research has been carried out to explore the role of FOXO6 in glycolysis of HCC cells and paclitaxel resistance. Today, along with the increasing incidence and mortality of HCC, chemotherapy resistance of HCC also poses a serious challenge. Therefore, this study was set out to investigate the effect of FOXO6 on glycolysis and cytotoxicity of paclitaxel in HCC cells and its potential mechanism. The levels of FOXO6 mRNA and protein were detected by qRT-PCR and Western blot, respectively. In addition, paclitaxel-resistant cell lines of HCC cells were established, whose activity was assessed by CCK-8 assay, among which the invasion ability was assessed by Transwell and the apoptosis rate by flow cytometry. What is more, glycolysis levels were evaluated by measuring glucose consumption and lactic acid production, and the protein levels of p-PI3K and p-protein kinase B (Akt) were determined by Western blot. Compared with normal human hepatocytes, FOXO6 was highly expressed in HCC cells, which was of high real value for HCC. FOXO6 knockdown inhibited the proliferation and invasion and induced apoptosis of HCC cells. In addition, FOXO6 knockdown suppressed glycolysis, reversed resistance to chemotherapy in Hep3B/PTX cells and inactivated PI3K and Akt proteins, thus inhibiting the PI3K/Akt signaling pathway. Furthermore, it was found that when activated by 740Y-P, PI3K/Akt signaling pathway could resist the effects of FOXO6 knockdown on the cytotoxicity and glycolysis of paclitaxel in HCC cells. Vice versa, inhibition of PI3K/Akt pathway by LY294002 could resist the effect of FOXO6 overexpression on chemotherapy, cytotoxicity and glycolysis of HCC cells. FOXO6 knockdown can inhibit glycolysis of HCC cells and reduce their resistance to chemotherapy by inhibiting the PI3K/Akt signaling pathway, which may be a new target for the treatment of HCC.


Pay for obesity? Pay-for-performance metrics neglect increased complication rates and cost for obese patients.
Rates of surgical complications are increasingly being used for pay-for-performance reimbursement structures. We hypothesize that morbid obesity has a significant effect on complication rates and costs following commonly performed general surgical procedures. We studied 30,502 patients who underwent cholecystectomy for cholecystitis and 6,390 patients who underwent appendectomy for acute appendicitis using administrative claims data from seven Blue Cross and Blue Shield Plans over a 7-year period (2002-2008). We compared 30-day complications as well as total 30-day direct medical costs for obese and non-obese patients. Multivariate regressions were performed to determine the relationship of morbid obesity to complications and cost. Obese patients were more likely to have a complication within 30 days after surgery than non-obese patients (19.2% vs. 15.7% for cholecystectomy, p < 0.0001; 20.2% vs. 15.2%, p < 0.0001, for appendectomy). The mean total 30-day postoperative cost for obese patients were $1,109 higher following a cholecystectomy (p < 0.0001) and $666 higher following an appendectomy (p = 0.09). Morbid obesity is associated with a higher rate of complications for two commonly performed general surgical procedures and is associated with higher costs for cholecystectomy. Pay-for-performance metrics should account for the increased risk of complications and higher cost in this population.


Assessing the Temperamental Basis of the Sense of Humor: Adaptation of the English Language Version of the State-Trait Cheerfulness Inventory Long and Standard Form.
The State-Trait Model of Cheerfulness assesses the temperamental basis of the sense of humor with the traits and respective states of cheerfulness, seriousness, and bad mood. Cheerfulness is a dominant factor in current measures of the sense of humor and explains both, the disposition to engaging in smiling and laughter, as well as humor behaviors, and trait seriousness and bad mood are antagonistic to the elicitation of amusement (albeit for different reasons). Several studies have shown the validity and reliability of the STCI questionnaire in German and other language versions (i.e., Spanish). In this study, the English language version with 106 items (STCI-T <106>) was translated, checked for its item and scale characteristics, and tested with a confirmatory factor analysis approach (N = 1101) to investigate the factorial validity of the STCI-T <106> scale. Results show good psychometric characteristics, good internal consistencies, and a fit to the postulated underlying structure of the STCI-T. Then, the standard form with 60 items (STCI-T <60>) was developed and the psychometric characteristics initially tested. In an independent sample (N = 169), the characteristics of the standard form were compared to the parent form and German equivalent. It showed good psychometric characteristics, internal consistencies, as well as a good self- and peer-report congruence. To conclude, the STCI-T <106> is the measure of choice for the assessment of the temperamental basis of the sense of humor and the separate facets of the traits, while the standard form (60 items) allows of an economic assessment of cheerfulness, seriousness, and bad mood, free of context-saturated items and humor preferences.


Long-term outcome of a covered vs. uncovered transjugular intrahepatic portosystemic shunt in Budd-Chiari syndrome.
The clinical outcome of a covered vs. uncovered transjugular intrahepatic portosystemic shunt (TIPS) for patients with Budd-Chiari syndrome (BCS) is as yet largely unknown. To compare patency rates of bare and polytetrafluoroethylene (PTFE)-covered stents, and to investigate clinical outcome using four prognostic indices [Child-Pugh score, Rotterdam BCS index, modified Clichy score and Model for End-Stage Liver Disease (MELD)]. Consecutive patients with BCS who had undergone TIPS between January 1994 and March 2006 were evaluated in a retrospective review in a single centre. Twenty-three TIPS procedures were performed on 16 patients. The primary patency rate at 2 years was 12% using bare and 56% using covered stents (P=0.09). We found marked clinical improvement at 3 months post-TIPS as determined by a drop in median Child-Pugh score (10-7, P=0.04), Rotterdam BCS index (1.90-0.83, P=0.02) and modified Clichy score (7.77-2.94, P=0.003), but not in MELD (18.91-17.42, P=0.9). Survival at 1 and 3 years post-TIPS was 80% (95% CI: 59-100%) and 72% (95% CI: 48-96%). Four patients (25%) died and one required liver transplantation. A transjugular intrahepatic portosystemic shunt using PTFE-covered stents shows better patency rates than bare stents in BCS. Moreover, TIPS leads to an improvement in important prognostic indicators for the survival of patients with BCS.


Reactive perforating collagenosis of diabetes mellitus and renal failure.
We believe that the disease we are reporting is associated with diabetes, particularly in patients on renal dialysis, and the perforation is initiated by scratching. Decreasing pruritus is the only needed treatment as the lesions tend to resolve on their own. While this entity has been called Kyrle's disease, it more correctly is reactive perforating collagenosis, both clinically and histologically. Whether this is a variant of what Kyrle originally described is not clear. We propose that this entity be called reactive perforating collagenosis of diabetes and renal failure.


Isolation and characterization of the recA gene of Rhizobium meliloti.
Interspecific complementation of an Escherichia coli recA mutant with plasmids containing a gene bank of Rhizobium meliloti DNA was used to identify a clone which contains the recA gene of R. meliloti. The R. meliloti recA protein can function in recombination and in response to DNA damage when expressed in an E. coli recA host, and hybridization studies have shown that DNA sequence homology exists between the recA gene of E. coli and that of R. meliloti. The isolated R. meliloti recA DNA was used to construct a recA R. meliloti, and this bacterium was not deficient in its ability to carry out symbiotic nitrogen fixation.


Multiple sclerosis and the role of immune cells.
Multiple sclerosis (MS) is a complex disease with many different immune cells involved in its pathogenesis, and in particular T cells as the most recognized cell type. Recently, the innate immune system has also been researched for its effect on the disease. Hence, cells of the immune system play vital roles in either ameliorating or exacerbating the disease. The genetic and environmental factors, as well as the etiology and pathogenesis are of utmost importance for the development of MS. An insight into the roles play by T cells, B cells, natural killer cells, and dendritic cells in MS and the animal model experimental autoimmune encephalomyelitis, will be presented. Understanding the mechanisms of action for current therapeutic modalities should help developing new therapeutic tools to treat this disease and other autoimmune diseases.


DESPERATE TIMES CALL FOR DESPERATE MEASURES: GOVERNMENT SPENDING MULTIPLIERS IN HARD TIMES.
We investigate state-dependent effects of fiscal multipliers and allow for endogenous sample splitting to determine whether the U.S. economy is in a slack state. When the endogenized slack state is estimated as the period of the unemployment rate higher than about 12%, the estimated cumulative multipliers are significantly larger during slack periods than nonslack periods and are above unity. We also examine the possibility of time-varying regimes of slackness and find that our empirical results are robust under a more flexible framework. Our estimation results point out the importance of the heterogenous effects of fiscal policy and shed light on the prospect of fiscal policy in response to economic shocks from the current COVID-19 pandemic. (JEL C32, E62, H20, H62).


Bimanual training for children with cerebral palsy: exploring the effects of Lissajous-based computer gaming.
Hemiplegic cerebral palsy often results in impaired bimanual coordination, partly due to strong coupling between the arms. We aimed at inducing more flexibility in this coupling, to improve bimanual coordination. We designed computer games involving simple perceptual goals, based on Lissajous feedback. Such feedback implicitly facilitates the performance of complex rhythmic bimanual coordination patterns. A sample of six children received 9 h of computer training over a 6 weeks period. The effects of this training on functional bimanual performance were explored using the Assisting Hand Assessment (AHA). Gaming performance and bimanual rhythmic antiphase coordination improved after training. The AHA results were mixed. Two children improved significantly, but at a group level no significant effects were found. The results were evaluated in relation to the specificity of the AHA and the potential benefit of combining the proposed training with dedicated bimanual functional training programs.


Computational Prediction of Pathogenic Network Modules in Fusarium verticillioides.
Fusarium verticillioides is a fungal pathogen that triggers stalk rots and ear rots in maize. In this study, we performed a comparative analysis of wild type and loss-of-virulence mutant F. verticillioides co-expression networks to identify subnetwork modules that are associated with its pathogenicity. We constructed the F. verticillioides co-expression networks from RNA-Seq data and searched through these networks to identify subnetwork modules that are differentially activated between the wild type and mutant F. verticillioides, which considerably differ in terms of pathogenic potentials. A greedy seed-and-extend approach was utilized in our search, where we also used an efficient branch-out technique for reliable prediction of functional subnetwork modules in the fungus. Through our analysis, we identified four potential pathogenicity-associated subnetwork modules, each of which consists of interacting genes with coordinated expression patterns, but whose activation level is significantly different in the wild type and the mutant. The predicted modules were comprised of functionally coherent genes and topologically cohesive. Furthermore, they contained several orthologs of known pathogenic genes in other fungi, which may play important roles in the fungal pathogenesis.


Immune Reconstitution Therapy or Continuous Immunosuppression for the Management of Active Relapsing-Remitting Multiple Sclerosis Patients? A Narrative Review.
The majority of disease-modifying drugs (DMDs) available for the management of active relapsing-remitting multiple sclerosis (RMS) depend on continuous drug intake for maintained efficacy, with escalation to a more active drug when an unacceptable level of disease activity returns. Among continuously applied regimens, interferons and glatiramer acetate act as immunomodulators, while dimethyl fumarate, fingolimod, ocrelizumab, natalizumab and teriflunomide are associated with continuous immunosuppression. By contrast, immune reconstitution therapy (IRT) provides efficacy that outlasts a short course of treatment. Autologous hemopoietic stem cell transplantation is perhaps the classic example of IRT, but this invasive and intensive therapy has challenging side-effects. A short treatment course of a pharmacologic agent hypothesized to act as an IRT, such as Cladribine Tablets 3.5 mg/kg or alemtuzumab, can provide long-term suppression of MS disease activity, without need for continuous treatment (the anti-CD20 mechanism of ocrelizumab has the potential to act as an IRT, but is administered continuously, at 6-monthly intervals). Cladribine Tablets 3.5 mg/kg shows some selectivity in targeting adaptive immunity with a lesser effect on innate immunity. The introduction of IRT-like disease-modifying drugs (DMDs) challenges the traditional maintenance/escalation mode of treatment and raises new questions about how disease activity is measured. In this review, we consider a modern classification of DMDs for MS and its implications for the care of patients in the IRT era.


Pictures of you: Dot stimuli cause motor contagion in presence of a still human form.
In this study, we investigate which visual cues induce participants to encode a non-human motion stimulus in their motor system. Participants performed reach-to-grasp actions to a target after observing a dot moving in a direct or higher-arcing path across a screen. Dot motion occurred in the presence of a meaningless (scrambled human model) stimulus, a still human model, or a human model performing a direct or exaggeratedly curved reach to a target. Our results show that observing the dot displacement causes motor contagion (changes in the height of the observer's hand trajectory) when a human form was visually present in the background (either moving or still). No contagion was evident, however, when this human context was absent (i.e., human image scrambled and not identifiable). This indicates that visual cues suggestive of human agency can determine whether or not moving stimuli are encoded in the motor system.


Evaluation of Right-Side Filling Pressure in Patients With Obesity With Heart Failure Using Handheld Ultrasound Score.
The goal of this investigation is to evaluate the accuracy of handheld ultrasound score in assessing right atrial (RA) pressure in patients with obesity with heart failure. We prospectively studied 123 patients with heart failure referred for right-sided cardiac catheterization. Handheld ultrasound was performed before catheterization to evaluate volume status by estimating RA pressure using end-expiratory inferior vena cava (IVC) dimension, IVC respiratory collapsibility, and right internal jugular (RIJ) vein respiratory collapsibility. A 3-point simple score was created using multiple logistic regression. The patients were divided into 2 groups based on body mass index. The performance of this score was assessed using the receiver operating characteristics curve in each subgroup and was compared with the performance of the 2-point score (expiratory IVC dimension, IVC respiratory collapsibility). Median age was 58 years (interquartile range 48 to 65), and 37% were women. The 3-point score including RIJ performed better than did the 2-point score in patients with obesity (area under the curve 0.84 [0.74 to 0.95] vs 0.69 [0.58 to 0.81], p = 0.001). The performance of the scores did not differ in patients without obesity (area under the curve 0.85 [0.74 to 0.95] vs 0.82 [0.71 to 0.93], p = 0.49). In patients with obesity, the 3-point score had a specificity of 100% and sensitivity of 21% (11% to 31%) for elevated RA pressure ≥10 mm Hg. In conclusion, a 3-point score including both RIJ and IVC assessment performed better in patients with obesity with heart failure and highlights the importance of comprehensive evaluation in patients with obesity to achieve an accurate, noninvasive assessment of volume status.


Expressions of EphA2 and EphrinA-1 in early squamous cell cervical carcinomas and their relation to prognosis.
By using immunohistochemistry we investigated the expression of EphA2 and EphrinA-1 in 217 early squamous cell cervical carcinomas and examine their prognostic relevance. For EphA2 expression, 21 tumors (10%) showed negative, 108 (50%) weak positive, 69 (32%) moderate positive and 19 (9%) strong positive, whereas for EphrinA-1 expression, 33 tumors (15%) showed negative, 91 (42%) weak positive, 67 (31%) moderate positive and 26 (12%) strong positive. In univariate analysis high expression (strong staining) of EphrinA-1 was associated with poor disease-free (P = 0.033) and disease-specific (P = 0.039) survival. However, in the multivariate analyses neither EphrinA-1 nor EphA2 was significantly associated to survival. The increased levels of EphA2 and EphrinA-1 in a relative high number of early stage squamous cell carcinomas suggested that these two proteins may play an important role in the development of a subset of early cervical cancers. However, EphA2 and EphrinA-1 were not independently associated with clinical outcome.


High-performance blue electroluminescent devices based on 2-(4-biphenylyl)-5-(4-carbazole-9-yl)phenyl-1,3,4-oxadiazole.
An electron transporting moiety (1,3,4-oxadiazole) and a hole transporting moiety (carbazole) were combined to create 2-(4-biphenylyl)-5-(4-carbazole-9-yl)phenyl-1,3,4-oxadiazole (CzOxa), a three layer device with a configuration of ITO/TPD(50 nm)/CzOxa(40 nm)/AlQ(40 nm)/Mg0.9Ag0.1(200 nm)/Ag(80 nm) which exhibited a blue emission peak at approximately 470 nm (x = 0.14, y = 0.19) with a maximum luminance of 26,200 cd m(-2) at a drive voltage of 15 V and a maximum luminous efficiency of 2.25 lm W(-1).


Influence of Biofilm Formation by Gardnerella vaginalis and Other Anaerobes on Bacterial Vaginosis.
Bacterial vaginosis (BV) is the worldwide leading vaginal disorder among women of reproductive age. BV is characterized by the replacement of beneficial lactobacilli and the augmentation of anaerobic bacteria. Gardnerella vaginalis is a predominant bacterial species, but BV is also associated with other numerous anaerobes, such as Atopobium vaginae, Mobiluncus mulieris, Prevotella bivia, Fusobacterium nucleatum, and Peptoniphilus species. Currently, the role of G. vaginalis in the etiology of BV remains a matter of controversy. However, it is known that, in patients with BV, a biofilm is usually formed on the vaginal epithelium and that G. vaginalis is typically the predominant species. So, the current paradigm is that the establishment of a biofilm plays a key role in the pathogenesis of BV. This review provides background on the influence of biofilm formation by G. vaginalis and other anaerobes, from the time of their initial adhesion until biofilm formation, in the polymicrobial etiology of BV and discusses the commensal and synergic interactions established between them to understand the phenotypic shift of G. vaginalis biofilm formation to BV establishment.


Trypanosome infection in dromedary camels in Eastern Ethiopia: Prevalence, relative performance of diagnostic tools and host related risk factors.
A cross-sectional study was conducted in Chifra and Dewe districts of Afar region, Eastern Ethiopia, to determine the prevalence, agreement between diagnostic tests and host related risk factors of trypanosome infection in camel. An overall prevalence of 2%, 24.1%, 21.3%, 9.5% and 7.8% was recorded with respectively Giemsa stained thin blood smear, CATT/T. evansi, RoTat1.2 PCR, 18S PCR and ITS-1PCR in a cohort of 399 animals. Only one T. vivax infection was confirmed by TvPRAC PCR indicating T. evansi as the predominant species affecting camels in the study area. No single animal was positive when tested with T. evansi type B specific EVAB PCR. There was slight agreement between the CATT/T. evansi and the molecular tests. Among the PCR methods, RoTat 1.2 PCR yielded a significantly higher positivity rate compared to 18S PCR and ITS-1 PCR. There was no significant difference in the positivity rate observed in each gender of camels (p>0.05). The positivity rate was significantly higher in camels with poor body condition and in older animals when tested using the CATT/T.evansi or RoTat 1.2 PCR (p>0.05). Camels that tested positive with all tests had significantly lower PCV's (p<0.05). This study provides further evidence that T. evansi is endemic in the Afar region of Ethiopia. The latent class analysis indicated an estimate overall prevalence of 19% (95% CI: 13-28). Moreover, the model indicated low sensitivity of CATT/T. evansi (43%) and the PCR tests (39-53%) but higher specificity of the PCR tests (86-99%) and low specificity of CATT/T. evansi (80%). This study suggests that improved sensitivity and reliability of the tests would help diagnosis of trypanosomosis. Further studies are required to determine the prevalence of clinical disease and losses due to trypanosomosis.


From war nursery to therapeutic milieu.
The issue of violence in childhood and society is reviewed from the comparative perspective of the care of children by Anna Freud and her colleagues during the bombing of World War II and the plight of seriously troubled children and adolescents living in poverty and in violent families in contemporary society. Consistent with observations reported by Mahron, violence among these children is understood as a response to a world experience that is depleting and overwhelming; some sense of being alive is provided through aggressive behavior. Founded on the concept of the therapeutic milieu as described by Aichhorn, Bettelheim, and Redl and Wineman, the psychoanalytic intervention program described here fosters enhanced capacity for tension management and ego development via techniques of crisis management within the group living situation, incorporating the life-space or marginal interview, therapeutic education, and psychotherapy.


Average reference EEG lateralization in schizophrenic patients.
The authors transformed 9 channels of electroencephalogram (EEG) to 10 channels of average reference data and compared EEG asymmetry between medication-free (for 2 weeks) schizophrenic male patients (n = 14), male patients with affective disorder (n = 9), and normal males (n = 13). Multivariate analyses failed to find lateralized differences between groups in resting and task EEG. Neuroleptic treatment (n = 11) was associated with asymmetrical changes in beta power rather than in alpha and theta, as previously reported. There were no relationships between clinical ratings (based on the Brief Psychiatric Rating Scale and subscales) and alpha asymmetry. The authors discuss conflicts with previous findings and the advantages of minimizing reference bias when studying EEG topography.


Is Sweden still a role model for safety? An overview of unintentional injury data over the past two decades.
This study investigates injury-related mortality and hospitalisations, during 1987-2007 in Sweden. Injuries were classified according to International Classification of Diseases (ICD)--8 for pre-1987 injuries, ICD-9 for 1987-1996 injuries and ICD-10 for injuries occurring in 1997 and later. Data on mortality from injuries during 1987-2007 were collected from Sweden's national Cause-of-Death Register, while data concerning injury diagnoses leading to hospitalisation stays of at least 24 h, occurring during 1987-2007, were obtained from the national Patient Register. Crude rates were derived for injury-related deaths and injury-related hospitalisations for age-gender groups, using population data from Statistics Sweden. Our results showed a mixed picture of injury-related hospitalisations and deaths over the study period. Absolute numbers of injury-related deaths and injury-related hospitalisations decreased over time for the population as a whole and for many, but not all, age-gender groups. When assessing crude injury-related death rates and crude injury-related hospitalisation rates over time, as categorised by gender and age groupings, we also found unchanging or increased risks for injury-related deaths and/or hospitalisations for several age-gender groups. While Sweden has made remarkable progress in reducing injury-related deaths and hospitalisations, there are clear differences in risk that remain.


[A factor activating protein synthesis in rat liver microsomes: its induction by a glucocorticoid hormone].
Injection of glucocorticoid hormone to adrenalectomized rats induces in liver microsomes a factor which stimulates polypeptide synthesis in a cell-free system. The factor is extractable from microsomes by 0.5 M KC1 followed by gel filtration, of the extract. Induction of the activator in glucocorticoid-treated rats contribute higher protein-synthesizing ability of the microsomes following hormone administration.


Aerobic exercise during pregnancy and presence of fetal-maternal heart rate synchronization.
It has been shown that short-term direct interaction between maternal and fetal heart rates may take place and that this interaction is affected by the rate of maternal respiration. The aim of this study was to determine the effect of maternal aerobic exercise during pregnancy on the occurrence of fetal-maternal heart rate synchronization. In 40 pregnant women at the 36th week of gestation, 21 of whom exercised regularly, we acquired 18 min. RR interval time series obtained simultaneously in the mothers and their fetuses from magnetocardiographic recordings. The time series of the two groups were examined with respect to their heart rate variability, the maternal respiratory rate and the presence of synchronization epochs as determined on the basis of synchrograms. Surrogate data were used to assess whether the occurrence of synchronization was due to chance. In the original data, we found synchronization occurred less often in pregnancies in which the mothers had exercised regularly. These subjects also displayed higher combined fetal-maternal heart rate variability and lower maternal respiratory rates. Analysis of the surrogate data showed shorter epochs of synchronization and a lack of the phase coordination found between maternal and fetal beat timing in the original data. The results suggest that fetal-maternal heart rate coupling is present but generally weak. Maternal exercise has a damping effect on its occurrence, most likely due to an increase in beat-to-beat differences, higher vagal tone and slower breathing rates.


Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas.
Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment. In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets. We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (β-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs). Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-β pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-β-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%-20% of PDTCs, and in 10%-14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected. Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-β pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment.


Degree of familiarity ART2 in knowledge-based landmine detection.
The self-organizing network ART2 is extended to provide a fuzzy output value, which indicates the degree of familiarity of a new analog input pattern to previously stored patterns in the long-term memory of the network. The outputs of the multilayer perceptron and this modified ART2 provide an analog value to a fuzzy rule-based fusion technique which also uses a processed polarization resolved image as its third input. In real-time situations these two classifier outputs indicate the likelihood of a surface landmine target when presented with a number of multispectral and textural bands. Due to the modifications in ART2 this updated alternative architecture (to that of a previous network in [3]) has improved real-time landmine detection capabilities although the registration of all bands is more critical to the accuracy of results in this case. The real-time fuzzy rule-based system in preliminary tests has detected two of the three landmines and the landmine surrogate with two false alarms. Advanced tests on 30 images using the fuzzy rule-based system further confirmed the distinct advantages of fusion and improved detection rates.


Proteomic analysis of V-ATPase-rich cells harvested from the kidney and epididymis by fluorescence-activated cell sorting.
Proton-transporting cells are located in several tissues where they acidify the extracellular environment. These cells express the vacuolar H(+)-ATPase (V-ATPase) B1 subunit (ATP6V1B1) in their plasma membrane. We provide here a comprehensive catalog of the proteins that are expressed in these cells, after their isolation by enzymatic digestion and fluorescence-activated cell sorting (FACS) from transgenic B1-enhanced green fluorescent protein (EGFP) mice. In these mice, type A and B intercalated cells and connecting segment cells of the kidney, and narrow and clear cells of the epididymis, which all express ATP6V1B1, also express EGFP, while all other cell types are negative. The proteome of renal and epididymal EGFP-positive (EGFP(+)) cells was identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and compared with their respective EGFP-negative (EGFP(-)) cell populations. A total of 2,297 and 1,564 proteins were detected in EGFP(+) cells from the kidney and epididymis, respectively. Out of these proteins, 202 and 178 were enriched by a factor greater than 1.5 in EGFP(+) cells compared with EGFP(-) cells, in the kidney and epididymis respectively, and included subunits of the V-ATPase (B1, a4, and A). In addition, several proteins involved in intracellular trafficking, signaling, and cytoskeletal dynamics were identified. A novel common protein that was enriched in renal and epididymal EGFP(+) cells is the progesterone receptor, which might be a potential candidate for the regulation of V-ATPase-dependent proton transport. These proteomic databases provide a framework for comprehensive future analysis of the common and distinct functions of V-ATPase-B1-expressing cells in the kidney and epididymis.


Stability of normal human fecal flora during a chemically defined, low residue liquid diet.
Ten adult male volunteers (medical students) subsisted for seven days upon a chemically defined, low residue liquid diet, and consumed 1200-1800 calories per day. All stools were collected; three were cultured within the hour-a prediet stool, one collected on the seventh day, and a postdiet stool. Specimens were diluted anaerobically, and anaerobic cultures were streaked upon plates of prereduced agar media and incubated in Brewer jars. During the low residue diet, total fecal mass was relatively small and each subject passed only two or three stools. The mean reduction in daily fecal output was 70%. Mean counts of total aerobes were 10-7/gm throughout the study, and mean counts of total anaerobes were 10-10/gm. There was no overgrowth by opportunistic bacteria or fungi. The low residue food did not alter fecal flora; there was neither disappearance nor reduction of any bacterial group.


The Biology of the Triatomine Bugs Native to South Central Texas and Assessment of the Risk They Pose for Autochthonous Chagas Disease Exposure.
Triatomine bugs are a group of hematophagous arthropods that can serve as biological vectors for Trypanosoma cruzi , the etiological agent of American trypanosomiasis (Chagas disease). Because of differences in the biology and feeding habits among triatomine species, some are more likely than others to be involved in zoonotic and/or human-to-human transmission cycles of T. cruzi . In an attempt to assess the risk for Chagas disease exposure in south-central Texas, human habitations across Texas Health Service Region 8 (HSR 8) and surrounding counties were surveyed for triatomines to characterize the geographic distribution, species-specific biology, and T. cruzi -infection prevalence better. Between May 2010 and August 2013, a total of 545 triatomines representing all 5 known indigenous species (Triatoma gerstaeckeri, Triatoma indictiva, Triatoma lecticularia, Triatoma sanguisuga, and Triatoma protracta woodi) were collected from 59 sites across the region. Triatoma gerstaeckeri was the species most commonly found in domestic and peridomestic ecotopes across Texas HSR 8, representing over 80% of the triatomines collected. Adult T. gerstaeckeri exhibited a seasonal dispersal pattern that began in late April, peaked in mid-May, and then continued into August. On homes with available crevices in the exterior walls, adult T. gerstaeckeri were observed emerging from or entering these protective microhabitats, suggesting possible opportunistic colonization of some exterior walls compartments. Laboratory testing of triatomine hindgut contents for T. cruzi by PCR demonstrated the adult T. gerstaeckeri-infection prevalence across Texas HSR 8 to be 64%. Monitoring peridomestic adult T. gerstaeckeri over the seasonal dispersal peak demonstrated statistically significant increases in both their T. cruzi -infection prevalence (P < 0.01) and tendency to invade human dwellings (P < 0.01) in the later aspect of the emergence peak. In addition to the adult insects, variably sized and staged nymphs were recovered from the inside of 6 separate homes across Texas HSR 8. The results of this study show that T. gerstaeckeri is a widespread and common triatomine species across Texas HSR 8 and documented it to have some notable synanthropic tendencies. The high prevalence of T. cruzi infection in native triatomines, and the high frequency with which T. gerstaeckeri is recovered from human habitations, suggests that there is a risk for human exposure to T. cruzi in Texas HSR 8. Because of this, Chagas disease should be considered on the list of differential diagnoses for cases of cardiac arrhythmia, dilated cardiomyopathy, or heart failure in south-central Texas.


A halothane test to detect turkeys prone to developing pale, soft, and exudative meat.
The turkey industry suffers from pale, soft, and exudative meat (PSE) that is unsuitable for further processing because of excessive color variation, poor meat binding, and depressed water holding ability. This condition is caused by accelerated postmortem muscle metabolism and is thought to be related to a similarly inherited condition in swine. A quick, nondestructive method of screening animals is needed to avoid further propagation of PSE in breeding flocks. In this study, a halothane test used with swine was evaluated as a possible detection method for PSE-susceptible turkeys. In Experiment 1, a commercial strain of 4-wk-old male turkeys (n = 116) was exposed to 3% halothane gas for 3 min (6 L/min) and examined for leg muscle rigidity. Experiment 2 followed similar testing measures, using two strains of growth-selected turkeys (n = 504). Measurements of pH, R-value (ratio of inosine:adenosine), color, and expressible moisture content were made from each bird's breast fillet to determine whether the muscles of the responding birds would develop PSE characteristics. Five percent of tested birds in the first experiment and 2% in the second experiment exhibited rigid legs, indicating some of the discriminating power of this test. However, the data indicated that the characteristics of muscles from these birds did not differ from those of the nonresponding birds (P < 0.05). Possibly, the birds may need to be screened or slaughtered at a different age or using different methods.


Effect of salt shock on stability of lambdaimm434 lysogens.
The affinities of the bacteriophage 434 repressor for its various binding sites depend on the type and/or concentration of monovalent cations. The ability of bacteriophage 434 repressor to govern the lysis-lysogeny decision depends on the DNA binding activities of the phage's cI repressor protein. We wished to determine whether changes in the intracellular ionic environment influence the lysis-lysogeny decision of the bacteriophage lambda(imm434). Our findings show that the ionic composition within bacterial cells varies with the cation concentration in the growth media. When lambda(imm434) lysogens were grown to mid-log or stationary phase and subsequently incubated in media with increasing monovalent salt concentrations, we observed a salt concentration-dependent increase in the frequency of bacteriophage spontaneous induction. We also found that the frequency of spontaneous induction varied with the type of monovalent cation in the medium. The salt-dependent increase in phage production was unaffected by a recA mutation. These findings indicate that the salt-dependent increase in phage production is not caused by activation of the SOS pathway. Instead, our evidence suggests that salt stress induces this lysogenic bacteriophage by interfering with 434 repressor-DNA interactions. We speculate that the salt-dependent increase in spontaneous induction is due to a direct effect on the repressor's affinity for DNA. Regardless of the precise mechanism, our findings demonstrate that salt stress can regulate the phage lysis-lysogeny switch.


Ultrasound-Assisted Hydrothermal Synthesis of Highly Fluorescent Sulfur Quantum Dots for Fe3+ Ion and Ascorbic Acid Detection in Real Samples.
In this work, the ultrasound-assisted hydrothermal synthesis method offers a facile method to synthesize highly efficient photoluminescence sulfur quantum dots (SQDs). Impressively, a switchable fluorescent "on-off-on" sensor was developed using the acquired SQDs, which are capable of sequentially detecting iron ions (Fe3+) and ascorbic acid (AA) with exceptional sensitivity and selectivity. Meanwhile, SQDs and Fe3+ formed complexes through coordination, causing the fluorescence quenching of SQDs because of the static quenching effect. Upon the addition of AA into the SQDs/Fe3+ system, a redox-reaction-mediated mechanism leads to the recovery of fluorescence. The fluorescence intensity of SQDs exhibits a linear relationship with the concentrations of Fe3+ and AA in the ranges 5-30 and 20-100 μM, respectively. Notably, the detection limits achieved are 14.31 nM for Fe3+ and 0.64 μM for AA. Moreover, the chemosensor was successfully employed for monitoring Fe3+ in real water samples and AA in fruits. These results demonstrate the excellent analysis and detection capabilities of SQDs in the complex environment.


Online Size-exclusion and Ion-exchange Chromatography on a SAXS Beamline.
Biological small angle X-ray scattering (BioSAXS) is a powerful technique in molecular and structural biology used to determine solution structure, particle size and shape, and surface-to-volume ratio of macromolecules. The technique is applicable to a very wide variety of solution conditions spanning a broad range of concentrations, pH values, ionic strengths, temperatures, additives, etc., but the sample is required to be monodisperse. This caveat led to the implementation of liquid chromatography systems on SAXS beamlines. Here, we describe the upstream integration of size-exclusion (SEC) and ion-exchange chromatography (IEC) on a beamline, different methods for optimal background subtraction, and data reduction. As an example, we describe how we use SEC- and IEC-SAXS on a fragment of the essential vaccinia virus protein D5, consisting of a D5N helicase domain. We determine its overall shape and molecular weight, showing the hexameric structure of the protein.


IL-23 is required for the development of severe egg-induced immunopathology in schistosomiasis and for lesional expression of IL-17.
In infection with the trematode helminth Schistosoma mansoni, the severity of CD4 T cell-mediated hepatic granulomatous and fibrosing inflammation against parasite eggs varies considerably in humans and among mouse strains. In mice, either the natural high pathology, or high pathology induced by concomitant immunization with schistosome egg Ags (SEA) in CFA (SEA/CFA), results from a failure to contain a net proinflammatory cytokine environment. We previously demonstrated that the induction of severe immunopathology was dependent on the IL-12/IL-23 common p40 subunit, and correlated with an increase in IL-17, thus implying IL-23 in the pathogenesis. We now show that mice lacking the IL-23-specific subunit p19 are impaired in developing severe immunopathology following immunization with SEA/CFA, which is associated with a marked drop of IL-17 in the granulomas, but not in the draining mesenteric lymph nodes, and with a markedly suppressed SEA-specific IFN-gamma response regulated by a striking increase in IL-10. The granulomas are characterized by a significant reduction in Gr-1(+) cell recruitment and by alternative macrophage activation. Taken together, these results demonstrate that IL-23 per se is not necessary for the generation of IL-17-producing T cells, but is essential for the development of severe schistosome egg-induced immunopathology, and its absence cannot be overcome with other possible compensatory mechanisms.


Absolute quantitation of isoforms of post-translationally modified proteins in transgenic organism.
Post-translational modification isoforms of a protein are known to play versatile biological functions in diverse cellular processes. To measure the molar amount of each post-translational modification isoform (P(isf)) of a target protein present in the total protein extract using mass spectrometry, a quantitative proteomic protocol, absolute quantitation of isoforms of post-translationally modified proteins (AQUIP), was developed. A recombinant ERF110 gene overexpression transgenic Arabidopsis plant was used as the model organism for demonstration of the proof of concept. Both Ser-62-independent (14)N-coded synthetic peptide standards and (15)N-coded ERF110 protein standard isolated from the heavy nitrogen-labeled transgenic plants were employed simultaneously to determine the concentration of all isoforms (T(isf)) of ERF110 in the whole plant cell lysate, whereas a pair of Ser-62-dependent synthetic peptide standards were used to quantitate the Ser-62 phosphosite occupancy (R(aqu)). The P(isf) was finally determined by integrating the two empirically measured variables using the following equation: P(isf) = T(isf) · R(aqu). The absolute amount of Ser-62-phosphorylated isoform of ERF110 determined using AQUIP was substantiated with a stable isotope labeling in Arabidopsis-based relative and accurate quantitative proteomic approach. The biological role of the Ser-62-phosphorylated isoform was demonstrated in transgenic plants.


Cucurbitacin B induces autophagy and apoptosis by suppressing CIP2A/PP2A/mTORC1 signaling axis in human cisplatin resistant gastric cancer cells.
Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a human oncoprotein that is overexpressed in multiple kinds of tumors including gastric cancer (GC). Mammalian target of rapamycin complex 1 (mTORC1) over-activation is detected in GC and many other cancers. Previous study found that CIP2A/mTORC1 controls cell growth and autophagy through direct association. CIP2A plays an 'oncogenic nexus' in several cancer types to participate in the tumorigenic transformation and chemoresistance. In the present study, we investigated whether Cucurbitacin B (CuB), a natural compound found in Cucurbitaceae, can be used in cisplatin (DDP)-resistant human GC cell line SGC7901/DDP. Results demonstrated that CuB treatment significantly suppressed SGC7901/DDP cell proliferation, induced caspase-dependent apoptosis, and autophagy. The activation of autophagy was mediated through CuB-induced inhibition of mTORC1. Furthermore, CuB inhibited mTORC1 via the activation of protein phosphatase 2A (PP2A) which is mediated by CIP2A inhibition. These findings indicated that CuB can inhibit the proliferation, induce caspase-dependent apoptosis, and autophagy of SGC7901/DDP cells by suppressing CIP2A/PP2A/mTORC1 signaling axis. Thus, CuB may be a novel effective candidate to treat DDP-resistant human GC cells.


Transfer of drug resistance to myxococcus from bacteria carrying drug-resistance factors.
Resistance to chloramphenicol was successfully transferred from strains of Escherichia coli carrying R factors representative of compatibility groups F, W, S and N to strains of Myxococcus xanthus and M. fulvus. Resistance to kanamycin was transferred from an R factor in group S, and to neomycin from an R factor of group P. Myxobacterial strains differed in their capacity to take up the resistances and also in the stability of the resistance character. strains of M. fulvus were obtained that acquired resistance to chloramphenicol without exposure to R plus eubacterial strains. Cell-free preparations of all the chloramphenicol-resistant strains catalysed the acetylation of the drug. Cholramphenicol resistance was successfully transferred from the presumed R plus strains of Myxococcus and also from the spontaneously occurring chloramphenicol-resistant M. fulvus to other Myxococcus strains. Moreover, recombinants resistant to both rifampicin and 5-fluorouracil were obtained, though infrequently, by mixing Myococcus strains resistant to rifampicin and chloramphenicol with other myxococci resistant to 5-fluorouracil, both when the chloramphenicol resistance was derived from S-a (group W) and when it was the endogenous M fulvus resistance. Thus it appears that S-a and a new chloramphenicol resistance factor from M. fulvus will mobilize a chromosomal genetic marker in Myxococcus.


Isolated broad ligament leiomyomatosis.
Leiomyomas of an extrauterine nature are rare and often present a more challenging diagnosis process for the clinician. Our patient presented with lower abdominal pain associated with menorrhagia over a period of 6 months. Laparoscopic surgery revealed a right-sided broad ligament myoma consisting of multiple soft and diffused fibroids, of more than 400 in total. The myomas were enucleated and completely removed by laparoscopic surgery with minimal blood loss. Histopathological examination and analysis revealed the multiple nodules to be benign leiomyomatosis. The finding of isolated broad ligament leiomyomatosis rates this case as a unique kind of leiomyoma.


The effects of an infant-feeding classroom activity on the breast-feeding knowledge and intentions of adolescents.
This study examined the impact of an infant-feeding classroom activity on the breast-feeding knowledge and intentions of adolescents living in Nova Scotia, Canada. One hundred twenty-one students attending two high schools were administered one pretest and two posttest questionnaires. Students were arbitrarily assigned to a control or intervention group. The intervention group partook in a 60-minute classroom activity on infant feeding. Findings indicated that students in the intervention group demonstrated significantly greater breast-feeding knowledge at Posttest 1 and at 10 weeks postintervention. Students in the intervention group reported a significantly greater intention toward breast-feeding their own future children; an increase was sustained at 10 weeks. These findings suggest that adolescents' knowledge of and intention toward breast-feeding may be positively influenced during their teen years. School nurses are well positioned to support and encourage the inclusion of breast-feeding content in school curricula to enhance adolescents' knowledge and intentions toward breast-feeding.


Development of thermoplastic polyurethane/polyaniline-doped membranes for the separation of glycine through electrodialysis.
Recently, membrane-based separation processes, particularly electrodialysis, have attracted attention for the separation and purification of organic and amino acids from animal feedstock waste. In this study, cation exchange membranes were synthesized by making a composite of thermoplastic polyurethane and polyaniline (PANI) via the doping of various aromatic sulfonic acids, such as β -naphthol sulfonic acid and phenol sulfonic acid. The PANI was prepared using a standard method, which was further used in the composite blending at varying concentrations of 10%-20%. The impact of the concentration of PANI and the nature of the dopant on the membrane characteristics were comparatively studied. The membranes were analyzed by electric conductivity, water swelling, morphological studies (SEM), and thermogravimetric analysis. The membranes were used for the separation of glycine hydrochloride via electrodialysis.


Involvement of mammalian Mus81 in genome integrity and tumor suppression.
Mus81-Eme1 endonuclease has been implicated in the rescue of stalled replication forks and the resolution of meiotic recombination intermediates in yeast. We used gene targeting to study the physiological requirements of Mus81 in mammals. Mus81-/- mice are viable and fertile, which indicates that mammalian Mus81 is not essential for recombination processes associated with meiosis. Mus81-deficient mice and cells were hypersensitive to the DNA cross-linking agent mitomycin C but not to gamma-irradiation. Remarkably, both homozygous Mus81-/- and heterozygous Mus81+/- mice exhibited a similar susceptibility to spontaneous chromosomal damage and a profound and equivalent predisposition to lymphomas and other cancers. These studies demonstrate a critical role for the proper biallelic expression of the mammalian Mus81 in the maintenance of genomic integrity and tumor suppression.


Thymidylate synthase as a translational regulator of cellular gene expression.
Studies from our laboratory have shown that the folate-dependent enzyme, thymidylate synthase (TS), functions as an RNA binding protein. There is evidence that TS, in addition to interacting with its own TS mRNA, forms a ribonucleoprotein complex with a number of other cellular mRNAs, including those corresponding to the p53 tumor suppressor gene and the myc family of transcription factors. Using both in vitro and in vivo model systems, we have demonstrated that the functional consequence of binding of TS protein to its own cognate mRNA, as well as binding of TS to the p53 mRNA, is translational repression. Herein, we review current work on the translational autoregulatory control of TS expression and discuss the molecular elements that are required for the TS protein-TS mRNA interaction. TS may play a critical role in regulating the cell cycle and the process of apoptosis through its regulatory effects on expression of p53 and perhaps other cell cycle related proteins. Finally, the ability of TS to function as a translational regulator may have important consequences with regard to the development of cellular resistance to various anticancer drugs.


Conclusions in systematic reviews of mammography for breast cancer screening and associations with review design and author characteristics.
Debates about the benefits and harms of mammography continue despite the accumulation of evidence. We sought to quantify the disagreement across systematic reviews of mammography and determine whether author or design characteristics were associated with conclusions that were favourable to the use of mammography for routine breast cancer screening. We identified systematic reviews of mammography published between January 2000 and November 2015, and extracted information about the selection of evidence, age groups, the use of meta-analysis, and authors' professions and financial competing interest disclosures. Conclusions about specific age groups were graded as favourable if they stated that there were meaningful benefits, that benefits of mammography outweighed harms, or that harms were inconsequential. The main outcome measures were the proportions of favourable conclusions relative to review design and author characteristics. From 59 conclusions identified in 50 reviews, 42% (25/59) were graded as favourable by two investigators. Among the conclusions produced by clinicians, 63% (12/19) were graded as favourable compared to 32% (13/40) from other authors. In the 50-69 age group where the largest proportion of systematic reviews were focused, conclusions drawn by authors without financial competing interests (odds ratio 0.06; 95% CI 0.07-0.56) and non-clinicians (odds ratio 0.11; 95% CI 0.01-0.84) were less likely to be graded as favourable. There was no trend in the proportion of favourable conclusions over the period, and we found no significant association between review design characteristics and favourable conclusions. Differences in the conclusions of systematic reviews of the evidence for mammography have persisted for 15 years. We found no strong evidence that design characteristics were associated with greater support for the benefits of mammography in routine breast cancer screening. Instead, the results suggested that the specific expertise and competing interests of the authors influenced the conclusions of systematic reviews.


Delayed growth and puberty in patients with Gaucher disease type 1: natural history and effect of splenectomy and/or enzyme replacement therapy.
Growth retardation in childhood was only recently recognized as a prominent feature of Gaucher disease type 1, but there are few data on both the pubertal development and the final outcome of growth and sexual maturation. To investigate the natural pattern of growth and puberty in patients with Gaucher disease type 1 and the effect of splenectomy and enzyme replacement therapy. We retrospectively analyzed growth and puberty in 57 patients with Gaucher disease type 1; 52 were followed since childhood and/or prepuberty and 42 have reached sexual maturity and final height. In the analysis we considered severity of disease, time of splenectomy, and start of enzyme replacement therapy. Deceleration of growth at age 3-5 years was observed in 30 of 57 patients followed since early childhood while untreated: height-SDS decreased from -0.34 +/- 0.42 at age 0-3 years to -1.93 +/- 0.95 (P < 0.01) at age 7-10 years and was more pronounced with severe disease. A high prevalence (59.6%) of delayed puberty, which was more frequent with severe disease, was observed in 47 patients followed before and throughout puberty. No primary endocrine pathology was found. All patients, untreated as well as treated, with growth and pubertal delay had a spontaneous catch-up, achieved full sexual maturation, and most (83.3%) reached a final height within the range of parental height-standard deviation score. Splenectomy (partial and/or total) performed in 20 patients while still growing had a beneficial effect on growth, which was temporary in some and did not affect puberty. ERT improved growth in 11 patients who started therapy before puberty, as evidenced by a progressive increase in the height-SDS, and seemed to normalize the onset of puberty. Growth retardation in childhood and delay of puberty are characteristic of Gaucher disease type 1 and are more frequent with severe disease. There is a spontaneous catch-up later in life and most patients reach a final height within their genetic growth potential. Enzyme replacement therapy apparently normalizes growth and possibly also the onset of puberty.


Stimulus and hormonal determinants of flehmen behavior in cats.
Felids are the main group of animals, other than ungulates, that display flehmen behavior during sociosexual interactions. In ungulates the behavior is evoked most readily by olfactory investigation of urine and vaginal secretions, and is believed to be involved in the transport of fluid-borne chemical stimuli, such as sex pheromones, from the oral cavity to the vomeronasal organ. In this study of cats flehmen was virtually always preceded by nasooral contact with the stimulus material, supporting the notion that flehmen in this species is also involved in the transport of fluid-borne stimuli. As in ungulates, flehmen in cats during heterosexual encounters was found to be displayed by males only. However, the sexual dimorphism was situation specific. In exploring a urine-marked room without another cat present, females also performed flehmen, albeit less frequently than males, and when urine was applied to the nasooral surface, flehmen was evoked equally reliably in females and males. Administration of testosterone propionate to spayed female cats paired with estrogen-treated females markedly increased their tendency to genitally inspect the female partner and subsequently perform flehmen. Thus the sexually dimorphic attributes of flehmen behavior are not only stimulus dependent, but also influenced by concurrent hormone stimulation.


Probing FtsZ and tubulin with C8-substituted GTP analogs reveals differences in their nucleotide binding sites.
The cytoskeletal proteins, FtsZ and tubulin, play a pivotal role in prokaryotic cell division and eukaryotic chromosome segregation, respectively. Selective inhibitors of the GTP-dependent polymerization of FtsZ could constitute a new class of antibiotics, while several inhibitors of tubulin are widely used in antiproliferative therapy. In this work, we set out to identify selective inhibitors of FtsZ based on the structure of its natural ligand, GTP. We found that GTP analogs with small hydrophobic substituents at C8 of the nucleobase efficiently inhibit FtsZ polymerization, whereas they have an opposite effect on the polymerization of tubulin. The inhibitory activity of the GTP analogs on FtsZ polymerization allowed us to crystallize FtsZ in complex with C8-morpholino-GTP, revealing the binding mode of a GTP derivative containing a nonmodified triphosphate chain.


A Review on T Cell Epitopes Identified Using Prediction and Cell-Mediated Immune Models for Mycobacterium tuberculosis and Bordetella pertussis.
In the present review, we summarize work from our as well as other groups related to the characterization of bacterial T cell epitopes, with a specific focus on two important pathogens, namely, Mycobacterium tuberculosis (Mtb), the bacterium that causes tuberculosis (TB), and Bordetella pertussis (BP), the bacterium that causes whooping cough. Both bacteria and their associated diseases are of large societal significance. Although vaccines exist for both pathogens, their efficacy is incomplete. It is widely thought that defects and/or alteration in T cell compartments are associated with limited vaccine effectiveness. As discussed below, a full genome-wide map was performed in the case of Mtb. For BP, our focus has thus far been on the antigens contained in the acellular vaccine; a full genome-wide screen is in the planning stage. Nevertheless, the sum-total of the results in the two different bacterial systems allows us to exemplify approaches and techniques that we believe are generally applicable to the mapping and characterization of human immune responses to bacterial pathogens. Finally, we add, as a disclaimer, that this review by design is focused on the work produced by our laboratory as an illustration of approaches to the study of T cell responses to Mtb and BP, and is not meant to be comprehensive, nor to detract from the excellent work performed by many other groups.


Axons and astrocytes release ATP and glutamate to evoke calcium signals in NG2-glia.
NG2-glia are an abundant population of cells in the adult CNS that make up a novel glial cell type. Here, we have examined calcium signals in NG2-glia identified by expression of the fluorescent protein DsRed under the control of the NG2 promoter in the white matter of the mouse optic nerve. We focused on mice aged postnatal day (P)12-16, after the main period of oligodendrocyte generation. Using fluo-4 and fura-2 calcium imaging in isolated intact nerves, we show that glutamate and ATP evoke Ca(2+) signals in NG2-glia in situ, acting on AMPA-type glutamate receptors and P2Y(1) and P2X(7) purine receptors; NMDA evoked a weak Ca(2+) signal in a small proportion of NG2-glia. We show that axonal action potentials and mechanical stimulation of astrocytes effect the release of glutamate and ATP to act on NG2-glia; ATP alone evokes robust Ca(2+) signals, whereas glutamate did not unless AMPA receptor desensitization was blocked with cyclothiazide. We identify the precise contacts that NG2-glia form with axons at nodes of Ranvier, and the intricate bipartite sheaths formed between the processes of NG2-glia and astrocytes. In addition, we provide evidence that NG2-glia express synaptophysin, indicating they have mechanisms for transmitting as well as receiving signals. This study places NG2-glia within a neuron-glial network, and identifies roles for glutamate and ATP in communication with astrocytes as well as axons.


Mannose binding lectin polymorphisms as a disease-modulating factor in women with systemic lupus erythematosus from Canary Islands, Spain.
To determine whether mannose binding lectin (MBL) polymorphisms are associated with clinical characteristics and with susceptibility to systemic lupus erythematosus (SLE) in women from the Canary Islands, Spain. MBL alleles and genotypes were determined by polymerase chain reaction in 89 female patients and 188 female controls. No differences in the allelic or genotypic frequencies were observed between patients and controls. Anti-U1RNP autoantibodies were less frequent in association with mutated alleles (p = 0.037), and in association with MBL deficient genotypes, although this association was not statistically significant. The patients with low or nonproducer genotypes exhibited a decreased frequency of anti-Sm antibodies (p = 0.059). A nonsignificant trend toward lower prevalence of anti-Sm and anticardiolipin antibodies in association with both mutated alleles and low or nonproducer genotypes was also observed. The prevalence of more than one autoantibody was lower in association with mutated alleles (p = 0.022) and with low or nonproducer genotypes (p = 0.052). Homozygous or heterozygous patients with mutated alleles were significantly older at disease onset and at SLE diagnosis (p = 0.005, p = 0.014, respectively). An increase in the mean age at disease onset and at SLE diagnosis was observed with regard to the number of nonproducer alleles present (p = 0.021, p = 0.038, respectively). MBL deficiency is not a risk factor for SLE in women from the Canary Islands, but it is associated with lower prevalence of autoantibodies and with later age at disease onset and at SLE diagnosis.


Kinetic analysis of the accumulation of a half-sandwich organo-osmium pro-drug in cancer cells.
The organo-osmium half-sandwich complex [(η6-p-cymene)Os(Ph-azopyridine-NMe2)I]+ (FY26) exhibits potent antiproliferative activity towards cancer cells and is active in vivo. The complex is relatively inert, but rapidly activated in cells by displacement of coordinated iodide. Here, we study time-dependent accumulation of FY26 in A2780 human ovarian cancer cells at various temperatures in comparison with the chlorido metabolite [(η6-p-cymene)Os(Ph-azopyridine-NMe2)Cl]+ (FY25). Mathematical models described the time evolution of FY26 and FY25 intracellular and extracellular concentrations taking into account both cellular transport (influx and efflux) and the intracellular conversion of FY26 to FY25. Uptake of iodide complex FY26 at 37 °C was 17× faster than that of chloride complex FY25, and efflux 1.4× faster. Osmium accumulation decreased markedly after 24 h of exposure. Modelling revealed that this phenomenon could be explained by complex-induced reduction of osmium uptake, rather than by a model involving enhanced osmium efflux. The intracellular osmium concentration threshold above which reduction in drug uptake was triggered was estimated as 20.8 μM (95% confidence interval [16.5, 30]). These studies provide important new insight into the dynamics of transport of this organometallic anticancer drug candidate.


Levels, sources and health risks of carbonyls and BTEX in the ambient air of Beijing, China.
The atmospheric concentrations of carbonyls and BTEX (benzene, toluene, ethylbenzene, m,p-xylene and o-xylene) were measured simultaneously at a same sampling site in Beijing from September 2008 to August 2010. The average concentrations of the total measured carbonyls during autumn, winter, spring, and summer were 37.7, 31.3, 39.7, 50.5 microg/m3, respectively, and maximal values for their diurnal variations usually happened at noontime. In contrast to carbonyls, the average concentrations of the total measured BTEX during the four seasons were 27.2, 31.9, 23.2, 19.1 microg/m3, respectively, and minimal values for their diurnal variations always occurred in the early afternoon. The average concentration for carbonyls increased about 24% from September 2008-August 2009 to September 2009-August 2010, for BTEX, increased about 15%. Integrated life time cancer risks for three carcinogens (benzene, formaldehyde and acetaldehyde) in Beijing exceeded the value of 1E-06, and the hazard quotient (HQ) of non-cancer risk of exposure to formaldehyde exceeded unity.


A potentiometric and 51V NMR study of the aqueous H+/H2VO4-/H2O2/L-alpha-alanyl-L-histidine system.
The speciation in the quaternary aqueous H+/H2VO4-/H2O2/L-alpha-alanyl-L-histidine (Ah) system has been determined from quantitative 51V NMR measurements and potentiometric data (glass electrode). The study was performed in 0.150 M Na(Cl) medium at 25 degrees C. Data were evaluated with the computer program LAKE, which is able to treat combined EMF and NMR data. The pKa values for Ah were determined as 8.06, 6.72 and 2.64. In the ternary H+/H2VO4-/Ah system, two complexes, (H+)p(H2VO4-)q(Ah)r, for which (p, q, r) values of (0, 1, 1) and (1, 1, 1) with log beta(0,1,1) = 2.52 +/- 0.03 and log beta(1,1,1) = 9.40 +/- 0.05 (pKa = 6.88), respectively, explain all data. The errors given are 3sigma. In the quaternary H+/H2VO4-/H2O2/Ah system, eight complexes were determined in addition to all binary and ternary complexes, four with a V/X/Ah ratio 1:1:1 and four with a ratio 1:2:1 (X = peroxo ligand). VX2Ah2- and VX2Ah- (pKa = 8.19) are the main complexes and predominate in the pH range 5 to 9. Three additional minor species have also been found but their compositions could not be determined owing to their small amounts. Equilibria are slow, significant decomposition of peroxide occurs only in acidic solutions. Data in the pH range 5 to 10 have been used for the LAKE calculations. Chemical shifts, compositions, and formation constants for the eight quaternary complexes are given, and equilibrium conditions are illustrated in distribution diagrams. Structural proposals for VX2Ah2- and VX2Ah- are made from 1H and 13C NMR measurements.


In vitro biodistribution studies on clinically approved FGFR inhibitors ponatinib, nintedanib, erlotinib and the investigational inhibitor KP2692.
Binding towards human serum albumin (HSA) and α1-acid glycoprotein (AGP) of three approved fibroblast growth factor receptor (FGFR) inhibitors ponatinib (PON), nintedanib (NIN) and erdafitinib (ERD), as well as the experimental drug KP2692 was studied by means of spectrofluorometric and UV-visible spectrophotometric methods. Additionally, proton dissociation processes, lipophilicity, and fluorescence properties of these four molecules were investigated in detail. The FGFR inhibitors were predominantly presented in their single protonated form (HL+) at pH 7.4 (at blood pH). At gastric pH (pH 1-2) the protonated forms (+1 - +3) are present, which provide relatively good aqueous solubility of the drugs. All of the four inhibitors are highly or extremely lipophilic at pH 7.4 (logD7.4 ≥ 2.7). At acidic pH 2.0 PON and ERD are rather lipophilic, NIN is amphiphilic, while KP2692 is highly hydrophilic. All four compounds bind to HSA and AGP. Moderate binding of PON, KP2692 and NIN was found towards albumin (logK' = 4.5-4.7), while their affinity for AGP was about one order of magnitude higher (logK' = 5.2-5.7). ERD shows a larger affinity for both proteins (logK'HSA ≈ 5.2, logK'AGP ≈ 7.0). The computed constants were used to model the distribution of the FGFR inhibitors in blood plasma under physiological and pathological (acute phase) conditions. The changing levels of the two proteins under pathological conditions compensate each other for PON and NIN, so that the free drug fractions do not change considerably. In the case of ERD the higher AGP levels distinctly reduce the free available fraction of the drug. Comparison with clinical pharmacokinetic data indicates that the here presented solution distribution studies can very well predict the conditions in cancer patients.


Nonlocal effects in nonisothermal hydrodynamics from the perspective of beyond-equilibrium thermodynamics.
We examine the origins of nonlocality in a nonisothermal hydrodynamic formulation of a one-component fluid of particles that exhibit long-range correlations, e.g., due to a spherically symmetric, long-range interaction potential. In order to furnish the continuum modeling with physical understanding of the microscopic interactions and dynamics, we make use of systematic coarse graining from the microscopic to the continuum level. We thus arrive at a thermodynamically admissible and closed set of evolution equations for the densities of momentum, mass, and internal energy. From the consideration of an illustrative special case, the following main conclusions emerge. There are two different source terms in the momentum balance. The first is a body force, which in special circumstances can be related to the functional derivative of a nonlocal Helmholtz free energy density with respect to the mass density. The second source term is proportional to the temperature gradient, multiplied by the nonlocal entropy density. These two source terms combine into a pressure gradient only in the absence of long-range effects. In the irreversible contributions to the time evolution, the nonlocal contributions arise since the self-correlations of the stress tensor and heat flux, respectively, are nonlocal as a result of the microscopic nonlocal correlations. Finally, we point out specific points that warrant further discussions.


Cholesterol vehicle in experimental atherosclerosis. Part 18. Comparison of North American, African and South American peanut oils.
Peanut oils were obtained from the United States (NAPNO), Africa (APNO), and South America (SAPNO) and their effects on atherosclerosis in rabbits fed 2% cholesterol were determined. The major differences among the oils were in the content of oleic (NAPNO, 48.9%; APNO, 58.6%; SAPNO, 36.4%) and linoleic (NAPNO, 29.6%; APNO, 21.7%; SAPNO, 41.1%) acids. In a series of 4 experiments it was found that South American peanut oil was 7% more atherogenic than African peanut oil and 18% more atherogenic than North American peanut oil. American peanut oil was 14% more atherogenic that corn oil (CO). South American peanut oil gave highest serum and liver lipid levels. The differences in atherogenicity may be due to the structure of the triglycerides of the various peanut oils.


Long-term marrow culture of cells from patients with acute myelogenous leukemia. Selection in favor of normal phenotypes in some but not all cases.
Long-term cultures were initiated with leukemic marrow aspirate cells from each of 13 newly diagnosed acute myelogenous leukemia (AML) patients. Initial assessment of the clonogenic potential of the marrow suggested that normal hemopoietic progenitors were reduced in most cases and progenitors of abnormal colonies and clusters were present in 10 cases. Subsequent assays of both nonadherent and adherent fractions of long-term cultures revealed two patterns of progenitor cell behavior. The most common pattern (nine cases) featured the detection after 1-4 wk of near normal numbers of typical erythroid, granulopoietic, and mixed colony-forming progenitor cells. Progenitors of abnormal (blast) colonies and clusters initially demonstrable in eight of these nine cases were, in these cases, not sustained in long-term culture and could not be found after 4 wk. Conversion to cytogenetic normalcy in long-term culture was confirmed in two experiments in this group. The second pattern (four cases) was characterized by the failure of progenitors capable of normal differentiation to become detectable in long-term cultures, and the concomitant maintenance of blast progenitors in the two cases in this group where such cells were initially demonstrable. Although progenitors capable of producing abnormal (blast) colonies or clusters in methylcellulose were not detected in either of the other two experiments, the maintenance for 6 wk of a hypercellular nonadherent blast population in one of these suggested the persisting activity of an "adherent layer-dependent" leukemic progenitor cell. Taken together, these findings indicate a strong correlation between the presence of leukemic blasts and their progenitors and a decreased level of normal hemopoiesis. In addition, the failure of leukemic cells to be maintained in long-term marrow cultures from some (but not all) AML patients suggests new applications of this methodology for studies of early stages of leukemic cell development.


Effects of nitric oxide synthase inhibitors on bone formation in rats.
NO is synthesized from L-arginine by at least three isoforms of nitric oxide synthase (NOS) and is known to function as a vasodilator and neurotransmitter. NO is produced by bone cells but its function in bone biology is, as yet, unclear. We hypothesized that NOS mediates bone formation in remodeling regions of the skeleton. We studied the effects of two NOS inhibitors: N(G)-nitro-L-arginine methyl ester (L-NAME), which is a general inhibitor of NOS activity and is known to inhibit the vasodilatory effects of the endothelial NOS (eNOS) isoform; and aminoguanidine, which is a selective inhibitor of the inducible NOS (iNOS) isoform. Our hypothesis was tested by treating rats with NOS inhibitors and measuring bone formation rates in the tibial epiphysis and diaphysis. Bone formation indices were measured using standard bone histomorphometry. L-NAME treatment significantly raised mean arterial blood pressure (MAP). This effect was partially reversed by addition of L-arginine. Aminoguanidine had no significant effect on MAP, indicating that it did not block eNOS. The treatments also had substantial effects on bone formation in remodeling trabecular bone. L-NAME did not significantly change trabecular bone formation rate, whereas aminoguanidine reduced bone formation rate in the tibial epiphysis by 79% compared with control. This reduction was completely reversed by L-arginine, suggesting that bone formation during remodeling is, in part, mediated through L-arginine metabolism. No effect of aminoguanidine on bone formation was seen in the tibial diaphysis, a site that undergoes minimal bone remodeling. This finding suggests that the L-arginine-NO pathway is important in bone remodeling.


Extensive genomic analysis in patients with KRAS-mutated solid tumors shows high frequencies of concurrent alterations and potential targets but has limited clinical impact.
This study aimed to investigate the distribution and frequency of concurrent alterations in different cancers across KRAS subtypes and in different KRAS subtypes across cancers, and to identify potentially actionable targets and patients who received targeted treatment matched to their genomic profile (GP). In this descriptive and single-center study, we included 188 patients with solid tumors harboring KRAS mutations in codon 12, 13, 61, 117, or 146, referred to the Phase 1 Unit, Rigshospitalet, Copenhagen, Denmark from mid-2016 to 2020. Genomic co-alterations were detected with whole-exome sequencing, RNA sequencing, SNP array, and mRNA expression array on fresh biopsies. The study is part of the Copenhagen Prospective Personalized Oncology study (NCT02290522). The majority of patients had colorectal cancer (60.1%), non-small cell lung cancer (11.2%), or pancreatic cancer (10.6%). Most tumors were KRAS-mutated in codon 12 or 13 (93.7%) including G12D (27.1%), G12V (26.6%), G12C (11.7%), and G13D (11.2%). A total of 175 different co-alterations were found, most frequently pathogenic APC and TP53 mutations (55.9% and 46.4%, respectively) and high expression of CEACAM5 (73.4%). Different cancers and KRAS subtypes showed different patterns of co-alterations, and 157 tumors (83.5%) had potentially actionable targets with varying evidence of targetability (assessed using ESMO Scale for Clinical Actionability of molecular Targets). Of the 188 patients included in the study, 15 (7.4%) received treatment matched to their GP (e.g., immunotherapy and synthetic lethality drugs), of whom one had objective partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Performing extensive genomic analysis in patients with known KRAS-mutated solid tumors may contribute with information to the genomic landscape of cancers and identify targets for immunotherapy or synthetic lethality drugs, but currently appears to have overall limited clinical impact, as few patients received targeted therapy matched to their GP.


1990 South Carolina Physician Survey of tick, spider and fire ant morbidity.
A population of 2,366 primary care physicians in South Carolina was surveyed by mail to estimate the number of cases of insect morbidity treated in 1990. A response rate of 42.3 percent was obtained. Cases reported totaled 414 for Rocky Mountain spotted fever, 334 for Lyme disease, 143 black widow and 478 brown recluse spider bites and 4,975 fire ant stings. These are counts of cases from a mail survey, not from a research-based study. Five deaths were also reported; two for Rocky Mountain spotted fever, two due to black widow spider bites and one fire ant anaphylaxis.


Perspectives and recommendations of opioid overdose survivors experiencing unsheltered homelessness on housing, overdose, and substance use treatment in Boston, MA.
Opioid overdose causes one in four deaths among people experiencing homelessness in Boston, MA. To reduce overdose risks, the experience and perspectives of people experiencing homelessness should be incorporated into housing, overdose prevention, and substance use treatment efforts. In 2021, we conducted qualitative interviews with 59 opioid overdose survivors to inform equitable access to treatment services. In response to policy debate surrounding a public drug scene near a key recruitment site, we conducted a targeted thematic analysis of transcribed interview data from a subset of participants experiencing unsheltered homelessness (n=29) to explore their perspectives and recommendations on housing, overdose prevention, and substance use treatment. Among 29 participants who identified as non-Hispanic Black (n=10), Hispanic/Latinx (n=10), or as non-Hispanic White (n=9), the median number of self-reported opioid overdoses in the past three months was 2.0 (SD 3.7). Three themes emerged from this targeted analysis: (1) Participants described inadequate housing resources and unwelcoming shelter environments. (2) Participants near a large public drug scene explained how unsheltered homelessness was chaotic, dangerous, and disruptive to recovery goals. (3) Participants provided recommendations for improving housing and addiction treatment systems and including their perspectives in the development of solutions to the intersecting housing and opioid overdose crises. The overdose prevention, housing and substance use treatment systems must address the needs of opioid overdose survivors experiencing unsheltered homelessness. Overdose survivors experiencing unsheltered homelessness described a chaotic public drug scene but resorted to residing in nearby encampments because the existing shelter, housing, and addiction treatment systems were unwelcoming, difficult to navigate, or unaffordable. Despite efforts to provide low-threshold housing in Boston, additional low-barrier housing services (i.e., including harm reduction resources and without "sobriety" requirements) could promote the health and safety of people who use drugs and are experiencing homelessness.