Association of walking speed in late midlife with mortality: results from the Whitehall II cohort study.
Slow walking speed is associated with increased mortality in the elderly, but it is unknown whether a similar association is present in late midlife. Our aim was to examine walking speed in late midlife as a predictor of mortality, as well as factors that may explain this association. Data are drawn from the Whitehall II longitudinal cohort study of British civil servants. The analyses are based on 6,266 participants (29% women; mean age = 61 years, SD = 6) for whom "walking speed at usual pace" was measured over 8 ft (2.44 m) at baseline. Participants were followed for all-cause and cause-specific mortalities during a mean of 6.4 (SD = 0.8) years. During this period, 227 participants died. Participants in the bottom sex-specific third of walking speed (men, <1.26 m/s; women, <1.09 m/s) had an increased risk of death compared to those in the middle and top thirds (age- and sex-adjusted hazard ratio = 1.89, 95% confidence interval (CI) = 1.45-2.46), with no evidence of effect modification by age or sex (interactions, P ≥ 0.40). The association between walking speed and mortality was partially explained by baseline inflammatory markers (percentage reduction of the association 22.8%), height and body mass index (16.6%), chronic diseases (14.0%), and health behaviors (13.4%). Together these and other baseline factors (socioeconomic status, cardiovascular risk factors, cognitive function) explained 48.5% of the association (adjusted hazard ratio = 1.39, 95% CI = 1.04-1.84). In conclusion, walking speed measured in late midlife seems to be an important marker of mortality risk; multiple factors, in particular inflammatory markers, partially explain this association.


Intra-accumbens delta 1-opioid agonist, pC1-DPDPE, differentially affects patterns of locomotor activity.
The effects of bilateral microinjections of a new potent and highly selective delta-opioid receptor agonist pCl-DPDPE (0.00, 0.1, 1.0, or 2.5 micrograms/side) were tested in rats for 60 min in activity monitors. The durations of horizontal movement time, rearing time, and stereotypy time were measured during six consecutive 10-min time blocks. The pCl-DPDPE resulted in short-lived biphasic effects of attenuation followed by potentiation for the three measures. These data in part replicate the behavioral effects of other delta-opioid receptor agonists.


An alternative method to prepare samples of the pathogenic yeast Cryptococcus neoformans for scanning electron microscopy analysis.
In this work, an alternative to conventional preparation procedures for scanning electron microscopy (SEM) analysis of Cryptococcus neoformans was performed. The cells were fixed directly in the agar culture. This method is simpler than others already reported and the morphology of the cells was well preserved.


The effect of oxygen free radical scavengers on the recovery of regional myocardial function after acute coronary occlusion and surgical reperfusion.
This study investigated the effects of the oxygen free radical scavengers superoxide dismutase and catalase, the peroxide ion inhibitor, in crystalloid potassium cardioplegic solution on infarct size and global and regional myocardial function after occlusion of the left anterior descending artery and surgical reperfusion in young sheep on cardiopulmonary bypass. After 1 hour of occlusion, the animals were randomized to receive either routine potassium cardioplegia or cardioplegia with superoxide dismutase and catalase. Global hemodynamics measured by maximum rate of pressure rise showed significant improvement after 5 hours of reperfusion in the group treated with superoxide dismutase and catalase (1843 +/- 163 versus 979 +/- 191, p less than 0.001). Regional myocardial function was measured by ultrasonic crystals implanted in the ischemic area and in a nonischemic control segment. The percent systolic shortening or bulging was calculated. At end of reperfusion in the animals treated with superoxide dismutase and catalase, there was active shortening in the ischemic area after reperfusion of +9.2% +/- 0.4% versus 2.1% +/- 0.8% in untreated animals (p less than 0.001). Infarct size measured by triphenyltetrazolium chloride staining showed significant difference (p less than 0.001) between animals treated with superoxide dismutase and catalase (0.9% +/- 0.1%) and control animals (61% +/- 70%). Superoxide dismutase and catalase given in the cardioplegic solution before reperfusion of an acutely ischemic area of myocardium enhances recovery of contractile function and results in a significant reduction in infarct size, which suggests improved salvage of the ischemic myocardium.


Consensus guided incomplete multi-view spectral clustering.
Incomplete multi-view clustering which aims to solve the difficult clustering challenge on incomplete multi-view data collected from diverse domains with missing views has drawn considerable attention in recent years. In this paper, we propose a novel method, called consensus guided incomplete multi-view spectral clustering (CGIMVSC), to address the incomplete clustering problem. Specifically, CGIMVSC seeks to explore the local information within every single-view and the semantic consistent information shared by all views in a unified framework simultaneously, where the local structure is adaptively obtained from the incomplete data rather than pre-constructed via a k-nearest neighbor approach in the existing methods. Considering the semantic consistency of multiple views, CGIMVSC introduces a co-regularization constraint to minimize the disagreement between the common representation and the individual representations with respect to different views, such that all views will obtain a consensus clustering result. Experimental comparisons with some state-of-the-art methods on seven datasets validate the effectiveness of the proposed method on incomplete multi-view clustering.


Tuberpulchrosporum sp. nov., a black truffle of the Aestivum clade (Tuberaceae, Pezizales) from the Balkan peninsula.
Knowledge on the diversity of hypogeous sequestrate ascomycetes is still limited in the Balkan Peninsula. A new species of truffle, Tuberpulchrosporum, is described from Greece and Bulgaria. Specimens were collected from habitats dominated by various oak species (i.e. Quercusilex, Q.coccifera, Q.robur) and other angiosperms. They are morphologically characterised by subglobose, ovoid to irregularly lobed, yellowish-brown to dark brown ascomata, usually with a shallow basal cavity and surface with fissures and small, dense, almost flat, trihedral to polyhedral warts. Ascospores are ellipsoid to subfusiform, uniquely ornamented, crested to incompletely reticulate and are produced in (1-)2-8-spored asci. Hair-like, hyaline to light yellow hyphae protrude from the peridium surface. According to the outcome of ITS rDNA sequence analysis, this species forms a distinct well-supported group in the Aestivum clade, with T.panniferum being the closest phylogenetic taxon.


Mutagenic activity of a nitrosated early Maillard product: DNA synthesis (DNA repair) induced in HeLa S3 carcinoma cells by nitrosated 1-(N-L-tryptophan)-1-deoxy-D-fructose.
HeLa S3 cells in suspension were incubated at 37 degrees C with various concentrations of the Amadori compound 1-(N-L-tryptophan)-1-deoxy-D-fructose (Trp-Fru), of its nitrosated analogue NO-Trp-Fru and of sodium nitrite, for varying periods of time, and were assayed for viability (trypan blue exclusion test) and for intracellular DNA, RNA and protein synthesis. None of the compounds tested had any effect on cell viability, or on RNA and protein synthesis apart perhaps from a slightly inhibitory action. While Trp-Fru remained ineffective also as far as intracellular DNA synthesis was concerned, both NO-Trp-Fru and NaNO2 had a major effect on DNA synthesis. With NaNO2, stimulation of DNA synthesis occurred at concentrations above 1 mM in the growth medium, but with NO-Trp-Fru synthesis increased at concentrations below 1 microM. The excess DNA synthesis (i.e. synthesis above control activity) observed with NO-Trp-Fru and also with NaNO2 was due to DNA repair. This was verified by keeping the cells under conditions that prevented normal semi-conservative replication but permitted DNA repair ('unscheduled DNA synthesis'). Two major routes are suggested by which NO-Trp-Fru could damage DNA.


Synthesis and binding studies of a 1-alkyl-3,6-diamino-4-quinolone based receptor for N-acylated dipeptides.
The synthesis and binding properties of a semirigid host for N-acyldipeptide carboxylic acids is presented. The design is based on the rigidification of a peptide strand, coupled to the use of a substituted quinoline as a hydrogen bond acceptor for the proton of a carboxylic acid.


Liquid chromatographic isolation of vincristine and vinblastine.
A fundamentally new method is described for the separation of the dimeric indole alkaloids vincristine and vinblastine from monomeric indole alkaloid impurities. This method uses an RP-18 high-performance liquid chromatography column with a methanol-water mobile phase containing an inorganic acid and an unusually low concentration of inorganic buffer. By keeping the buffer concentration low, the elution of all indole alkaloids is retarded, but the dimeric ones are retarded more than the monomeric ones. A theoretical model developed to explain this behavior postulates that the anions of the buffer solubilize the protonated indole alkaloids by pairing with them. Lowering the buffer concentration reduces the availability of pairing ions and thus decreases the mobile phase affinity of protonated alkaloids, particularly those having a 2+ charge. A similar approach may be applicable in other situations where ionogenic organic compounds having a particular valence must be separated from related compounds having different valences, or from non-ionogenic compounds.


Natural cocktail of bioactive factors conjugated on nanofibrous dressing for improved wound healing.
Any interference in the timely and orderly progression through all the phases of healing process can turn a minor injury into a chronic wound. Most of the wound dressings available in the market are moderately effective and have not shown satisfactory improvement in healing. Along with the appropriate wound management, it is imperative for a dressing to facilitate the wound repair process too. In the present research, we hypothesize to improve the wound healing process by applying cost effective natural cocktail of various bioactive factors. Bovine colostrum contains high levels of immunoglobulins, lactoferrin, hormones and cytokines which play significant role in wound healing. Hence, multifunctional colostrum conjugated PCL-PEG based nanofibrous dressings were developed and analyzed for their physicochemical properties and cellular responses. The dressings were also evaluated for cell migration, antioxidant, anti-inflammatory and anti-bacterial properties. In-vivo wound healing ability was validated on a rat wound model. Numerous growth factors present in the colostrum showed their role in stimulation of skin repair and regeneration by direct action on genetic material. Significantly less inflammation in colostrum treated wounds was observed due to anti-inflammatory properties of lactoferrin. Thus obtained results confirmed the suitability of these multifunctional colostrum conjugated nanofibrous dressings for improved wound healing.


Undescribed amino acid-sesquiterpene lactone adducts and sesquiterpene glycosides from the roots of Saussurea lappa and their anti-HBV activity.
Saussurea lappa (Asteraceae family), a traditional Chinese medicine, has been found to possess anti-inflammatory, immune-promoting, antibacterial, antitumor, anti-HBV, cholestatic, and hepatoprotective activities. Herein, two undescribed amino acid-sesquiterpene lactone adducts, saussureamines G and H (1 and 2), and two new sesquiterpene glycosides, saussunosids F and G (3 and 4), along with 26 known sesquiterpenoids (5-30) have been isolated from the roots of S. lappa. Their structures and absolute configurations of these compounds were established by physical data analyses such as HRESIMS, IR, 1D and 2D NMR and ECD calculations. All isolated compounds were tested for anti-hepatitis B virus (anti-HBV) activity. Ten compounds (5, 6, 12, 13, 17, 19, 23, 26, 29, and 30) exhibited activities against the secretions of HBsAg and HBeAg. In particular, compound 6 showed inhibition of HBsAg and HBeAg secretion with IC50 values of 11.24 and 15.12 μM, with SI values of 1.25 and 0.93, respectively. Molecular docking studies were also conducted on the anti-HBV compounds. Overall, this study provides insights into the potential therapeutic uses of the compounds found in the roots of S. lappa, particularly in the treatment of hepatitis B virus infections.


Dialysis modality, vascular access and mortality in end-stage kidney disease: A bi-national registry-based cohort study.
There remains debate on which dialysis modality offers better survival outcomes for patients. We compare the survival of patients undergoing home haemodialysis (HD) with a permanent vascular access, facility HD with a permanent vascular access, facility HD with a central venous catheter or peritoneal dialysis. We considered adult patients from the Australia and New Zealand Dialysis and Transplant Registry who commenced dialysis between 1 October 2003 and 31 December 2011. Patients were followed until death, transplant, loss to follow-up or 31 December 2011. Marginal structural models for mortality were used to account for time-varying treatment, comorbidities and baseline covariates. Unmeasured differences between treatment groups may remain even after adjustment for measured differences, so the potential effects of unmeasured confounding were explicitly modelled. There were 20,191 patients who underwent ≥90 days of dialysis (median 2.25 years, interquartile range 1-3.75 years). There were significant differences in age, gender, comorbidities and other variables between treatment groups at baseline. Thirty per cent of patients had at least one treatment change. Relative to facility HD with permanent access, the risk of death for home HD patients with a permanent access was lower in the first year (at 9 months: hazard ratio 0.41, 95% CI 0.25-0.67, adjusted for all baseline covariates). Findings were robust to unmeasured confounding within plausible ranges. Relative to facility HD with permanent vascular access, home HD conferred better survival prospects, while peritoneal dialysis was associated with a higher risk and facility HD with a catheter the highest risk, especially within the first year of dialysis.


[Susceptibility of RD-9H8 cells derived from RD cells to enteroviruses and its application for measuring neutralizing antibodies against coxsackievirus group B].
We carried out cloning of RD cells and obtained cloned cell line RD-9H8, which is highly sensitive to enteroviruses. Cytopathic effect (CPE) of RD-9H8 cells was more remarkable than that of original RD cells. The RD-9H8 cells were used to measure the neutralizing antibodies to coxsackievirus group B in sera from 93 medical students collected in Oct. 1990 at Iwate Medical University. The proportions of confirmed positive sera were coxsackievirus type B1 44.1%, type B2 50.5%, type B3 46.2%, type B4 64.5%, type B5 53.8% and type B6 4.4%.


Mucolipidosis II: correlation between radiological features and histopathology of the bones.
Twelve cases of Mucolipidosis II (I-cell disease) with a wide range of severity of skeletal involvement were studied. Pathological findings in two cases provided helpful information in understanding the radiographic features of dysostosis multiplex. Inhibition of the growth plate cartilage calcification and rickets-like lesions were observed in the metaphyses. Enhanced subperiosteal remodelling and paratrabecular fibrosis were also evident in the diaphyses. High levels of parathormone were found in one case. This finding supports the hypothesis that bone lesions may be secondary, at least in part, to damage in such viscera as the kidney and/or the liver and that they are mediated by vitamin D and parathormone.


PE38KDEL-loaded anti-HER2 nanoparticles inhibit breast tumor progression with reduced toxicity and immunogenicity.
The clinical use of Pseudomonas exotoxin A (PE)-based immunotoxins is limited by the toxicity and immunogenicity of PE. To overcome the limitations, we have developed PE38KDEL-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles conjugated with Fab' fragments of a humanized anti-HER2 monoclonal antibody (rhuMAbHER2). The PE38KDEL-loaded nanoparticles-anti-HER2 Fab' bioconjugates (PE-NP-HER) were constructed modularly with Fab' fragments of rhuMAbHER2 covalently linked to PLGA nanoparticles containing PE38KDEL. Compared with nontargeted nanoparticles that lack anti-HER2 Fab', PE-NP-HER specifically bound to and were sequentially internalized into HER2 overexpressing breast cancer cells, which result in significant cytotoxicity in vitro. In HER2 overexpressing tumor xenograft model system, administration of PE-NP-HER showed a superior efficacy in inhibiting tumor growth compared with PE-HER referring to PE38KDEL conjugated directly to rhuMAbHER2. Moreover, PE-NP-HER was well tolerated in mice with a higher LD(50) (LD(50) of 6.86 +/- 0.47 mg/kg vs. 2.21 +/- 0.32 mg/kg for PE-NP-HER vs. PE-HER (mean +/- SD); n = 3), and had no influence on the plasma level of plasma alanine aminotransferase (ALT) of animals when injected at a dose of 1 mg/kg where PE-HER caused significant increase of serum ALT in the treated mice. Notably, PE-NP-HER was of low immunogenicity in development of anti-PE38KDEL neutralizing antibodies and was less susceptible to inactivation by anti-PE38KDEL antibodies compared with PE-HER. This novel bioconjugate, PE-NP-HER, may represent a useful strategy for cancer treatment.


Expression of inducible nitric oxide synthase in mast cells contributes to the regulation of inflammatory cytokines in irritable bowel syndrome with diarrhea.
Nitric oxide (NO) and mast cells (MCs) are possibly involved in the development of irritable bowel syndrome (IBS), but details on their role and interactions still remain undetermined. We aimed to investigate the expression of inducible NO synthase (iNOS) in MCs of the colon of IBS with diarrhea (IBS-D), and elucidated a potential role of NO in the differential regulation of cytokines in MCs. Colonic mucosal biopsies of 19 IBS-D patients and 16 healthy controls were collected. The expression of tryptase and iNOS was investigated by immunohistochemistry, Western blotting, and real-time PCR. Effects of NO on the expression of cytokines in rat bone marrow MCs (BMMCs) were examined using a cytokine array by NG-nitro-l-arginine methyl ester (L-NAME) treatment. Immunohistochemistry for tryptase revealed an increase in number of MCs with extensive iNOS expression in the colonic mucosa of IBS-D. Tryptase, iNOS and interleukin (IL)-1β mRNA and protein levels were upregulated in IBS-D compared with healthy controls. Specifically, a positive correlation between tryptase and iNOS protein expression was observed in the colon of IBS-D (r = 0.667, p < 0.05). Supernatant from IBS-D increased iNOS expression in BMMCs. Antibody array showed that agrin, beta-nerve growth factor, fractalkine, granulocyte-macrophage colony-stimulating factor, IL-1β, IL-1R6, IL-13, leptin, tumor necrosis factor alpha were suppressed, and cytokine-induced neutrophil chemoattractant (CINC)-1, CINC-2α, CINC-3, monocyte chemotactic protein-1, matrix metalloproteinase-8 were strongly produced in L-NAME treated BMMCs, comparable to levels in the control group. Our findings provide new evidence that NO is able to regulate many cytokines in MCs that may be involved in the development of IBS.


Complexity, incongruity, pre-exposure and the familiarity effect in visual selection.
A consistent finding in the literature concerning visual selection is that subjects spend more time viewing unfamiliar stimuli than familiar stimuli. In the present investigation a procedure to measure competitive viewing times to familiar and unfamiliar stimuli was used. Results of the analyses of viewing times showed that the magnitude of the familiarity effect was a positive function of the duration of stimulus pre-exposure. In addition no differences were found in subjects' "preference" for familial and unfamiliar stimuli as measured by "like-disliked" ratings.


Characterization of local and circulating bovine γδ T cell responses to respiratory BCG vaccination.
The Mycobacterium bovis Bacillus Calmette-Guerin (BCG) vaccine is administered parenterally to infants and young children to prevent tuberculosis (TB) infection. However, the protection induced by BCG is highly variable and the vaccine does not prevent pulmonary TB, the most common form of the illness. Until improved TB vaccines are available, it is crucial to use BCG in a manner which ensures optimal vaccine performance. Immunization directly to the respiratory mucosa has been shown to promote greater protection from TB in animal models. γδ T cells play a major role in host defense at mucosal sites and are known to respond robustly to mycobacterial infection. Their positioning in the respiratory mucosa ensures their engagement in the response to aerosolized TB vaccination. However, our understanding of the effect of respiratory BCG vaccination on γδ T cell responses in the lung is unknown. In this study, we used a calf model to investigate the immunogenicity of aerosol BCG vaccination, and the phenotypic profile of peripheral and mucosal γδ T cells responding to vaccination. We observed robust local and systemic M. bovis-specific IFN-γ and IL-17 production by both γδ and CD4 T cells. Importantly, BCG vaccination induced effector and memory cell differentiation of γδ T cells in both the lower airways and peripheral blood, with accumulation of a large proportion of effector memory γδ T cells in both compartments. Our results demonstrate the potential of the neonatal calf model to evaluate TB vaccine candidates that are to be administered via the respiratory tract, and suggest that aerosol immunization is a promising strategy for engaging γδ T cells in vaccine-induced immunity against TB.


Cerebral gumma mimicking glioblastoma multiforme.
This article reports an unusual case of a syphilitic gumma with a clinical and radiographical presentation initially suggestive of glioblastoma multiforme. Pathological evaluation was essential in establishing the diagnosis of neurosyphilis and in excluding neoplastic involvement. Cerebral gumma should be considered as part of the differential diagnosis of a midline intracranial lesion observed on magnetic resonance imaging.


Transcriptomic analysis of human pulmonary microvascular endothelial cells treated with LPS.
Acute respiratory distress syndrome (ARDS) has a rapid onset and progression, which lead to the severity and complexity of the primary disease and significantly increase the fatality rate of patients. Transcriptomics provides some ideas for clarifying the mechanism of ARDS, exploring prevention and treatment targets, and searching for related specific markers. In this study, RNA-Seq technology was used to observe the gene expression of human pulmonary microvascular endothelial cells (PMVECs) induced by LPS, and to excavate the key genes and signaling pathways in ARDS process. A total of 2300 up-regulated genes were detected, and a corresponding 1696 down-regulated genes were screened. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, and protein-protein interaction (PPI) were also used for functional annotation of key genes. TFDP1 was identified as a cell cycle-dependent differentially expressed gene, and its reduced expression was verified in LPS-treated PMVECs and lung tissues of CLP-induced mice. In addition, the inhibition of TFDP1 on inflammation and apoptosis, and the promotion of proliferation were confirmed. The decreased expression of E2F1, Rb, CDK1 and the activation of MAPK signaling pathway were substantiated in the in vivo and in vitro models of ARDS. Moreover, SREBF1 has been demonstrated to be involved in cell cycle arrest in PMVECs by inhibiting CDK1. Our study shows that transcriptomics combined with basic research can broaden the investigation of ARDS mechanisms and may provide a basis for future mechanistic innovations.


Identification of multiple glutathione S-transferases from Daphnia magna.
1. Six anionic glutathione S-transferases (GST) were purified from the crustacean, Daphnia magna, by means of affinity chromatography, that are responsible for ca. 40% of cytosolic GST activity. 2. Electrophoresis in the presence of sodium dodecyl sulfate (SDS) revealed the presence of three proteins, with molecular weights of 27,500, 28,000, and 30,200. 3. Separation under nondenaturing conditions revealed six proteins, all of which exhibited GST activity, with molecular weights ranging from 55,000 to 61,700. 4. Ethacrynic acid is a competitive inhibitor of activity towards CDNB of all six GSTs, binding each with similar affinities. 5. Chlorinated phenols are also competitive inhibitors of the enzyme, with the degree of inhibition being directly correlated with the lipophilicity of the compounds. 6. Analysis of inhibition of separated isoforms reveals that form 4 is most strongly inhibited by these chlorinated phenols, with forms 5 and 6 being inhibited to a lesser degree.


Boundary transgressions in the psychotherapeutic framework: who is the injured party?
The authors emphasize the therapeutic value of establishing and maintaining boundaries between clinician and patient. No universal definition of a therapeutic boundary exists, and this ambiguous term spans a diverse spectrum from benign crossings to harmful violations. Understanding of the traumatic nature of faulty boundaries in psychotherapy has derived largely from the study of severe sexual transgressions by therapists. In contrast, this paper highlights the importance of recognizing a wider and more subtle variety of boundary crossings, especially those by patients, which can compromise the integrity of treatment and traumatize the vulnerable therapist. This is exemplified here in the case study of an incest survivor and a novice clinician.


Biomarker evidence for mild central nervous system injury after surgically-induced circulation arrest.
Previously, we identified 14-3-3 beta and zeta isoforms and proteolytic fragments of alpha-spectrin as proteins released from degenerating neurons that also rise markedly in cerebrospinal fluid (CSF) following experimental brain injury or ischemia in rodents, but these proteins have not been studied before as potential biomarkers for ischemic central nervous system injury in humans. Here we describe longitudinal analysis of these proteins along with the neuron-enriched hypophosphorylated neurofilament H (pNFH) and the deubiquitinating enzyme UCH-L1 in lumbar CSF samples from 19 surgical cases of aortic aneurysm repair, 7 involving cardiopulmonary bypass with deep hypothermic circulatory arrest (DHCA). CSF levels of the proteins were near the lower limit of detection by Western blot or enzyme-linked fluorescence immunoassay at the onset of surgical procedures, but increased substantially in a subset of cases, typically within 12-24 h. All cases involving DHCA were characterized by >3-fold elevations in CSF levels of the two 14-3-3 isoforms, UCH-L1, and pNFH. Six of 7 also exhibited marked increases in alpha-spectrin fragments generated by calpain, a protease known to trigger necrotic neurodegeneration. Among cases involving aortic cross-clamping but not DHCA, the proteins rose in CSF preferentially in the subset experiencing acute neurological complications. Our results suggest the neuron-enriched 14-3-3beta, 14-3-3zeta, pNFH, UCH-L1, and calpain-cleaved alpha-spectrin may serve as a panel of biomarkers with clinical potential for the detection and management of ischemic central nervous system injury, including for mild damage associated with surgically-induced circulation arrest.


Analysis of prognostic factors and applicability of Kohne's prognostic groups in patients with metastatic colorectal cancer treated with first-line irinotecan or oxaliplatin-based chemotherapy.
The objective of this study was to analyze prognostic factors for survival and to assess the applicability of Kohne's classification in patients treated with irinotecan- or oxaliplatin-based first-line chemotherapy. One hundred forty-two consecutive cases from a single center were retrospectively reviewed. Median patient age was 62 years. Sixty percent were men. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0/1 in 88%. Primary tumor resection (PTR) was performed in 80.6% of patients who initially had stage IV disease. Chemotherapy consisted of fluoropyrimidines or raltitrexed plus irinotecan (50.5%), oxaliplatin (38.5%), or both (11%). Univariate and multivariate analyses for survival were performed using pretreatment patient characteristics. Median follow-up was 33.9 months and median overall survival was 15.9 months. Significantly unfavorable prognostic factors were PTR not being performed, disease involvement of >1 organ, liver metastases, undifferentiated histology, EGOG PS>1, increased serum carcinoembryonic antigen and cancer antigen 19.9 levels, hypoalbuminemia, leucocytosis, and elevated alkaline phosphatase and lactate dehydrogenase (LDH) levels. Only ECOG PS, PTR, increased LDH level, no hypoalbuminemia, and number of organs involved retained prognostic value in the multivariate analysis. The incidence and median survival for Kohne's prognostic groups were as follows: good (54.2%; 20 months), intermediate (26.8%; 15.7 months), and poor (19%; 6.8 months). For patients with stage IV disease at presentation, PTR was associated with a significantly longer survival, mainly in patients with an ECOG PS of 0/1. Eastern Cooperative Oncology Group PS, PTR, serum albumin, increased LDH levels, and organ involvement were the main prognostic indicators in our series. Kohne's prognostic groups, developed in the era of 5-fluorouracil treatment, also seem to be applicable to patients treated with combination chemotherapy. Primary tumor resection should always be considered, especially in patients with an ECOG PS of 0/1. However, the benefit of PTR and multiple-agent chemotherapy is questionable in patients with an ECOG PS of >1.


More than hemifacial spasm? A case of unilateral facial spasms with systematic review of red flags.
Unilateral facial spasms (UFS) are frequently caused by hemifacial spasm (HFS), a disorder that usually results from vascular loop compression at the root exit zone of the facial nerve. However, UFS can also be a manifestation of other conditions, including brainstem tumours or demyelination, post-Bell's synkinesis, lesions of the facial nerve in the Faloppio canal and the parotid gland, dystonia, epilepsy, psychogenic conditions, tics and hemimasticatory spasm. In this report, we present a case of UFS, not due to HFS, highlighting clinical red flags for an alternative diagnosis. In addition, a systematic review was conducted to provide a comprehensive summary of UFS differential diagnoses with a list of red flags to assist neurologists in the evaluation of patients with UFS.


Different protein kinase C isozymes could modulate bradykinin-induced extracellular calcium-dependent and -independent increases in osteoblast-like MC3T3-E1 cells.
Effects of protein kinase C (PKC) on bradykinin (BK)-induced intracellular calcium mobilization, consisting of rapid Ca2+ release from internal stores and a subsequent sustained Ca2+ inflow, were examined in Fura-2-loaded osteoblast-like MC3T3-E1 cells. The sustained Ca2+ inflow as inferred with Mn2+ quench method was blocked by Ni2+ and a receptor-operated Ca2+ channel blocker SK&F 96365, but not by nifedipine. The short-term pretreatment with phorbol 12-myristate 13-acetate (PMA), inhibited BK-stimulated Ca2+ inflow, and the prior treatment with PKC inhibitors, H-7 or staurosporine, enhanced the initial internal release and reversed the PMA effect. Moreover, 6 h pretreatment with PMA caused similar effect on the BK-induced inflow to that obtained with PKC inhibitors, whereas 24 h pretreatment was necessary to affect the internal release. On the other hand, the translocation and down-regulation of PKC isozymes were examined after PMA treatment of MC3T3-E1 cells by immunoblot analyses of PKCs with the isozyme-specific antibodies. 6 h treatment with PMA induced down-regulation of PKC beta, whereas longer treatment was needed for down-regulation of PKC alpha. Taken together, it was suggested that the BK-induced initial Ca2+ peak and the sustained Ca2+ inflow through the activation of a receptor-operated Ca2+ channel, are differentially regulated by PKC isozymes alpha and beta, respectively, in osteoblast-like MC3T3-E1 cells.


Free radical-induced megamitochondria formation and apoptosis.
Pathophysiological meaning and the mechanism of the formation of megamitochondria (MG) induced under physiological and pathological conditions remain obscure. We now provide evidence suggesting that the MG formation may be a prerequisite for free radical-mediated apoptosis. MG were detected in primary cultured rat hepatocytes, rat liver cell lines RL-34 and IAR-20 and kidney cell line Cos-1 treated for 22 h with various chemicals known to generate free radicals: hydrazine, chloramphenicol, methyl-glyoxal-bis-guanylhydrazone, indomethacin, H2O2, and erythromycin using a fluorescent dye Mito Tracker Red CMXRos (CMXRos) for confocal laser microscopy and also by electron microscopy. Remarkable elevations of the intracellular level of reactive oxygen species (ROS), monitored by staining of cells with a fluorescent dye carboxy-H2-DCFDA, were detected before MG were formed. Prolongation of the incubation time with various chemicals, specified above, for 36 h or longer has induced distinct structural changes of the cell, which characterize apoptosis: condensation of nuclei, the formation of apoptotic bodies, and the ladder formation. Cells treated with the chemicals for 22 h were arrested in G1 phase, and apoptotic sub-G1 populations then became gradually increased. The membrane potential of MG induced by chloramphenicol detected by CMXRos for flow cytometry was found to be decreased compared to that of mitochondria in control cells. Rates of the generation of H2O2 and O2- from MG isolated from the liver of rats treated with chloramphenicol or hydrazine were found to be lower than those of mitochondria of the liver of control animals. We suggest, based on the present results together with our previous findings, that the formation of MG may be an adaptive process at a subcellular level to unfavorable environments: when cells are exposed to excess amounts of free radicals mitochondria become enlarged decreasing the rate of oxygen consumption. Decreases in the oxygen consumption of MG may result in decreases in the rate of ROS production as shown in the present study. This will at the same time result in decreases in ATP production from MG. If cells are exposed to a large amount of free radicals beyond a certain period of time, lowered intracellular levels of ATP may result in apoptotic changes of the cell.


The effect of long-term treatment with antidepressant drugs on the hippocampal mineralocorticoid and glucocorticoid receptors in rats.
The effects of long-term (28 days) and short-term (2 days) administration of imipramine or amitriptyline (10 mg/kg p.o., twice daily) on the density (Bmax) and affinity (Kd) of mineralocorticoid (MR) and glucocorticoid receptors (GR) were determined in the rat hippocampus. MR and GR were examined by an in vitro [3H]corticosterone binding to soluble molecules in the cytosol, using the selective GR agonist RU 28362 to discriminate between MR and GR. Long-term treatment with antidepressant drugs significantly increased the Bmax of GR (by 22-45%; both 2 and 72 h after their last dose), but did not modify the Bmax of MR and the Kd of GR and MR. The above data suggest that up-regulation of GR may be involved in the effect of antidepressant drugs on the activity of the hypothalamic-pituitary-adrenal axis.


Intravascular platelet activation in the hemolytic uremic syndrome.
We studied intravascular platelet activation in patients with typical (epidemic) and atypical (sporadic) HUS and found defective aggregation, decreased platelet and increased plasma serotonin in both groups. The findings were present not only on admission during the thrombocytopenic stage of the disease, but persisted for several weeks after recovery of the platelet count. Reduced endothelial PGI2 production was significantly more common in plasma from atypical than typical cases. Plasma from both typical and atypical HUS patients induced aggregation of normal platelets, but this phenomenon was unrelated to both the presence of thrombocytopenia or the stage of the disease. Serum platelet aggregating activity was higher in the atypical HUS patients, and was not associated with immune complexes detectable by polyethylene glycol precipitation. The data indicate that intravascular platelet activation is a feature of both forms of HUS, and may be initiated by different mechanisms in the two subgroups. While abnormal PGI2 synthesis appears to be important in the atypical cases, neither defective PGI2 production nor platelet aggregation by plasma factors adequately accounts for platelet activation in the majority of typical cases.


Esophageal infections: risk factors, presentation, diagnosis, and treatment.
Infections of the esophagus are unusual in the general population and strongly imply immunodeficiency, although immunocompetent individuals are not exempt. HIV infection is predominant among risk factors for infectious esophagitis. For all immunocompromised patients, the most frequently identified esophageal pathogens are Candida, CMV, and HSV. Peculiar to HIV-infected patients are idiopathic esophageal ulcers as well as unusual bacteria and parasites. Patterns of presentation differ with each infecting organism, and clinical features should be used as a guide in achieving a correct diagnosis. For example, a patient with AIDS presenting with esophageal symptoms and thrush, along with abdominal pain, nausea, vomiting, and fever, is unlikely to resolve all symptoms with empiric antifungal therapy alone. Parsimony of diagnosis does not hold among immunodeficient patients in whom concurrent infections are common. Accurate and timely diagnoses are essential as effective treatments are available for particular etiologies. Finally, among immunocompromised patients, all esophageal symptoms are not necessarily due to an infection, and possible diagnoses of pill esophagitis, acid-peptic injury, or structural and functional abnormalities should not be overlooked.


The influence of annual precipitation, topography, and vegetative cover on soil moisture and summer drought in southern California.
The influence of annual precipitation and vegetation cover on soil moisture and on the length of the summer drought was estimated quantitatively using 9 years of soil moisture data collected at Echo Valley in southern California. The measurements support the conclusions that in the semi-arid mediterranean climate a soil drought will occur regardless of vegetation cover and annual precipitation, but the length of the drought is greatly dependent on soil depth and rockiness. Evergreen species which can survive this drought tend to accentuate the drought, especially in deep soil levels, by developing a canopy with a large transpiring surface.


Progressive myelopathy and neuropathy in New Zealand Huntaway dogs.
To investigate the nature and cause of a progressive ataxia in three 20-month-old Huntaway dogs that were litter mates. Affected dogs were examined before they were humanely killed and submitted to necropsy. Selected formalin-fixed tissues were examined by light and electron microscopy. The lesions were those of axon and myelin degeneration within sensory, proprioceptive and motor tracts of the spinal cord and to a lesser degree some peripheral nerves. A progressive myelopathy and neuropathy, tentatively described as a central-peripheral distal axonopathy, was present in all 3 dogs. The cause was not determined but was likely to be either genetic or nutritional. In the early stages of this disease, careful examination may be necessary to distinguish the signs of ataxia from orthopaedic disease such as hip dysplasia. Affected animals are unlikely to be of use as working dogs.


Genome-wide identification and expression analysis of brassinosteroid biosynthesis and metabolism genes regulating apple tree shoot and lateral root growth.
In plants, brassinosteroid biosynthesis and metabolism genes affect endogenous brassinosteroid metabolic processes as well as stem and root growth. However, there is little information available regarding these genes in apple. In this study, 22 brassinosteroid biosynthesis and metabolism genes were identified in apple (Malus domestica). These genes were named according to their chromosomal locations and the Arabidopsis thaliana homologs. Their conserved characteristic domains, evolutionary relationships, syntenic relationships, chemical characteristics, gene/protein structures, interactions among the encoded proteins, promoter sequences, and functions were investigated. These 22 genes were clustered with their A. thaliana homologs based on bioinformatics analyses, which suggested they are functionally similar in apple and A. thaliana. Tissue-specific expression levels revealed that most of these genes are important for stem growth and development, while several of these genes affect lateral root formation. The transcription patterns of these genes in shoot tips were investigated following diverse treatments [brassinosteroid (shoot tips and roots), brassinazole, auxin, and temperature]. Gene expression levels were also examined in different grafting combinations ('Nagafu No. 2'/Malling 9 and 'Nagafu No. 2'/'Nagafu No. 2') and shoot varieties ('Yanfu No. 6' and 'Nagafu No. 2'). The results indicated that these genes may be involved in apple stem and root growth. The comprehensive genome-wide analysis of brassinosteroid biosynthesis and metabolism genes presented herein may be useful for breeding new apple cultivars with increased vigor. The data also represent a rich genetic resource for future apple gene functional investigations that may have implications for the genetic improvement of apple tree species.


Pharmacologic Treatment Options in Mild, Moderate, and Severe Acne Vulgaris.
Most patients with acne have a disease that responds to acute treatment and can be controlled long term with a maintenance regimen of topical therapy. It is the minority of patients-generally, but not exclusively-the most severely affected, who respond poorly to acute therapy and require continued systemic therapy. The goals of therapy are resolution of visible lesions, prevention of new lesions, avoidance of scarring, and improvement of patient quality of life. Treatment choices are made on the basis of lesion type, number, and size, with consideration given to the presence of physical and psychological scarring. Semin Cutan Med Surg 34(supp5):S82-S85.


Identification of novel lipid biomarkers in xmrk- and Myc-induced models of hepatocellular carcinoma in zebrafish.
Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and is accompanied by complex dysregulation of lipids. Increasing evidence suggests that particular lipid species are associated with HCC progression. Here, we aimed to identify lipid biomarkers of HCC associated with the induction of two oncogenes, xmrk, a zebrafish homolog of the human epidermal growth factor receptor (EGFR), and Myc, a regulator of EGFR expression during HCC. We induced HCC in transgenic xmrk, Myc, and xmrk/Myc zebrafish models. Liver specimens were histologically analyzed to characterize the HCC stage, Oil-Red-O stained to detect lipids, and liquid chromatography/mass spectrometry analyzed to assign and quantify lipid species. Quantitative real-time polymerase chain reaction was used to measure lipid metabolic gene expression in liver samples. Lipid species data was analyzed using univariate and multivariate logistic modeling to correlate lipid class levels with HCC progression. We found that induction of xmrk, Myc and xmrk/Myc caused different stages of HCC. Lipid deposition and class levels generally increased during tumor progression, but triglyceride levels decreased. Myc appears to control early HCC stage lipid species levels in double transgenics, whereas xmrk may take over this role in later stages. Lipid metabolic gene expression can be regulated by either xmrk, Myc, or both oncogenes. Our computational models showed that variations in total levels of several lipid classes are associated with HCC progression. These data indicate that xmrk and Myc can temporally regulate lipid species that may serve as effective biomarkers of HCC progression.


No gender influences on clinical outcomes or durability of repair following carotid angioplasty with stenting and carotid endarterectomy.
To determine if gender influences clinical outcomes and durability of repair after carotid angioplasty with stenting (CAS) or carotid endarterectomy (CEA), an analysis of patient records was performed. This study included 89 CAS patients (47 men and 42 women) and 93 CEA patients (53 men and 40 women). Patients underwent duplex scans 6, 12, 24 months post procedure. The outcomes of periprocedural mortality, major adverse events, strokes, and myocardial infarctions were assessed. Incidence of critical restenosis and recurrence of symptoms was also assessed. No significant differences were noted between men and women who had undergone either CAS or CEA (P > .05) for clinical outcomes and durability of repair. No differences for periprocedural mortality, major adverse events, critical restenosis, recurrent neurologic symptoms, and adverse event free survival were found. These results do not indicate substantial gender influences on clinical outcomes or durability of repair following CAS and CEA.


Effect of perioperative intravenous lidocaine for patients undergoing spine surgery: A meta-analysis and systematic review.
Perioperative intravenous lidocaine has been reported to have analgesic and opioid-sparing effects in many kinds of surgery. Several studies have evaluated its use in the settings of spine surgery. The aim of the study is to examine the effect of intravenous lidocaine in patients undergoing spine surgery. We performed a quantitative systematic review. Databases of PubMed, Medline, Embase database and Cochrane library were investigated for eligible literatures from their establishments to June, 2019. Articles of randomized controlled trials that compared intravenous lidocaine to a control group in patients undergoing spine surgery were included. The primary outcome was postoperative pain intensity. Secondary outcomes included postoperative opioid consumption and the length of hospital stay. Four randomized controlled trials with 275 patients were included in the study. postoperative pain compared with control was reduced at 6 hours after surgery (WMD -0.50, 95%CI, -0.76 to -0.25, P < .001), at 24 hours after surgery (WMD -0.50, 95%CI, -0.70 to -0.29, P < .001) and at 48 hours after surgery (WMD -0.57, 95%CI, -0.96 to -0.17, P = .005). The effect of intravenous lidocaine on postoperative opioid consumption compared with control revealed a significant effect (WMD -15.36, 95%CI, -21.40 to -9.33 mg intravenous morphine equivalents, P < .001). This quantitative analysis of randomized controlled trials demonstrated that the perioperative intravenous lidocaine was effective for reducing postoperative opioid consumption and pain in patients undergoing spine surgery. The intravenous lidocaine should be considered as an effective adjunct to improve analgesic outcomes in patients undergoing spine surgery. However, the quantity of the studies was very low, more research is needed.


Evaluation of the patient with a possible phagocytic disorder.
This article presents an outline of a rational approach to the patient with recurrent infections. The different categories of phagocytic defects are reviewed, and a brief discussion of the various tests of phagocyte function is presented.


[Isolation culture and identification of human neural stem cells from human embryos].
To obtain and culture the human neural stem cells from the aborted human embryos. The neural stem cells were isolated and purified by the specific proliferous culture system of neural stem cells, and the molecular maker and multi-potency of the obtained neural stem cells were identified. Human neural stem cells, which were isolated from 8 - 10 month old aborted human embryos, could express nestin ( a kind of specified antigen of the neural stem cell), and it could be differentiate into neurons and glials. Neural stem cells can exist in human embryos, and it can be expanded in vitro.


Portal-systemic shunt through the right renal vein developing following portal tumor thrombus.
Despite the semi-routine use of color Doppler sonography for evaluating portal circulation abnormalities, there is a relative paucity of information on portal-systemic (P-S) shunt through the right renal vein (P-SR shunt). We report such a case. The patient was a 60-year-old woman with hepatocellular carcinoma on liver cirrhosis. Serial sonography showed an aggravation in findings; an increase in the size of the tumor was followed by formation of a portal tumor thrombus, and then occurrence of a P-SR shunt. We present this case, with a comparison between the patient's clinical course and the color Doppler results. To our knowledge, this is the first report to make such a comparison in a P-SR shunt case. We also briefly review the literature.


Morningness orientation is an important determinant to circadian misalignment and tolerance: an Asian perspective.
Diurnal preferences refers to one's preference of performing timely activities where one may prefer for late timings and the other for earlier, which account for their chronotype that is controlled partly by genetic factors and are also influenced by environmental factors. Individual's circadian preference can be drawn using questionnaire tools as well as can be externally validated by studying various physiological parameters that has a rhythmicity. Determination of chronotype is well studied worldwide but mostly in European and American countries. Asia being the largest continent, comprising so many countries still did not have widespread studies over chronotype assessment and its implications. This review aims at jotting down the available literature regarding the chronotype evaluation and the various contributing factors in Asian perspectives such that there can be huge cross-cultural studies emphasizing environmental, geographical differences, lifestyle habits, work schedule, and other contributing factors regarding the understanding of circadian preference of humans, which is really hard to define. The dearth in studies regarding diurnal preferences and physiological altercations, which is in turn influenced by the work schedule and the resultant sleep-wake pattern disorientation, needs further investigation worldwide and this available literature may put some light in the path of future research scope.


Progressive resistive exercise in weaning high quadriplegics from the ventilator.
Acutely high level quadriplegics may experience neuromuscular respiratory insufficiency secondary to loss of use of intercostal and abdominal muscles as well as partial involvement of the phrenic nerve. Frequently, these patients will require mechanical ventilation in the initial stages of their treatment. These patients may present difficulty with weaning off the ventilator. In addition, poor respiratory reserve increases the risk of episodic decompensation. We have instituted a progressive resistive exercise protocol (PRE) analogous to PRE commonly used in training skeletal muscle, to wean patients off the ventilator. This involves determining the patient's endurance to the development of fatigue while off the ventilator. Patients are re-evaluated weekly until they are weaned from the ventilator. Three case studies are reported in which this protocol was used. In addition to our standard respiratory therapy and physical therapy protocols, values for vital capacity and maximum inspiratory force at admission and post-weaning were recorded. After completion of the programme, none of the patients required re-intubation or subsequent mechanical ventilation. This method of diaphragm training may be useful in weaning high level quadriplegics from the ventilator.


Concomitant cyclosporine and micafungin pharmacokinetics in healthy volunteers.
Cyclosporine is a marketed immunosuppressive agent and a known substrate for CYP3A. Micafungin is an antifungal agent and a mild inhibitor of CYP3A-mediated metabolism in vitro. The objectives of this study were to evaluate the pharmacokinetics of cyclosporine and micafungin before and with concomitant administration. The pharmacokinetics of single-dose oral cyclosporine (5 mg/kg) were estimated on days 1, 9, and 15 (n = 27). Subjects received micafungin (100 mg/d over 1 hour) on days 7, 9, and 11 through 15. Micafungin pharmacokinetics were estimated on days 7, 9, and 15. Mean apparent oral cyclosporine clearances were estimated to be 645+/-236 mL/h/kg, 546+/-101 mL/h/kg (P = .01), and 540+/-104 mL/h/kg (P = .02) for days 1, 9, and 15, respectively. Micafungin appears to be a mild inhibitor of cyclosporine metabolism.


Autocystectomy following extensive genitourinary tuberculosis: presentation and management.
Genitourinary tuberculosis is an important cause of morbidity in developing and developed countries. We describe a case of extensive genitourinary tuberculosis in which there was complete destruction of the right kidney, stricture of the entire left ureter and an autocystectomized bladder. He presented in azotemia with urinary incontinence and was managed by right nephroureterectomy, ileal replacement of left ureter and ileal neobladder after a preliminary nephrostomy and antituberculous chemotherapy.


Postural and kinetic coordination following cortical stimuli which induce flexion movements in the cat's limbs.
The relationship between movement and the postural adjustment associated with it has been studied following flexion movements of a limb induced by cortical stimulation in chronically implanted cats. Variations in the vertical force exerted by each limb, as well as the displacement of the centre of gravity (projected onto the plane of stance), were investigated. It was established that: The pattern of postural adjustment observed in these conditions is diagonal; that is to say, flexion of one limb is accompanied by diminution in the vertical force exerted by the diagonally opposite limb and an increase in the force exerted by the other two. The displacement of the projected centre of gravity is sterotyped during the first phase of variation in forces. Its extent may be considered as an index of the efficiency of postural adjustment. The study of the latencies of the changes in force indicates, at least in the case of hindlimb movements, that postural adjustment is an active phenomenon and does not arise passively from the interplay of purely mechanical forces. In the same conditions, an analysis of the time course and latency of recorded changes in force indicates that postural adjustment is not triggered reflexly by the disequilibrium brought about by movement but is a result of a central nervous command.


Specific association between alcohol intake, high grade of differentiation and 4q34-q35 deletions in hepatocellular carcinomas identified by high resolution allelotyping.
One of the most frequent deletions in hepatocellular carcinoma (HCC) is that involving the long arm of chromosome 4 (30 to 70% of the cases). These chromosomal deletions are closely related to hepatitis B virus (HBV) infection. A tumor suppressor gene (TSG) located on 4q has been proposed in liver carcinogenesis, but has not been identified as yet. Despite previous LOH studies focused on 4q in HCC, a clear minimal common region of deletion (MCRD) could not be delimited. To further investigate the role of chromosome 4q LOH in the pathogenesis of HCC, 85 microsatellite markers spanning chromosome 4q were systematically analysed in a series of 154 well-characterized primary liver tumors. In 59 tumors (38%), LOHs were observed for at least two adjacent markers. Analysis of 31 tumors demonstrating a partial or interstitial 4q deletion allowed to define three MCRDs of 15, 9 and 8 Mb at the 4q22, 4q34 and 4q35 regions, respectively. Seven putative candidate genes located in 4q22, DAPP1, BMPR1B, PKD2, HERC3, SMARCAD1, CEB1 and ENH were screened for mutations but no somatic alterations were identified. Search for relationships between the specific regions of deletion and clinical parameters showed a significant association between loss of the 4q34-35 region with alcohol intake (P=0.005) and with high grade of differentiation (P=0.02). These results are in contrast with the close association between HBV infection and the whole 4q LOH and reveal heterogeneity of 4q LOH in relation to different risk factors. In the light of these new findings, which link different 4q LOH regions to different etiologic factors, the molecular mechanisms underlying 4q deletions in HCC and the targeted gene(s) remain to be identified.


Digital subtraction angiography (DSA) in the evaluation of brain death. A comparison of conventional cerebral angiography with intravenous and intraarterial DSA.
Demonstration that intracranial circulation has ceased is the ultimate proof of brain death. This study was performed to evaluate digital subtraction angiography (DSA) compared with conventional cerebral angiography in the diagnosis of brain death. Intravenous as well as intraarterial DSA was found suitable in the diagnosis of arrested intracranial circulation.


Population genetic study of 34 X-Chromosome markers in 5 main ethnic groups of China.
As a multi-ethnic country, China has some indigenous population groups which vary in culture and social customs, perhaps as a result of geographic isolation and different traditions. However, upon close interactions and intermarriage, admixture of different gene pools among these ethnic groups may occur. In order to gain more insight on the genetic background of X-Chromosome from these ethnic groups, a set of X-markers (18 X-STRs and 16 X-Indels) was genotyped in 5 main ethnic groups of China (HAN, HUI, Uygur, Mongolian, Tibetan). Twenty-three private alleles were detected in HAN, Uygur, Tibetan and Mongolian. Significant differences (p < 0.0001) were all observed for the 3 parameters of heterozygosity (Ho, He and UHe) among the 5 ethnic groups. Highest values of Nei genetic distance were always observed at HUI-Uygur pairwise when analyzed with X-STRs or X-Indels separately and combined. Phylogenetic tree and PCA analyses revealed a clear pattern of population differentiation of HUI and Uygur. However, the HAN, Tibetan and Mongolian ethnic groups were closely clustered. Eighteen X-Indels exhibited in general congruent phylogenetic signal and similar cluster among the 5 ethnic groups compared with 16 X-STRs. Aforementioned results proved the genetic polymorphism and potential of the 34 X-markers in the 5 ethnic groups.


Serum amylase isoenzymes in ectopic pregnancy.
In general, significant amylase elevation was not documented in women with tubal pregnancies, compared with normal IUPs in the first trimester and a nonpregnant control range. One of 49 samples in 25 patients with tubal pregnancy was mildly elevated for salivary amylase.


Immunomodulating properties of lymphocytes activated by farmer's lung associated bacterium Thermoactinomyces vulgaris in vitro.
Thermoactinomyces vulgaris, one of the aetiological agents of farmer's lung, was analysed for its ability to activate non-immune spleen lymphocytes from 10- to 14- week-old mice. The lymphocytes were found to exert both enhancing and suppressing signals after activation, depending on the secondary stimulation used. The enhancing effect is due to interleukin-2 secreted mainly by L3T4+ lymphocytes. The suppressive action is associated with Lyt2+ lymphocytes, which are probably activated by prostaglandins or histamine; but the suppression inducer action of L3T4+ lymphocytes may also be important. Genetic regulation, independent of H-2K and D, was also detected between different inbred strains of mice in response to T. vulgaris. The genetic regulation appeared associated with the different responsiveness of Lyt-2 positive lymphocytes between different strains. These results emphasize the importance of nonspecific activation in hypersensitivity disorders induced by microbiol antigens.


Volunteer contributions to Wikipedia increased during COVID-19 mobility restrictions.
Wikipedia, the largest encyclopedia ever created, is a global initiative driven by volunteer contributions. When the COVID-19 pandemic broke out and mobility restrictions ensued across the globe, it was unclear whether contributions to Wikipedia would decrease in the face of the pandemic, or whether volunteers would withstand the added stress and increase their contributions to accommodate the growing readership uncovered in recent studies. We analyze [Formula: see text] million edits contributed from 2018 to 2020 across twelve Wikipedia language editions and find that Wikipedia's global volunteer community responded resiliently to the pandemic, substantially increasing both productivity and the number of newcomers who joined the community. For example, contributions to the English Wikipedia increased by over [Formula: see text] compared to the expectation derived from pre-pandemic data. Our work sheds light on the response of a global volunteer population to the COVID-19 crisis, providing valuable insights into the behavior of critical online communities under stress.


Extended treatment in cerebral ischemia score 2c or 3 as goal of successful endovascular treatment is associated with clinical benefit.
Successful reperfusion, defined as a modified treatment in cerebral ischemia (mTICI) score 2b or 3, is an important goal for endovascular treatment (EVT) of stroke. Recently, an extension of the mTICI score with an additional grade 2c indicating near-complete reperfusion (expanded TICI, eTICI) and a revised definition of success as eTICI 2c or 3 were proposed. We evaluate whether eTICI 2c translates into improved clinical outcome compared to eTICI 2b. Consecutive patients with large vessel occlusion in the anterior circulation who underwent EVT between December 2013 and December 2020 were included. Clinical outcome measures were favorable functional outcome at 90 days (modified Rankin Scale [mRS] scores 0 to 2 or return to pre-stroke mRS) and early neurological improvement (National Institutes of Health Stroke Scale [NIHSS] improvement ≥4 points or a score of 0-1 at 24 h). Of 1282 included patients (median age 76, median NIHSS 16), reperfusion was classified as eTICI 2b in 410 (32%), eTICI 2c in 242 (19%) and eTICI 3 in 464 (36%). eTICI 2c differed significally from 2b with respect to early neurological improvement (aOR = 1.49, 95% CI = 1.01-2.19). No statistically significant difference in favorable functional outcome at 90 days was found (eTICI 2c vs 2b, aOR = 1.31, 95% CI = 0.88-2.00). Our study indicates early clinical benefit at 24 h of achieving eTICI 2c compared to eTICI 2b, but no significant difference was seen in favorable functional outcome at 90 days. Our results support eTICI 2c and 3 as the goal of a successful thrombectomy but do not exclude eTICI 2b as an acceptable result.


Retention of a new-defined intron changes pharmacology and kinetics of the full-length P2X2 receptor found in myenteric neurons of the guinea pig.
P2X2 plays an important role in ATP signaling in guinea pig myenteric plexus. Here, we cloned and characterized three P2X2 isoforms expressed in myenteric neurons. RT/PCR was used to amplify the cDNA of P2X2 variants. These were expressed in Xenopus oocytes, and nucleotide-induced membrane currents were recorded with the two-electrode voltage clamp technique. Three P2X2 cDNAs were identified in myenteric single neurons, named P2X2-1, P2X2-2 and P2X2-4. Based on the analysis of the structural organization of these variants we predicted that P2X2-2 is the fully processed variant, which lead us to propose a new exon-intron arrangement of P2X2 receptor gene with 12 exons and 11 introns. In agreement with this new model, the intron 11 is retained in P2X2-1 and P2X2-4 variants by alternative splicing. Expression of P2X2-1, P2X2-2 and P2X2-4 were found in 92, 42 and 37%, respectively, out of 40 analyzed single neurons. P2X2-4 does not form functional channels, and homomeric channels formed by P2X2-1 and P2X2-2 have different pharmacological profile. Thus, the former receptor is more sensitive to ATP, BzATP, and PPADS, whereas, suramin inhibited both receptors in a biphasic- and monophasic-manner, respectively. α,β-meATP has very low efficacy on either channel. Furthermore, ionic currents mediated by P2X2-1 have slower desensitization than P2X2-2. These results indicate that P2X2-1 was the most common P2X2 transcript in myenteric neurons and displays significant phenotypical changes implicating that retention of the intron 11 plays a major role in ATP signaling in the intestinal myenteric plexus.


trans-Di-aqua-bis-(N,N,N'-tri-methyl-ethylenedi-amine)-nickel(II) dichloride.
In the title salt, [Ni(C5H12N2)2(H2O)2]Cl2, the asymmetric unit is comprised of half of the complex cation and a chloride ion with the NiII atom of the cation situated about a twofold rotation axis. The six-coordinate NiII atom of the cation is connected to four N atoms from two methyl-substituted ethyelenedi-amine ligands and two water mol-ecules in a slightly distorted octa-hedral environment. The five-membered chelate ring is in a slight envelope conformation. The crystal packing features O-H⋯Cl and N-H⋯Cl inter-molecular inter-actions with the Cl- ion forming weak bifurcated hydrogen bonds with nearby water mol-ecules and N-H inter-actions, leading to a three-dimensional supra-molecular network structure.


Outbreak of Salmonella Newport linked to imported frozen cooked crayfish in dill brine, Sweden, July to November 2019.
In autumn 2019, the Public Health Agency of Sweden identified a cluster of Salmonella Newport cases by whole genome sequencing (WGS). Cases' distribution in place and time indicated a nation-wide ongoing outbreak. An investigation was initiated to identify the source and prevent further cases. We conducted a case-case study based on notified salmonellosis cases and a Salmonella trawling questionnaire, comparing 20 outbreak cases and 139 control cases. Food exposures were compared by adjusted odds ratios (aOR) with 95% confidence interval (CI) using logistic regression. Implicated foods were sampled. Outbreak cases were more likely to have consumed crayfish (aOR = 26; 95% CI: 6.3-105). One specific brand of imported frozen, pre-cooked whole crayfish in dill brine was identified as the source. Salmonella Newport was later detected in different batches from retail and in one sample from border control. Isolates from food samples clustered with the human outbreak strain by WGS. Although the retailer made a complete recall, two more cases were identified long afterwards. This investigation demonstrated the successful use of a case-case study and targeted microbiological testing to identify the source. The immediate action taken by the retailer was important to confirm the source and stop the outbreak.


Acute uveal effusion during phacoemulsification with preoperative central serous chorioretinopathy: a case report.
We report a case of acute uveal effusion during phacoemulsification in an eye with preoperative chronic central serous chorioretinopathy (CSC). A 55-year-old man with a history of chronic CSC for >18 months presented with bilateral opaque lenses. A preoperative ophthalmic examination showed suspected lenticonus and risky anatomical features, including a thick ciliary body, and anterior rotation of the ciliary process and iris root in both eyes. Optical coherence tomography (OCT) detected CSC in the left eye, but the results of fundus photography and B-scan ultrasonography were unremarkable. The anterior chamber flattened during phacoemulsification. Anterior vitrectomy was quickly performed for suspected infusion misdirection syndrome, and was followed by uneventful surgery. On postoperative day 1, fundus photography, type B ultrasound, and OCT revealed uveal exudation in the macula of the left eye. On postoperative day 50, the patient's visual acuity recovered to 20/32, and fundus photography, ultrasonography, and OCT revealed complete resolution of the uveal effusion. This case suggests an association between preoperative CSC and uveal effusion during surgery, because choroidal hyperperfusion and hyperpermeability were present in the patient's CSC-affected eyes.


Oophorectomy did not show any additional effect on bone density and mineral content in thyroxine treated mice.
Experimental hyperthyroidism (thyroxine administration for 21 days) caused a significant decrease in ash mass, bone density and mineral content in the femora of mice, the same degree of reduction in individual measures of bone mass being found in oophorectomized and intact mice treated with thyroxine. It may be suggested that estrogens did not protect the skeleton against the resorbing action of thyroxine or triiodothyronine.


Bilateral hydrothorax complicating central venous catheterization in a child: case report.
It is necessary to consider catheter-related events when a previously stable patient has an acute change in cardiopulmonary status, regardless of the duration of catheter use; and to recognize that hydrothorax from vein perforation may be bilateral, necessitating bilateral drainage procedures.


MSRE-HTPrimer: a high-throughput and genome-wide primer design pipeline optimized for epigenetic research.
Methylation-sensitive restriction enzymes-polymerase chain reaction (MSRE-PCR) has been used in epigenetic research to identify genome-wide and gene-specific DNA methylation. Currently, epigenome-wide discovery studies provide many candidate regions for which the MSREqPCR approach can be very effective to confirm the findings. MSREqPCR provides high multiplexing capabilities also when starting with limited amount of DNA-like cfDNA to validate many targets in a time- and cost-effective manner. Multiplex design is challenging and cumbersome to define specific primers in an effective manner, and no suitable software tools are freely available for high-throughput primer design in a time-effective manner and to automatically annotate the resulting primers with known SNPs, CpG, repeats, and RefSeq genes. Therefore a robust, powerful, high-throughput, optimized, and methylation-specific primer design tool with great accuracy will be very useful. We have developed a novel pipeline, called MSRE-HTPrimer, to design MSRE-PCR and genomic PCR primers pairs in a very efficient manner and with high success rate. First, our pipeline designs all possible PCR primer pairs and oligos, followed by filtering for SNPs loci and repeat regions. Next, each primer pair is annotated with the number of cut sites in primers and amplicons, upstream and downstream genes, and CpG islands loci. Finally, MSRE-HTPrimer selects resulting primer pairs for all target sequences based on a custom quality matrix defined by the user. MSRE-HTPrimer produces a table for all resulting primer pairs as well as a custom track in GTF file format for each target sequence to visualize it in UCSC genome browser. MSRE-HTPrimer, based on Primer3, is a high-throughput pipeline and has no limitation on the number and size of target sequences for primer design and provides full flexibility to customize it for specific requirements. It is a standalone web-based pipeline, which is fully configured within a virtual machine and thus can be readily used without any configuration. We have experimentally validated primer pairs designed by our pipeline and shown a very high success rate of primer pairs: out of 190 primer pairs, 71 % could be successfully validated. The MSRE-HTPrimer software is freely available from http://sourceforge.net/p/msrehtprimer/wiki/Virtual_Machine/ as a virtual machine.


Changes in interneuronal phenotypes regulated by estradiol in the adult rat hippocampus: a potential role for neuropeptide Y.
Ovarian hormones regulate pyramidal cell synapse formation and excitability and interneuronal GABAergic tone in the CA1 region of the adult female rat hippocampus. The role of 17beta-estradiol in these effects is complex and appears to involve a subset of hippocampal interneurons, which express different calcium-binding protein and neuropeptide phenotypes and nuclear estrogen receptor alpha. We found that, in the hippocampus, nuclear estrogen receptor alpha-immunoreactive interneurons co-express neuropeptide Y, calbindin-D28k and calretinin but do not parvalbumin or cholecystokinin. Moreover, a proportion of neuropeptide Y-immunoreactive interneurons co-expresses calbindin-D28k and calretinin. This pattern is similar in the presence or absence of 17beta-estradiol treatment in ovariectomized rats. We then used immunohistochemistry and in situ hybridization to determine whether 17beta-estradiol treatment regulates expression of CA1 interneuronal phenotypic markers via nuclear estrogen receptor alpha activation. We found that 17beta-estradiol treatment of ovariectomized rats increased neuropeptide Y mRNA levels (25%) and the neuropeptide Y mRNA-associated grain density per cell (11%), as well as the number of neuropeptide Y-immunoreactive cells (11%), predominantly in the pyramidal cell layer (stratum pyramidale). Treatment with CI628, a selective estrogen response modulator that acts as an antagonist for nuclear estrogen receptor, blocked 17beta-estradiol-induced increase of neuropeptide Y mRNA levels. 17beta-Estradiol treatment did not alter the number of parvalbumin, calretinin, and cholecystokinin immunoreactive cells, nor mRNA levels for parvalbumin and cholecystokinin. Therefore, the present study has identified neuropeptide Y expression as the main interneuronal phenotype that co-expresses nuclear estrogen receptor alpha and shown that neuropeptide Y is responsive to 17beta-estradiol in CA1 pyramidal cell layer. We suggest that 17beta-estradiol may regulate neuropeptide Y expression mediated by nuclear estrogen receptor alpha-dependent activation in a subset of hippocampal interneurons, and we speculate that subsequent neuropeptide Y release may indirectly contribute to regulate glutamate-dependent neuronal activity in the adult rat hippocampus.


Lateral antebrachial cutaneous neuropathy following the long head of the biceps rupture.
Lateral antebrachial cutaneous neuropathies present as purely sensory lesions, manifesting as elbow pain or dysesthetic pain over the lateral forearm. Classically, entrapment of the lateral antebrachial cutaneous nerve has been documented at the lateral edge of the biceps tendon as it exits the deep fascia in the antecubital fossa. We report a case of lateral antebrachial cutaneous nerve traction neuritis, rather than entrapment, resulting from a rupture of the long head of the biceps. The biceps displaced the nerve laterally, resulting in sensory loss and severe allodynia. The patient's symptoms were relieved with proximal biceps tenodesis.


Selection of deep brain stimulation candidates in private neurology practices: referral may be simpler than a computerized triage system.
The objective of this study is to compare a computerized deep brain stimulation (DBS) screening module (Comparing Private Practice vs. Academic Centers in Selection of DBS Candidates [COMPRESS], NeuroTrax Corp., Bellaire, TX, USA) with traditional triage by a movement disorders specialized neurologist as the gold standard. The COMPRESS consists of a combination of the Florida Surgical Questionnaire for Parkinson disease (FLASQ-PD), a cognitive assessment battery provided by MindStreams® (NeuroTrax Corp.), and the Geriatric Depression Scale and the Zung Anxiety Self-Assessment Scale. COMPRESS resulted in the classification of patients into three categories: "optimal candidate,""probable candidate," and "not a good candidate." Similar categorical ratings made by a referring private practice neurologist and by a trained movement disorders specialist were compared with the ratings generated by COMPRESS. A total of 19 subjects with Parkinson's disease were enrolled from five private neurological practices. The clinical impressions of the private practice neurologist vs. those of the movement disorders specialist were in agreement approximately half the time (10/19 cases). The movement disorders specialist and COMPRESS agreed on 15/19 cases. A further comparison between outcomes from the entire COMPRESS module and the FLASQ-PD questionnaire by itself resulted in high agreement (18/19 cases in agreement). The COMPRESS agreed with an in-person evaluation by a movement disorders neurologist approximately 80% of the time. The computerized COMPRESS did not provide any screening advantage over the short FLASQ-PD paper questionnaire. Larger studies will be needed to assess the utility and cost effectiveness of this computerized triage method for DBS.


Adsorption of a few heavy metals on natural and modified kaolinite and montmorillonite: a review.
The feasibility of using two important and common clay minerals, kaolinite and montmorillonite, as adsorbents for removal of toxic heavy metals has been reviewed. A good number of works have been reported where the modifications of these natural clays were done to carry the adsorption of metals from aqueous solutions. The modification was predominantly done by pillaring with various polyoxy cations of Zr4+, Al3+, Si4+, Ti4+, Fe3+, Cr3+or Ga3+, etc. Preparation of pillared clays with quaternary ammonium cations, namely, tetramethylammonium-, tetramethylphosphonium- and trimethyl-phenylammonium-, N'-didodecyl-N, N'-tetramethylethanediammonium, etc, are also common. Moreover, the acid treatment of clays often boosted their adsorption capacities. The adsorption of toxic metals, viz., As, Cd, Cr, Co, Cu, Fe, Pb, Mn, Ni, Zn, etc., have been studied predominantly. Montmorillonite and its modified forms have much higher metal adsorption capacity compared to that of kaolinite as well as modified-kaolinite.


Recent advancements in coralyne (COR)-based biosensors: Basic principles, various strategies and future perspectives.
As a kind of protoberberine alkaloid heterocyclic analogues, coralyne (COR) has been reported to exhibit superior antileukemic ability and used as anticancer drug agent. While, the severe hazards and side effects caused by unreasonable use have made its accurate detection more and more important. Although scientists have explored various methods to sense COR and other related targets, a systematical review which could not only elaborate recent developments and analyze current challenges of COR-based biosensors, but also present future perspective has not been reported and is urgently needed. In this review, we attempt to summarize latest advancements in COR-based biosensors in recent decade. Firstly, the operating principles, advantages and disadvantages of various strategies for COR detection (colorimetric, fluorescent, electrochemical and other ones) are comprehensively demonstrated and reviewed. Secondly, COR-assisted biosensors for detection of different non-COR targets (heparin, toxins, nucleic acids and other small molecules) are further discussed. Finally, we analyze current challenges and also suggest potential perspectives for this area.


Phosphorus influence Cd phytoextraction in Populus stems via modulating xylem development, cell wall Cd storage and antioxidant defense.
The soils in mining lands with cadmium (Cd) contamination usually are deficient in nutrients. Disclosing how P nutrition and N:P stoichiometric ratio influences Cd accumulation and stress tolerance in stems of Populus spp. will facilitate the phytoremediation of mining sites polluted by Cd. In this study, investigations at the anatomical and physiological levels were conducted using a clone of Populus × euramericana. Both phosphorus deficiency and cadmium exposure inhibited xylem development via reducing cell layers in the xylem. Under P-sufficient condition, appropriate P status and balanced N:P ratio in stem promoted xylem development under Cd exposure via stimulating cell division, which enhanced Cd accumulation in stems. Cd accumulation in cell walls of collenchyma tissues of the stem was enhanced by P application due to increased polysaccharide production and cell wall affinity for Cd. The low P concentrations (0.3-0.4 mg g-1) and imbalanced N:P ratio under P deficiency inhibited the production of APX and ascorbate-GSH cycle, which increased oxidative stress and lipid peroxidation as indicated by high MDA concentration in stem. Under P-sufficient condition, the interactions between phytohormones and antioxidants play crucial roles in the process of antioxidant defense under Cd exposure. In conclusions, appropriate P addition and balanced N:P ratio enhanced secondary xylem development and promoted cadmium accumulation and stress tolerance in Populus stems, which can benefit the phytoextraction of Cd from Cd-contaminated soil.


Effect of elastic resistance training on functional capacity in older adults: a systematic review with meta-analysis.
This systematic review and meta-analysis investigated the effects of Elastic Resistance Training (ERT) on functional capacity (FC) in older adults. The databases used were Embase, Virtual Health Library, PubMed, SciElo, Scopus, SPORTS Discus, and Web of Science. Eligibility criteria: aged ≥ 60 years; both sexes; intervention of at least 8 weeks; structured ERT; comparator group that performed other types of training or without any intervention; at least one functional test measurement. Functional tests were grouped according to their specificity for the sub-group meta-analyses. Twenty-six studies were considered eligible for qualitative synthesis, of which 16 were used for quantitative analysis. Favorable effects (p < .001) of ERT compared to the control group without intervention were observed in the 30-second sit to stand test, Timed Up and Go test, arm curl test, handgrip strength test, 6-minute walk test, lower and upper limb flexibility, and Short Physical Performance Battery (p = .007). Comparisons between ERT and other types of training were not performed because of the high heterogeneity of the studies. Our findings suggest that ERT is able to improve the FC of older adults when compared to older adults not involved in any type of training.


"Flow-void" sign in osseous metastatic renal cell carcinoma.
To evaluate the frequency of the "flow-void" sign in a large series of pathologically proven renal cell carcinoma (RCC) bone metastases referred to a specialist unit and to evaluate its correlation with both lesion size and imaging sequence. A further aim was to describe a proposed grading system for the description of the "flow-void" sign. A retrospective review of patients with magnetic resonance imaging (MRI) of pathologically proven RCC bone metastases between September 2007 and December 2017 was performed. MRI images were reviewed for the presence of the "flow-void" sign and a proposed grading system for this sign was applied. Statistical analysis was performed to determine the association between the presence of the "flow-void" sign and lesion size and MRI sequence. One hundred and forty bone lesions in 123 patients with histologically proven metastatic RCC were reviewed. One hundred and thirty-two (94.3%) lesions demonstrated the "flow-void" sign on at least one sequence in each study. A statistically significant difference was demonstrated between lesion size and the presence and type of "flow-void" sign. Lesions demonstrating type 3 "flow-void" sign had mean dimensions of 82.2 mm compared to 47.3 mm for lesions that did not demonstrate the "flow-void" sign (χ2(2) =11.4; p=0.01). T2-weighted, proton density and fat-saturated imaging also demonstrated the "flow-void" sign more frequently. The "flow-void" sign is a common imaging feature within RCC bone metastases. When observed, the "flow-void" sign can be a useful imaging feature in the diagnosis of RCC bone metastases.


A pilot study of synergy-based FES for upper-extremity poststroke rehabilitation.
A previous study indicated that synergy-based functional electrical stimulation (FES) may improve instantaneous upper-limb motor performance for stroke survivors. However, it remains unclear whether the improvements will sustain over time to achieve functional gains associated with a task-oriented training (TOT). This pilot study was designed to investigate whether there is any promising sign of functional benefits. A TOT protocol with repeated forward and lateral reaching movements assisted by synergy-based FES was conducted in 16 patients (9 FES, 7 Sham) with post-stroke hemiparesis. FES stimuli were applied to 7 upper-extremity muscles of elbow and shoulder during patient movements. Envelopes of stimuli were individualized by re-composing the muscle synergies extracted from a healthy subject. After a five-day training for one hour each day, synergy-based FES induced higher increases in Fugl-Meyer scores (6.67 ± 5.20) than did the Sham (2.00 ± 2.38, p < 0.05). Peak velocity of forward reaching movements increased with a slope 73% steeper in FES group than Sham. In lateral reaching movements, the change in synergy similarity correlated with the change in elbow flexion for the FES group, but not the Sham group. Our results indicate that synergy-based FES therapy induced clinically traceable signs of improvements in poststroke motor performance. The muscle activation in patients also showed promising sign of alteration by FES. Results suggest that a larger scale clinical trial of synergy-based FES may be feasible towards an individualized therapeutic regimen.


Duodenal cholinergic tuft cell number is increased in functional dyspepsia.
Low-grade duodenal inflammation has recently been identified in patients with functional dyspepsia (FD). Chemosensory tuft cells were reported to be associated with gastrointestinal diseases. We therefore assessed duodenal tuft cell density and microinflammation in patients with FD to determine whether these measures could serve as useful biomarkers, and also correlated tuft cell density and microinflammation in FD patients. Duodenal biopsy specimens were obtained from patients with FD and from controls. Tuft cells, eosinophils, and mast cells were immunochemically stained with specific antibodies. Tuft cells were identified by immunostaining for doublecortin-like kinase 1 (DCLK1); cholinergic tuft cells were assessed by double staining for choline acetyltransferase (ChAT) and DCLK1. Immune-type tuft cells were assessed by IL-25 mRNA expression using real-time PCR. The density of intramucosal eosinophils and mast cells was significantly higher in the duodenum of FD patients than in controls. The density of tuft cells was significantly higher in the duodenum of FD patients compared with controls, and significantly correlated with eosinophil density in the duodenum of FD patients and controls. Moreover, a fraction of ChAT-positive cells was DCLK1 positive; all duodenal DCLK1+ tuft cells were ChAT-immunoreactive in FD and in control subjects. Cholinergic tuft cell density was higher in the duodenum of patients with FD and significantly correlated with eosinophil density. Further studies are needed to investigate the pathophysiological significance of tuft cells in FD and may provide valuable clues to the pathophysiology of FD.


Pilot study of intense pulsed light for the treatment of systemic sclerosis-related telangiectases.
Telangiectases represent microvascular changes inherent in the systemic sclerosis (SSc) disease process. Intense pulsed light (IPL) is an effective treatment for non-SSc-related cutaneous telangiectases. This pilot study aimed to examine the efficacy, safety and tolerability of IPL treatment in an open study of patients with SSc. Patients underwent three treatments of IPL at monthly intervals and attended follow-up examinations at 1, 6 and 12 months after final treatment. Photographs, laser Doppler imaging (LDI) and thermography were used to measure changes at each visit. Seventeen patients completed the study. Photographs were graded (compared with baseline) as: at 1-month follow-up, four 'no change', four 'improved' and eight 'much improved'; at 6-month follow-up, four 'no change', eight 'improved'; and four 'much improved'; and at 12-month follow-up (eight images were available), three 'no change', two 'improved' and three 'much improved'. Perfusion as measured by LDI (perfusion units) was significantly reduced, compared with baseline [median 2·66, interquartile range (1·78-3·93)], at 1 month [1·70 (1·07-2·55), P = 0·006] and 6 months [2·05 (1·42-2·36), P = 0·008] post-treatment, but not at 12 months [1·61 (1·14-3·22), P =0·088]. No differences were found in skin temperature between baseline and follow-up visits. In this pilot study (the first of IPL treatment for SSc-related telangiectases) most patients improved after IPL treatment. However, the degree of improvement was not maintained in all patients at 6-12 months, suggesting that further treatments may be necessary. Longer term studies of this novel treatment approach are now required.


Axial Spondyloarthritis: Overcoming the Barriers to Early Diagnosis-an Early Inflammatory Back Pain Service.
To discuss the challenges to early diagnosis of axial spondyloarthritis (axSpA) and present the impact an early inflammatory back pain service (EIBPS) had on diagnostic delay in the UK. Diagnostic delay in axSpA varies greatly worldwide, and has continued in the UK at an average of 8.5 years. Education, public awareness, and accessibility to inflammatory back pain (IBP) pathways are some of the key barriers to achieving a prompt diagnosis. A recent national inquiry has highlighted insufficiencies in the availability of specialist axSpA services and limited provision of education and training to first contact practitioners and allied healthcare providers. We demonstrate diagnostic delay in axSpA can be successfully reduced to 3 years when an early inflammatory back pain service is embedded within a rheumatology department alongside a local educational and awareness campaign. Sharing these experiences and outcomes will enable other departments to engage in best practice and achieve similar results, facilitating a timely and accurate diagnosis.


Dysfunctions of brain oxytocin signaling: Implications for poor mothering.
Good mothering has profound impact on both the mother's and the young's well-being. Consequently, experiencing inadequate maternal care - or even neglect - in the first stages of life is a major risk factor for the development of psychiatric disorders, and even for poor parenting towards the future offspring. Thus, understanding the neurobiological basis of maternal neglect becomes crucial. Along with other neurotransmitters and neuropeptides, oxytocin (OXT) has long been known as one of the main modulators of maternal behavior. In rodents, disruptions of central OXT transmission have been associated with poor maternal responses, like impaired onset of nursing behaviors, and reduced care and defense of the pups. Importantly, such behavioral and molecular deficits can be transmitted through generations, creating a vicious circle of low-quality maternal behavior. Similarly, evidence from human studies shows that OXT signaling is defective in conditions of inadequate mothering and child neglect. On those premises, this review aims at providing a comprehensive overview of animal and human studies linking perturbed OXT transmission to poor maternal behavior. Considering the important fallouts of inadequate maternal responses, we believe that unraveling the alterations in OXT transmission might provide useful insights for a better understanding of maternal neglect and, ultimately, for future intervention approaches.


FOXI1 expression in chromophobe renal cell carcinoma and renal oncocytoma: a study of The Cancer Genome Atlas transcriptome-based outlier mining and immunohistochemistry.
FOXI1 is a forkhead family transcription factor that plays a key role in differentiation and functional maintenance for the renal intercalated cell (IC). The diagnostic utility of FOXI1 is rarely studied thus far. Comparative analyses of FOXI1 mRNA expression in normal kidney tissue and different renal neoplasms including chromophobe renal cell carcinoma (chRCC), renal oncocytoma (RO), and other renal cell carcinomas were conducted using transcriptomic data from The Cancer Genome Atlas (TCGA), Gene Expression Omnibus, and single-cell RNA-seq datasets, in combination with integrative analyses using mutant data, karyotype data, and digital slides for cases with anomalous FOXI1 expression in TCGA. Formalin-fixed, paraffin-embedded whole-tissue slides of varied primary renal neoplasms (n = 367) were subjected to FOXI1 staining for validating FOXI1 transcription levels. We confirmed that FOXI1 was significantly upregulated at mRNA levels in ICs, chRCCs, and ROs compared with other renal tubule cell and renal cell carcinoma subtypes. Furthermore, most of the cases with FOXI1 expression outliers were misclassified in the TCGA kidney cancer project. An underlying novel entity with frequent mutations involved in the mTOR pathway was also found. FOXI1 immunoreactivity was consistently noted in ICs of the distal nephron. FOXI1 staining was positive in 85 of 93 chRCCs and 13 of 18 ROs, respectively. FOXI1 staining was not seen in renal neoplasms (n = 254) derived from non-ICs. In conclusion, FOXI1 expression in normal kidney tissue is restricted to ICs. This cell type-specific expression is retained during neoplastic transformation from ICs to chRCCs or ROs. FOXI1 is thereby a potential biomarker of IC-related tumors.


Guiding principles for mechanistic modeling of bispecific antibodies.
System based pharmacokinetic (PK) models can be used to study and predict the distribution of antibody based drugs into target tissues and assess the pharmacobinding (PB) of the drug to the target and the subsequent pharmacodynamic (PD) changes. In the absence of relevant PD readouts, compounded in cases of novel mechanisms, one can rely on binding between the drug and the target, computed as target occupancy (TO), as a relevant biomarker. This approach assumes that at maximum TO across the dosing interval, the drug-target interaction must demonstrate the intended pharmacology. Such analysis can help set laboratory objectives for protein engineers and chemists and guide them to the appropriate design and binding affinity of the molecule. Analysis of mechanistic models to guide affinity optimization against soluble and membrane-bound targets has been done for monoclonal antibodies (mAbs) (Tiwari et al., The AAPS Journal, 2017). However, comparable understanding of bispecific antibodies (BsAb; drugs with two targets, which are either soluble, membrane-bound, or a combination of the two) is still lacking. We propose to extend the work done by Tiwari et al. (2017) to BsAb. We focus on describing a generic BsAb with two membrane-bound targets, and explore the impact of various parameters on the TO of the BsAb to each target. Performed analysis can guide the optimization of dissociation constant (KD) of the BsAb, and can also help in identifying druggable targets. Proposed model can be modified and tailored to specific biologics as needed.


The Prevalence of CKD in Rural Canadian Indigenous Peoples: Results From the First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis (FINISHED) Screen, Triage, and Treat Program.
Indigenous Canadians have high rates of risk factors for chronic kidney disease (CKD), in particular diabetes. Furthermore, they have increased rates of complications associated with CKD, such as kidney failure and vascular disease. Our objective was to describe the prevalence of CKD in this population. Cross-sectional cohort. Indigenous (First Nations) Canadians 18 years or older screened as part of the First Nations Community Based Screening to Improve Kidney Health and Prevent Dialysis (FINISHED) project, an initiative completed in 2015 that accomplished community-wide screening in 11 rural communities in Manitoba, Canada. Indigenous ethnicity and geographic location (communities accessible by road compared with those accessible only by air). Prevalence of CKD, presumed based on a single ascertainment of urine albumin-creatinine ratio (UACR) ≥ 30mg/g and/or estimated glomerular filtration rate (eGFR)<60mL/min/1.73m(2). Kidney function measured by eGFR (CKD-EPI creatinine equation) and UACR. 1,346 adults were screened; 25.5% had CKD, defined as UACR≥30mg/g or eGFR<60mL/min/1.73m(2). Communities accessible by road had a lower prevalence of CKD (17.6%) than more remote communities accessible only by air (34.4%). Of those screened, 3.3% had reduced kidney function (defined as eGFR<60mL/min/1.73m(2)). Severely increased albuminuria was present in 5.0% of those screened. Presumption of chronicity based on a single ascertainment. There is a possibility of sampling bias, the net direction of which is uncertain. We found a 2-fold higher prevalence of CKD in indigenous Canadians in comparison to the general population and a prevalence of severely increased albuminuria that was 5-fold higher. This is comparable to patients with diabetes and/or hypertension. Public health strategies to screen, triage, and treat all Canadian indigenous peoples with CKD should be considered.


Tentative biosynthetic pathways of some microbial diketopiperazines.
Cyclodipeptides and their derivatives, the diketopiperazines (DKPs), constitute a large class of natural products that exhibit various biological properties. Until recently, there are a few characterized DKP biosynthetic pathways. In all these cases, the formation of the cyclodipeptides that harbor the DKP scaffold is catalyzed either by nonribosomal peptide synthetases or by cyclodipeptide synthases. This review focuses on the DKP biosynthetic pathways and their associated molecular mechanisms.