A Scientometric Review of Alexithymia: Mapping Thematic and Disciplinary Shifts in Half a Century of Research.
The term "alexithymia" was introduced in the lexicon of psychiatry in the early '70s by Sifneos to outline the difficulties manifested by some patients in identifying and describing their own emotions. Since then, the construct has been broadened and partially modified. Today this describes a condition characterized by an altered emotional awareness which leads to difficulties in recognizing your own and others' emotions. In half a century, the volume of scientific products focusing on alexithymia has exceeded 5,000. Such an expansive knowledge domain poses a difficulty for those willing to understand how alexithymia research has developed. Scientometrics embodies a solution to this issue, employing computational, and visual analytic methods to uncover meaningful patterns within large bibliographical corpora. In this study, we used the CiteSpace software to examine a corpus of 4,930 publications on alexithymia ranging from 1980 to 2020 and their 100,251 references included in Web of Science. Document co-citation analysis was performed to highlight pivotal publications and major research areas on alexithymia, whereas journal co-citation analysis was conducted to find the related editorial venues and disciplinary communities. The analyses suggest that the construct of alexithymia experienced a gradual thematic and disciplinary shift. Although the first conceptualization of alexithymia came from psychoanalysis and psychosomatics, empirical research was pushed by the operationalization of the construct formulated at the end of the '80s. Specifically, the development of the Toronto Alexithymia Scale, currently the most used self-report instrument, seems to have encouraged both the entrance of new disciplines in the study of alexithymia (i.e., cognitive science and neuroscience) and an implicit redefinition of its conceptual nucleus. Overall, we discuss opportunities and limitations in the application of this bottom-up approach, which highlights trends in alexithymia research that were previously identified only through a qualitative, theory-driven approach.


Palmitoylation and trafficking of GAD65 are impaired in a cellular model of Huntington's disease.
HD (Huntington's disease) is caused by an expanded polyQ (polyglutamine) repeat in the htt (huntingtin protein). GABAergic medium spiny neurons in the striatum are mostly affected in HD. However, mhtt (mutant huntingtin)-induced molecular changes in these neurons remain largely unknown. The present study focuses on the effect of mhtt on the subcellular localization of GAD (glutamic acid decarboxylase), the enzyme responsible for synthesizing GABA (γ-aminobutyric acid). We report that the subcellular distribution of GAD is significantly altered in two neuronal cell lines that express either the N-terminus of mhtt or full-length mhtt. GAD65 is predominantly associated with the Golgi membrane in cells expressing normal htt; however, it diffuses in the cytosol of cells expressing mhtt. As a result, vesicle-associated GAD65 trafficking is impaired. Since palmitoylation of GAD65 is required for GAD65 trafficking, we then demonstrate that palmitoylation of GAD65 is reduced in the HD model. Furthermore, overexpression of HIP14 (huntingtin-interacting protein 14), the enzyme responsible for palmitoylating GAD65 in vivo, could rescue GAD65 palmitoylation and vesicle-associated GAD65 trafficking. Taken together, our data support the idea that GAD65 palmitoylation is important for the delivery of GAD65 to inhibitory synapses and suggest that impairment of GAD65 palmitoylation by mhtt may lead to altered inhibitory neurotransmission in HD.


Horizontal distance and height determining falling pattern.
Falling from a height, usually from a building, occurs ordinarily in suicide, in some accidents, and sometimes as an act of homicide. The point of trajectory, the horizontal distance and the impact point are closely related to the initial velocity, angle and height. This study examines the falling pattern in order to determine the mental status of the jumper as well as the manner of death. Initial velocity is found using horizontal movement and height. A serial study of athletes performing both the running jump (long jump) and standing jump (swimmer's start jump) via biomechanical methods is described. The initial velocity of the running jump and standing jump in normal athletics is 9.15 and 2.70 m/s with initial jumping angles of 21 and 38 deg, respectively. The maximal horizontal velocity of 9.15 m/s is closely related to maximal strength of initial velocity, angle of engaged force, and height. Theoretical estimation of the initial velocity between 2.70 and 9.15 m/s is correlative with the unique initial velocity and running jump to fall from a height that is closely related to the voluntary and attempted jump. Hence, the jumping victim with an initial velocity higher than 2.70 m/s implies suicide. These results indicate that horizontal distance and height are legitimate measures to use in speculating on the falling pattern and the manner of death. A unique case of suicide involving a run and jump with initial velocity greater than 2.70 m/s is illustrated.


[Anti-proteinase 3 antibodies in diffuse systemic sclerosis (SSc) with normotensive renal impairment: is it suggestive for an overlapping between SSc and idiopathic vasculitis? ]
OBJECTIVE: To test the prevalence of anti-neutrophil cytoplasmic antibodies (ANCA) in systemic sclerosis (SSc) and to verify a possible association of ANCA with normotensive renal involvement in SSc. PATIENTS AND METHODS: 51 patients affected by SSc, 35 with diffuse scleroderma (dSSc) and 16 with limited scleroderma (lSSc), were tested for ANCA by indirect immunofluorescence (IIF) on human ethanol and formalin-acetone-fixed granulocytes (before and after DNase treatment), by conventional enzyme linked immuno-sorbent assay (ELISA) and by capture-ELISA. RESULTS: Six out of 51 selected SSc patients had ANCA by IIF (11.7%) and five presented a perinuclear/nuclear atypical ANCA pattern. In all cases we only found anti-proteinase3 (aPR3) antibodies. All ANCA positive patients had diffuse form of SSc (17.1%), all were anti-Scl70 positive (aScl70), five patients had proteinuria, three had microscopic haematuria. All ANCA positive patients were normotensive with normal renin plasma levels, the mean erythrocyte sedimentation rate (ESR) was higher in this group compared to the other SSc patients. CONCLUSIONS: Our study shows that aPR3 is not rare in dSSc. According to the clinical and serological findings and to the recent literature, we can hypothesise that when ANCA are found in SSc, an overlapping of scleroderma with systemic necrotizing vasculitis should be suspected.


Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.
Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.


Pharyngeal carriage of Neisseria meningitidis before and after treatment of meningococcal disease.
The aim of the study was to determine whether patients with meningococcal disease carry meningococci in the throat both before and after treatment for the disease. During the 7 months of the study 106 patients with confirmed meningococcal disease were admitted to Danish hospitals, of whom 77 (73%) had a throat swab examined at least once and were included in the study. Sixty-two patients were examined on admission and 52 were examined on discharge; 37 were examined on both occasions. On admission, meningococci were isolated from 18 (49%) of 37 throat specimens examined selectively for pathogenic Neisseria spp. Meningococci were not isolated from any throat specimen taken on discharge from hospital; 47 (90%) of 52 of these specimens had been examined adequately. From an observed carriage rate of 0 out of 47 it can be judged that the carrier rate does not exceed 6.4% (95% confidence limit). From these results we conclude that it is unlikely that patients who have been treated for meningococcal disease according to the regimens used in Denmark can be the source of infection for secondary cases.


Calvarial deformity regeneration following subtotal craniectomy for craniosynostosis: a case report and theoretical implications.
We describe an infant with combined sagittal and unilateral coronal synostosis who underwent "total vault" craniectomy for skull reshaping. The operative procedure was interrupted without replacement of the calvarial bone grafts. Follow-up over the ensuing 2 months revealed regeneration of the entire cranium and supraorbital rims, as well as (in contrast to earlier reports) redevelopment of fusion within the suture at the same site noted in the initial operation, associated with similar skull deformity. These observations are reviewed with special emphasis on the theoretical implications for the etiology of craniosynostosis and skull deformity.


Antibody Biomimetic Material Made of Pyrrole for CA 15-3 and Its Application as Sensing Material in Ion-Selective Electrodes for Potentiometric Detection.
This work reports a very simple approach for creating a synthetic antibody against any protein of interest and its application in potentiometric transduction. The selected protein was Breast Cancer Antigen (CA 15-3), which is implicated in breast cancer disease and used to follow-up breast cancer patients during treatment. The new material with antibody-like properties was obtained by molecular-imprinting technology, prepared by electropolymerizing pyrrol (Py, 5.0 × 10-3 mol/L) around Breast Cancer Antigen (CA 15-3) (100 U/mL) on a fluorine doped tin oxide (FTO) conductive glass support. Cyclic voltammetry was employed for this purpose. All solutions were prepared in 4-(2-Hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) buffer, of pH 6.5. The biomarker was removed from the imprinted sites by chemical action of ethanol. The biomimetic material was then included in poly vinyl chloride (PVC) plasticized membranes to act as potentiometric ionophore, having or not a lipophilic ionic additive added. The corresponding selective electrodes were evaluated by calibration curves (in buffer and in synthetic serum) and by selectivity testing. The best analytical performance was obtained by selective electrodes including the plastic antibody and no lipophilic additive. The average limits of detection were 1.07 U/mL of CA 15-3, with a linear response from 1.44 to 13.2 U/mL and a cationic slope of 44.5 mV/decade. Overall, the lipophilic additives yielded no advantage to the overall potentiometric performance. The application of the MIP-based electrodes to the analysis of spiked synthetic serum showed precise and accurate results.


Effects of advanced oxidation processes (AOPs) on the toxicity of a mixture of pharmaceuticals.
The possibility of applying main AOP techniques, namely ozonation, H2O2/UV photolysis and TiO2 photocatalysis to provide a significant reduction of toxicity of pharmaceutical mixtures has been evaluated. For the preparation of the mixture six pharmaceuticals were chosen among those found at highest concentrations in Sewage Treatment Plant effluents, namely carbamazepine, clofibric acid, diclofenac, sulfamethoxazole, ofloxacin and propranolol. The blue-green alga Synechococcus leopoliensis and the rotifer Brachyonus calyciflorus were utilised to assess the toxicity of the mixtures after AOP treatments. All the toxicity tests were performed using chronic standardized bioassays. The best results were obtained with ozonation. With this type of treatment a complete removal of mixture toxicity on S. leopolensis was obtained even after the shortest time of application (1 min). The ozonation treatment leads also to removal of all the pharmaceutical mixture toxicity on B. calyciflorus, by applying the oxidizing agent for at least for 2 minutes.


Are spousal carers' perceptions of continuity and discontinuity within the relationship influenced by the symptoms of dementia?
Some spousal carers experience their current relationship with the person with dementia as a continuation of the loving relationship they shared prior to the onset of dementia. For others, the experience is one of discontinuity; the prior relationship is lost and replaced with a different kind of relationship. The aim of this study was to investigate whether these differences are associated with particular symptoms of dementia. Thirty-five spousal carers completed the Birmingham Relationship Continuity Measure, the Revised Memory and Behavior Checklist (providing scores relating to cognitive decline, depression and challenging interpersonal behaviour), the Communicative Effectiveness Index and the Bristol Activities of Daily Living Scale. Experiencing discontinuity in the relationship was significantly correlated with communication difficulties, challenging interpersonal behaviour and the need for assistance in activities of daily living, but not with cognitive decline or depression. In a multiple regression, only the measures of challenging interpersonal behaviour and activities of daily living made significant unique contributions to the variance in continuity/discontinuity scores. Discontinuity is associated with reduced psychological well-being for the spousal carer and the provision of less person-centred care. Understanding which symptoms are more likely to lead to discontinuity allows the identification of those at risk of these experiences. Those at risk may require support to enable them to make sense of, and adjust to, certain symptoms of dementia in a way that has a less negative impact on their relationship.


[Value of prostate-specific antigen measurements with newly developed enzyme immunoassay (MARKIT-M PA)].
Serum prostate-specific antigen (PSA) levels in patients with prostate cancer and benign prostate hypertrophy (BPH) were investigated with a newly developed enzyme immunoassay (MARKIT-M PA, Dainippon Pharmaceutical Co. Ltd., Osaka, Japan). Sensitivity of the assay system is 0.5 ng/ml and the detection range is 0.5-100 ng/ml. There was a high linear correlation (r = 0.987) between the assay and MARKIT-F PA, and values obtained with the assay were almost equal to those yielded by MARKIT-F PA assay. Using the BPH group as a negative control, the upper cut-off value in BPH patients was determined to be 3.6 ng/ml. Of the 48 patients with untreated prostate cancer, 77% was detectable by means of MARKIT-M PA assay. Using the BPH group as a negative control, specificity and efficiency were 93% and 86%, respectively. In another group of 27 BPH patients whose blood samples were taken immediately after digital prostatic examination, PSA was elevated in 15%. During follow-up of prostate cancer patients, PSA was elevated in 82% at the time of clinically detectable progression. In 15 patients whose disease was clinically well controlled, all levels of PSA were observed to be negative. These findings suggests that detection of serum PSA with this assay is of great use both in the diagnosis and monitoring of prostate cancer patients.


Identifying key genes related to inflammasome in severe COVID-19 patients based on a joint model with random forest and artificial neural network.
The coronavirus disease 2019 (COVID-19) has been spreading astonishingly and caused catastrophic losses worldwide. The high mortality of severe COVID-19 patients is an serious problem that needs to be solved urgently. However, the biomarkers and fundamental pathological mechanisms of severe COVID-19 are poorly understood. The aims of this study was to explore key genes related to inflammasome in severe COVID-19 and their potential molecular mechanisms using random forest and artificial neural network modeling. Differentially expressed genes (DEGs) in severe COVID-19 were screened from GSE151764 and GSE183533 via comprehensive transcriptome Meta-analysis. Protein-protein interaction (PPI) networks and functional analyses were conducted to identify molecular mechanisms related to DEGs or DEGs associated with inflammasome (IADEGs), respectively. Five the most important IADEGs in severe COVID-19 were explored using random forest. Then, we put these five IADEGs into an artificial neural network to construct a novel diagnostic model for severe COVID-19 and verified its diagnostic efficacy in GSE205099. Using combining P value < 0.05, we obtained 192 DEGs, 40 of which are IADEGs. The GO enrichment analysis results indicated that 192 DEGs were mainly involved in T cell activation, MHC protein complex and immune receptor activity. The KEGG enrichment analysis results indicated that 192 GEGs were mainly involved in Th17 cell differentiation, IL-17 signaling pathway, mTOR signaling pathway and NOD-like receptor signaling pathway. In addition, the top GO terms of 40 IADEGs were involved in T cell activation, immune response-activating signal transduction, external side of plasma membrane and phosphatase binding. The KEGG enrichment analysis results indicated that IADEGs were mainly involved in FoxO signaling pathway, Toll-like receptor, JAK-STAT signaling pathway and Apoptosis. Then, five important IADEGs (AXL, MKI67, CDKN3, BCL2 and PTGS2) for severe COVID-19 were screened by random forest analysis. By building an artificial neural network model, we found that the AUC values of 5 important IADEGs were 0.972 and 0.844 in the train group (GSE151764 and GSE183533) and test group (GSE205099), respectively. The five genes related to inflammasome, including AXL, MKI67, CDKN3, BCL2 and PTGS2, are important for severe COVID-19 patients, and these molecules are related to the activation of NLRP3 inflammasome. Furthermore, AXL, MKI67, CDKN3, BCL2 and PTGS2 as a marker combination could be used as potential markers to identify severe COVID-19 patients.


Indicaxanthin from Opuntia Ficus Indica (L. Mill) impairs melanoma cell proliferation, invasiveness, and tumor progression.
A strong, reciprocal crosstalk between inflammation and melanoma has rigorously been demonstrated in recent years, showing how crucial is a pro-inflammatory microenvironment to drive therapy resistance and metastasis. We investigated on the effects of Indicaxanthin, a novel, anti-inflammatory and bioavailable phytochemical from Opuntia Ficus Indica fruits, against human melanoma both in vitro and in vivo. The effects of indicaxanthin were evaluated against the proliferation of A375 human melanoma cell line and in a mice model of cutaneous melanoma. Cell proliferation was assessed by MTT assay, apoptosis by Annexin V-Fluorescein Isothiocyanate/Propidium Iodide staining, protein expression by western blotting, melanoma lesions were subcutaneously injected in mice with B16/F10 cells, chemokine release was quantified by ELISA. Data herein presented demonstrate that indicaxanthin effectively inhibits the proliferation of the highly metastatic and invasive A375 cells as shown by growth inhibition, apoptosis induction and cell invasiveness reduction. More interestingly, in vitro data were paralleled by those in vivo showing that indicaxanthin significantly reduced tumor development when orally administered to mice. The results of our study also clarify the molecular mechanisms underlying the antiproliferative effect of indicaxanthin, individuating the inhibition of NF-κB pathway as predominant. In conclusion, we demonstrated that indicaxanthin represents a novel phytochemical able to significantly inhibit human melanoma cell proliferation in vitro and to impair tumor progression in vivo. When considering the resistance of melanoma to the current therapeutical approach and the very limited number of phytochemicals able to partially counteract it, our findings may be of interest to explore indicaxanthin potential in further and more complex melanoma studies in combo therapy, i.e. where different check points of melanoma development are targeted.


Altruism among relatives and non-relatives.
Hamilton's [Hamilton, W.D., 1964. The genetical evolution of social behavior, I, II. J. Theor. Biol. 7, 1-52] kin-selection theory predicts that altruism will be greater with greater genetic overlap (degree of kinship) between giver and receiver. Kin may be identified in terms of social distance-the closer you feel to someone else, (a) the greater your genetic overlap with them should be, and (b) the more altruistic you should be toward them. The present experiment determined the amount of their own (hypothetical) monetary reward undergraduates were willing to forgo in order to give $75 to other people at various social distances. We found that (a) genetic relationship and (b) altruism varied inversely with social distance; the closer you feel to someone else, the closer their relation to you is likely to be, and the more altruistic you are likely to be toward them. However, even at the same social distance, participants were willing to forgo significantly more money for the benefit of relatives than for the benefit of non-relatives. These results are consistent with kin-selection theory and imply that altruism is determined by factors in addition to social distance.


Edible Medicinal Plants on Facilitating Childbirth: A Systematic Review.
Despite advances and the availability of newer drugs to facilitate childbirth, the interest in using natural treatments is on the rise. More than 20 percent of pregnancies require induction of labor, which is associated with side effects and increased risk of cesarean surgery. For this reason, the use of medicinal plants is considered healthier. The present study is a systematic review of the role of oral herbs in facilitating childbirth. This review was conducted via searching the Medline/PubMed, Google Scholar, Scopus, and SID databases. The review began systematically and with no time constraints. It lasted until December 29, 2020. Twenty clinical trials investigated the impact of edible plants on increasing cervical readiness, stimulating labor onset, reducing pain intensity, and shortening the duration of labor. Five studies have revealed the positive impact of saffron. Two studies reported the same effect by chamomile. Three studies showed the positive impact of boiled dill seeds, and two studies showed the impact of date and date syrup. Another study reported the impact of Descurainia Sophia, and six studies also showed the positive effect of castor oil on uterine stimulation, strengthening and relieving labor pains, which eventually lead to facilitating labor. One study also showed no improvement in bishop score after consumption of primrose capsules. The positive effect of edible medicinal plants on facilitating childbirth has been shown in the mentioned studies. However, more studies with a larger sample size are needed, and there is also a need for a more detailed study of the possible mechanisms of plant effects.


Functional expression and characterization of human D2 and D3 dopamine receptors.
Functional characteristics of human D2 and D3 receptors (DRs) were examined using a new bioassay suited for the study of Gi-protein-coupled receptors (GiRs). The bioassay utilizes pigment granule aggregation within cultured Xenopus laevis melanophores for the quantitative evaluation of ligands as agonists or antagonists upon particular GiRs. Initial feasibility studies were performed by analyzing a melanocyte receptor endogenous to the melanophores. In dose-dependent manners, melatonin inhibited melatonin-stimulating hormone-induced cAMP accumulation and caused pigment aggregation that could be monitored over time. Next, melanophores were transiently transfected with cDNAs coding for the human D2BR (short form) and D3R. Expression of either receptor conferred upon the cells the ability to aggregate their melanosomes in response to selective dopaminergic agonists. The same ligands also inhibited cAMP accumulation within the transfected melanophores, and the agonist-induced pigment aggregation was shown to be sensitive to pertussis toxin. EC50 and IC50 value determinations revealed that agonists activated the D2R and D3R at similar concentrations, while each of the antagonists displaying an effect was more potent upon the D2R. The results reveal functional similarities and differences between the D2R and D3R.


The mntH gene encodes the major Mn(2+) transporter in Bradyrhizobium japonicum and is regulated by manganese via the Fur protein.
The bacterial Nramp family protein MntH is a divalent metal transporter, but mntH mutants have little or no phenotype in organisms where it has been studied. Here, we identify the mntH homologue of Bradyrhizobium japonicum, and demonstrate that it is essential for Mn(2+) transport and for maintenance of cellular manganese homeostasis. Transport activity was induced under manganese deficiency, and Fe(2+) did not compete with (54)Mn(2+) for uptake by cells. The steady-state level of mntH mRNA was negatively regulated by manganese, but was unaffected by iron. Control of mntH expression and Mn(2+) transport by manganese was lost in a fur strain, resulting in constitutively high activity. Fur protected a 35 bp region of the mntH promoter in DNase I footprinting analysis that includes three imperfect direct repeat hexamers that are needed for full occupancy. Mn(2+) increased the affinity of Fur for the mntH promoter by over 50-fold, with a K(d) value of 2.2 nM in the presence of metal. The findings identify MntH as the major Mn(2+) transporter in B. japonicum, and show that Fur is a manganese-responsive regulator in that organism. Furthermore, Fe(2+) is neither a substrate for MntH nor a regulator of mntH expression in vivo.


Restriction maps and sequence homologies of two densovirus genomes.
The genomes of Junonia coenia densonucleosis virus (JcDNV) and Galleria mellonella densonucleosis virus (GmDNV) were analysed by restriction endonuclease analysis and Southern blot hybridization. A total of 37 and 33 restriction sites were mapped on JcDNV and GmDNV DNA, respectively. BglI, HaeII and BstEII were site-specific for JcDNV DNA, and BglII and ClaI for GmDNV DNA. The two genomes had nearly identical maps for several restriction endonucleases and Southern blot hybridization using a total genomic JcDNV probe indicated extensive DNA sequence homologies spanning the entire length of the two genomes. Symmetrical cleavage sites, mapping at the extremities of both genomes, confirmed the presence of inverted terminal repeats of at least 420 to 440 bases in length.


Human hemangiosarcomas have a common polymorphism but no mutations in the connexin37 gene.
Gap junctional intercellular communication is often impaired in cancers, and the genes which encode the connexin gap junction proteins are considered to be tumor-suppressor genes. In this study, we analyzed the presence of mutations in the connexin 37 (Cx37) gene in 22 human hepatic angiosarcomas, 6 and 4 of which were associated with exposure to vinyl chloride and Thorotrast, respectively. The other 12 samples were from patients with no history of exposure to these 2 agents. In 9 samples, a proline (ACC) to serine (ACT) amino acid change in codon 319 was detected. However, DNA from non-tumorigenic tissue of the same patients also showed this amino acid change, suggesting that this is a polymorphism rather than a mutation. Subsequent analysis of 84 DNA samples from normal donors revealed the frequencies of Pro/Pro, Pro/Ser and Ser/Ser alleles to be 65.5%, 23.8% and 10.7%, respectively, while among the group of angiosarcoma patients the corresponding figures were 59.1%, 31.8% and 9. 1%, respectively. Thus, there was no correlation between the polymorphism at codon 319 and hepatic angiosarcoma occurrence. However, among the 6 cases of vinyl chloride-associated angiosarcoma, the percentages of the polymorphic alleles were 33.3%, 66.7% and 0%, respectively. While the number of samples was too small to allow us to conclude that the Ser319 allele in Cx37 predisposes to this rare type of human cancer, it may be noted that codon 319 is located at the cytoplasmic tail of Cx37, where most regulatory sequences reside, and that it could be a site of phosphorylation for some protein kinases, which may in turn affect the function of Cx37, including intercellular communication.


Risk factors for and protective factors against adolescent suicidal behavior in Turkey.
This study investigated the possible role of depression, self-esteem, problem solving, assertiveness, social support, and some socioeconomic factors on adolescent suicidal behavior in youth in a small city located in the southwestern part of Turkey. Participants in the study were 805 (367 girls) first-year high school students between the ages of 13-18 years. Some 23% of participants reported having thought of killing themselves during the past 12 months or their lifetime. The percentage of students who said that they had attempted to kill themselves was 2.5. Suicidal ideation during one's lifetime or during the past 12 months was more frequent among girls than among boys but suicidal attempts were equally common in girls and boys. Girls scored significantly higher on depression and the Suicide Probability Scale (SPS) but also on assertiveness and perceived social support from friends than boys. Boys tended to score higher on self-esteem than girls. Depression and low self-esteem were the most consistent and independent predictors of suicidal thoughts, attempts, and SPS scores in both girls and boys. The results are discussed in terms of relevant literature with special reference to developmental and sociocultural issues. The implications of findings for the assessment and treatment of suicidal youths are highlighted.


A programmable microfluidic static droplet array for droplet generation, transportation, fusion, storage, and retrieval.
We present a programmable microfluidic static droplet array (SDA) device that can perform user-defined multistep combinatorial protocols. It combines the passive storage of aqueous droplets without any external control with integrated microvalves for discrete sample dispensing and dispersion-free unit operation. The addressable picoliter-volume reaction is systematically achieved by consecutively merging programmable sequences of reagent droplets. The SDA device is remarkably reusable and able to perform identical enzyme kinetic experiments at least 30 times via automated cross-contamination-free removal of droplets from individual hydrodynamic traps. Taking all these features together, this programmable and reusable universal SDA device will be a general microfluidic platform that can be reprogrammed for multiple applications.


Exposure of healthy volunteers to swine house dust increases formation of leukotrienes, prostaglandin D2, and bronchial responsiveness to methacholine.
Acute exposure of healthy subjects to swine house dust causes increased bronchial responsiveness to methacholine but no acute bronchoconstriction. The role of cysteinyl leukotrienes and mast cells in increased bronchial responsiveness is unclear. Ten non-asthmatic subjects were exposed to swine dust for three hours while weighing pigs in a piggery. Urine was collected prior to and for up to 12 hours after entering the piggery and at the same times five days before and the day after exposure. As indices of whole body leukotriene production and mast cell activation, urinary levels of leukotriene E4 (LTE4) and 9 alpha, 11 beta-PGF2, the earliest appearing urinary metabolite of prostaglandin D2 (PGD2), were measured. Bronchial responsiveness to methacholine was determined five days before and the day after the exposure. Methacholine PD20FEV1 decreased from 1.32 mg (95% CI 0.22 to 10.25) before exposure to 0.38 mg (95% CI 0.11 to 1.3) after exposure (p < 0.01). Associated with the increase in bronchial responsiveness there was a significant mean difference between post- and prechallenge levels of LTE4 (difference 38.5 ng/mmol creatinine (95% CI 17.2 to 59.8); p < 0.01) and 9 alpha, 11 beta-PGF2 (difference 69 ng/mmol creatinine (95% CI 3.7 to 134.3); p < 0.05) on the day of exposure to swine dust. Swine dust exposure induced a 24-fold increase in the total cell number and a 12-fold increase in IL-8 levels in the nasal lavage fluid. The levels of LTB4 and LTE4 in nasal lavage fluid following exposure also increased 5.5-fold and 2-fold, respectively. The findings of this study indicate that cysteinyl leukotrienes and other mast cell mediators contribute to the development of increased bronchial responsiveness following inhalation of organic swine dust.


Interpolation by fast Wigner transform for rapid calculations of magnetic resonance spectra from powders.
We introduce a novel interpolation strategy, based on nonequispaced fast transforms involving spherical harmonics or Wigner functions, for efficient calculations of powder spectra in (nuclear) magnetic resonance spectroscopy. The fast Wigner transform (FWT) interpolation operates by minimizing the time-consuming calculation stages, by sampling over a small number of Gaussian spherical quadrature (GSQ) orientations that are exploited to determine the spectral frequencies and amplitudes from a 10-70 times larger GSQ set. This results in almost the same orientational averaging accuracy as if the expanded grid was utilized explicitly in an order of magnitude slower computation. FWT interpolation is applicable to spectral simulations involving any time-independent or time-dependent and noncommuting spin Hamiltonian. We further show that the merging of FWT interpolation with the well-established ASG procedure of Alderman, Solum and Grant [J. Chem. Phys. 134, 3717 (1986)] speeds up simulations by 2-7 times relative to using ASG alone (besides greatly extending its scope of application), and between 1-2 orders of magnitude compared to direct orientational averaging in the absence of interpolation. Demonstrations of efficient spectral simulations are given for several magic-angle spinning scenarios in NMR, encompassing half-integer quadrupolar spins and homonuclear dipolar-coupled (13)C systems.


Novel modular DNA aptamer for human thrombin with high anticoagulant activity.
Aptamers based on nucleic acids are a promising alternative to antibodies in therapy and diagnostics. Several DNA aptamers against human thrombin have been developed by selection from random libraries: a 15-mer and its derivatives, a 29-mer, and a 31-mer. Some of them are patented and already under clinical trial. The 15-mer structure was determined by X-ray and NMR and turned out to be a monomolecular antiparallel G-quadruplex. The other aptamers mentioned above have higher inhibitory activity than the initial 15-mer, but there are not yet structural data explaining this phenomenon. Here, the initial 15-mer, 31-mer, and novel RA-36 aptamers are compared to establish the structure-function correlation, providing a solid ground for further rational aptameric drug design. For the molecular dynamic simulation of aptamers, the force field parmbsc0 was ported onto GROMACS, and the main stabilizing parameters were revealed, leading to the novel DNA aptamer RA-36. The functional properties of the DNA aptamers were studied by conventional coagulation tests, which do not directly elucidate the mechanism of thrombin inhibition by aptamers. Improved turbidimetric measurements provided data to develop detailed kinetics showing that the 31-mer and RA-36, in contrast to the 15-mer, are competitive inhibitors. These data revealed RA-36 to be an efficient thrombin inhibitor with a dose-dependent effect. Animal tests of the studied DNA aptamers suggested an unexpected species-specificity of the novel RA-36.


[Neurodevelopment of full-term small-for-gestational age infants in the second month of life].
The objective of the present study was to assess and to compare the neurodevelopment of full-term adequate (AGA) or small-for-gestational age (SGA) infants in the second month of life. Sixty-seven infants were evaluated: 43 AGA and 24 SGA, making use of the Bayley Scales of Infant Development. The SGA group Index Score (IS) was significantly lower in Mental and Motor Scales. Considering the body proportionality (Asymmetric, Symmetric-SGA and Control group) there was difference in Motor Scale (p=0.003) with lower scores in the Symmetric-SGA group. Comparing to the Control group IS percentiles, in Mental Scale there was difference between Asymmetric X Symmetric-SGA; in Motor Scale, there was difference between the Asymmetric X Control (p=0.039) and Symmetric-SGA X Control (p=0.007) groups; there was no difference between Asymmetric and Symmetric-SGA although both exhibited lower scores than the Control group.


Inhibition of JAK kinase activity enhances Fas-mediated apoptosis but reduces cytotoxic activity of topoisomerase II inhibitors in U266 myeloma cells.
Our previous work demonstrated that the Janus kinase (JAK)-Stat3 pathway regulates expression of Bcl-x(L) in the U266 human multiple myeloma cell line and prevents Fas-mediated apoptosis. Inhibition of this pathway by the JAK selective kinase inhibitor AG490 or dominant-negative Stat3 protein results in down-regulation of Bcl-x(L) expression and enhanced sensitivity to Fas-mediated apoptosis. Because Bcl-x(L) has also been implicated in resistance to chemotherapeutic drugs, we investigated whether inhibition of the JAK-Stat3 pathway and subsequent reduction in Bcl-x(L) expression would also enhance cytotoxic drug activity. Contrary to this prediction, pretreatment of U266 myeloma cells with AG490, followed by exposure to topoisomerase II- inhibiting agents, antagonized drug-induced apoptosis. This effect correlated with reduced cyclin D1 expression and cell cycle arrest. The cell cycle arrest following AG490 pretreatment further correlated with reduced mitoxantrone-induced DNA double-strand breaks and reduced cell death, findings consistent with the critical requirement of DNA damage for drug cytotoxicity. These studies demonstrate that inhibition of the JAK-Stat3 pathway can result in paradoxical effects relative to cytotoxic drug response. These paradoxical responses may be explained by the findings that JAK-Stat3 signaling regulates the expression of multiple genes involved in controlling cell proliferation and apoptosis. Thus, understanding the cellular context of inhibiting signal transduction pathways is essential for the design of novel combination therapies for cancer.


Melanoma Evolves Complete Immunotherapy Resistance through the Acquisition of a Hypermetabolic Phenotype.
Despite the clinical success of T-cell checkpoint blockade, most patients with cancer still fail to have durable responses to immunotherapy. The molecular mechanisms driving checkpoint blockade resistance, whether preexisting or evolved, remain unclear. To address this critical knowledge gap, we treated B16 melanoma with the combination of CTLA-4, PD-1, and PD-L1 blockade and a Flt3 ligand vaccine (≥75% curative), isolated tumors resistant to therapy, and serially passaged them in vivo with the same treatment regimen until they developed complete resistance. Using gene expression analysis and immunogenomics, we determined the adaptations associated with this resistance phenotype. Checkpoint resistance coincided with acquisition of a "hypermetabolic" phenotype characterized by coordinated upregulation of the glycolytic, oxidoreductase, and mitochondrial oxidative phosphorylation pathways. These resistant tumors flourished under hypoxic conditions, whereas metabolically starved T cells lost glycolytic potential, effector function, and the ability to expand in response to immunotherapy. Furthermore, we found that checkpoint-resistant versus -sensitive tumors could be separated by noninvasive MRI imaging based solely on their metabolic state. In a cohort of patients with melanoma resistant to both CTLA-4 and PD-1 blockade, we observed upregulation of pathways indicative of a similar hypermetabolic state. Together, these data indicated that melanoma can evade T-cell checkpoint blockade immunotherapy by adapting a hypermetabolic phenotype.


Differential Immune Responses and Underlying Mechanisms of Metabolic Reprogramming in Smooth and Rough Variants of Mycobacterium peregrinum Infections.
Mycobacterium peregrinum (Mpgm) is a rapidly growing mycobacteria that is classified as a nontuberculous mycobacterium (NTM) and is commonly found in environmental sources such as soil, water, and animals. Mpgm is considered an opportunistic pathogen that causes infection in immunocompromised individuals or those with underlying medical conditions. Although there have been clinical reports on Mpgm, reports of the immune response and metabolic reprogramming have not been published. Thus, we studied standard Mpgm-ATCC and two clinical strains (Mpgm-S and Mpgm-R) using macrophages and mouse bone marrow-derived cells. Mpgm has two types of colony morphologies: smooth and rough. We grew all strains on the 7H10 agar medium to visually validate the morphology. Cytokine levels were measured via ELISA and real-time PCR. The changes in mitochondrial function and glycolysis in Mpgm-infected macrophages were measured using an extracellular flux analyzer. Mpgm-S-infected macrophages showed elevated levels of inflammatory cytokines, including interleukin (IL)-6, IL-12p40, and tumor necrosis factor (TNF)-α, compared to Mpgm-ATCC- and Mpgm-R-infected macrophages. Additionally, our findings revealed metabolic changes in Mpgm-ATCC and two clinical strains (Mpgm-S and Mpgm-R) during infection; significant changes were observed in the mitochondrial respiration, extracellular acidification, and the oxygen consumption of BMDMs upon Mpgm-S infection. In summary, within the strains examined, Mpgm-S displayed greater virulence, triggered a heightened immune response, and induced more profound shifts in bioenergetic metabolism than Mpgm-ATCC and Mpgm-R. This study is the first to document distinct immune responses and metabolic reorganization following Mpgm infection. These findings lay a crucial foundation for further investigations into the pathogenesis of Mpgm.


Resolvin D1 Halts Remote Neuroinflammation and Improves Functional Recovery after Focal Brain Damage Via ALX/FPR2 Receptor-Regulated MicroRNAs.
Remote damage is a secondary phenomenon that usually occurs after a primary brain damage in regions that are distant, yet functionally connected, and that is critical for determining the outcomes of several CNS pathologies, including traumatic brain and spinal cord injuries. The understanding of remote damage-associated mechanisms has been mostly achieved in several models of focal brain injury such as the hemicerebellectomy (HCb) experimental paradigm, which helped to identify the involvement of many key players, such as inflammation, oxidative stress, apoptosis and autophagy. Currently, few interventions have been shown to successfully limit the progression of secondary damage events and there is still an unmet need for new therapeutic options. Given the emergence of the novel concept of resolution of inflammation, mediated by the newly identified ω3-derived specialized pro-resolving lipid mediators, such as resolvins, we reported a reduced ability of HCb-injured animals to produce resolvin D1 (RvD1) and an increased expression of its target receptor ALX/FPR2 in remote brain regions. The in vivo administration of RvD1 promoted functional recovery and neuroprotection by reducing the activation of Iba-1+ microglia and GFAP+ astrocytes as well as by impairing inflammatory-induced neuronal cell death in remote regions. These effects were counteracted by intracerebroventricular neutralization of ALX/FPR2, whose activation by RvD1 also down-regulated miR-146b- and miR-219a-1-dependent inflammatory markers. In conclusion, we propose that innovative therapies based on RvD1-ALX/FPR2 axis could be exploited to curtail remote damage and enable neuroprotective effects after acute focal brain damage.


Natural Soybean Milk-Derived Bioactive Coatings for Enhanced Wound Healing.
Foodborne biomaterials, derived from diets, comprise selfassembled collections of many micro- or nanoscale units with abundant nutrients and active substances. In this study, soybean milk (SBM) was selected as a tissue engineering product for simple and feasible wound repair. SBM is a common drink prepared from soybeans and is rich in soy protein, soy isoflavones, and other bioactive components. Thus, SBM has substantial potential for antioxidation and tissue remodeling. Here, the multifunctional effect of SBM as a bioactive coating for promoting wound healing was studied. The results showed that SBM has good biocompatibility and biological activity. It efficiently scavenges intracellular reactive oxygen species, significantly enhances epithelial cell migration, and improves angiogenesis, thereby accelerating tissue remodeling. The results of animal experiments further confirmed that the SBM-bioinspired coating has promising applications for cutaneous wound regeneration.


The relationship between skin symptoms and the scleroderma modification of the health assessment questionnaire, the modified Rodnan skin score, and skin pathology in patients with systemic sclerosis.
To determine how well skin symptoms considered specific to SSc are captured by patient reported outcomes currently used for assessing patients with SSc, the SHAQ, or skin disease, the Skindex-29; and how well these symptoms correlate with the extent of skin disease on physical exam and skin pathology. SSc patients completed the scleroderma modification of the Health Assessment Questionnaire (SHAQ), Skindex-29 and a Skin Symptom Assessment questionnaire developed for this study. Correlations were assessed between the Skin Symptom Assessment and SHAQ, Skindex-29, modified Rodnan skin score, and skin pathological features including myofibroblast staining completed on the same date. Tight, hard and rigid/stiff skin symptoms correlated moderately highly with the modified Rodnan skin score (r = 0.445, P = 0.0008; r = 0.486, P = 0.0002; and r = 0.488, P = 0.0002, respectively). Tight skin symptoms correlated moderately with myofibroblast infiltration (r = 0.544, P = 0.0023) and hyalinized collagen (r = 0.442, P = 0.0164), while both hard and rigid/stiff skin correlated moderately with inflammation (r = 0.401, P = 0.0310 and r = 0.513, P = 0.0045), myofibroblast infiltration(r = 0.480, P = 0.0084 and r = 0.527, P = 0.0033) and hyalinized collagen (r = 0.453, P = 0.0137 and r = 0.478, P = 0.0087), while the SHAQ was not found to correlate with any of these pathological changes. In contrast, painful skin symptoms correlated moderately with the SHAQ (r = 0.413, P = 0.0073), and with the three domains of Skindex-29: Symptoms, Emotions and Functioning. Skindex-29 indicates that dcSSc patient skin symptoms are nearly as severe as those of patients with psoriasis or atopic dermatitis. Patient reported skin symptoms correlate with clinical and pathological measures in the skin. A validated patient reported skin symptom instrument might considerably improve evaluation of SSc skin disease.


Historical overview: searching for replication help in all of the rec places.
For several decades, research into the mechanisms of genetic recombination proceeded without a complete understanding of its cellular function or its place in DNA metabolism. Many lines of research recently have coalesced to reveal a thorough integration of most aspects of DNA metabolism, including recombination. In bacteria, the primary function of homologous genetic recombination is the repair of stalled or collapsed replication forks. Recombinational DNA repair of replication forks is a surprisingly common process, even under normal growth conditions. The new results feature multiple pathways for repair and the involvement of many enzymatic systems. The long-recognized integration of replication and recombination in the DNA metabolism of bacteriophage T4 has moved into the spotlight with its clear mechanistic precedents. In eukaryotes, a similar integration of replication and recombination is seen in meiotic recombination as well as in the repair of replication forks and double-strand breaks generated by environmental abuse. Basic mechanisms for replication fork repair can now inform continued research into other aspects of recombination. This overview attempts to trace the history of the search for recombination function in bacteria and their bacteriophages, as well as some of the parallel paths taken in eukaryotic recombination research.


Current management of juvenile nasopharyngeal angiofibroma: a tertiary center experience 1999-2007.
Over the past 10 years, the management of juvenile nasopharyngeal angiofibroma (JNA) has been redefined because of the improvement of transnasal skull base techniques. However, the limits of endoscopic resection still have to be fully defined. The purpose of this study was to report on a series of patients presenting with JNA in an effort to further define an optimal treatment algorithm and improve outcomes. A retrospective review was performed of 18 patients presenting to a tertiary care institution with JNA from 1999 to 2007. Patients were categorized by Andrews stage and data were collected on presentation, operative technique, and postoperative course. All patients underwent preoperative embolization. Stages 1, 2, and one 3a lesions were approached endoscopically while the remainder underwent open resection. In the endoscopic group the intraoperative blood loss was almost half that of the open group (506 versus 934 mL) and the average hospital stay was 1 day less (3 vs. 4 days). Endoscopic resection is reasonable for Andrews stage 1, 2, and select 3a lesions and may allow for less bleeding and a shorter hospital stay. This study supports the current trend of expansion of indications for endoscopic JNA resection.


Specificity of the SH2 domains of SHP-1 in the interaction with the immunoreceptor tyrosine-based inhibitory motif-bearing receptor gp49B.
Inhibitory receptors on hemopoietic cells critically regulate cellular function. Despite their expression on a variety of cell types, these inhibitory receptors signal through a common mechanism involving tyrosine phosphorylation of the immunoreceptor tyrosine-based inhibitory motif (ITIM), which engages Src homology 2 (SH2) domain-containing cytoplasmic tyrosine or inositol phosphatases. In this study, we have investigated the proximal signal-transduction pathway of an ITIM-bearing receptor, gp49B, a member of a newly described family of murine NK and mast cell receptors. We demonstrate that the tyrosine residues within the ITIMs are phosphorylated and serve for the association and activation of the cytoplasmic tyrosine phosphatase SHP-1. Furthermore, we demonstrate a physiologic association between gp49B and SHP-1 by coimmunoprecipitation studies from NK cells. To address the mechanism of binding between gp49B and SHP-1, binding studies involving glutathione S-transferase SHP-1 mutants were performed. Utilizing the tandem SH2 domains of SHP-1, we show that either SH2 domain can interact with phosphorylated gp49B. Full-length SHP-1, with an inactivated amino SH2 domain, also retained gp49B binding. However, binding to gp49B was disrupted by inactivation of the carboxyl SH2 domain of full-length SHP-1, suggesting that in the presence of the phosphatase domain, the carboxyl SH2 domain is required for the recruitment of phosphorylated gp49B. Thus, gp49B signaling involves SHP-1, and this association is dependent on tyrosine phosphorylation of the gp49B ITIMs, and an intact SHP-1 carboxyl SH2 domain.


Estimating the Burden of Disease from Unsafe Injections in India: A Cost-benefit Assessment of the Auto-disable Syringe in a Country with Low Blood-borne Virus Prevalence.
Unsafe medical injections are a prevalent risk factor for viral hepatitis and HIV in India. This review undertakes a cost-benefit assessment of the auto-disable syringe, now being introduced to prevent the spread of hepatitis B virus, hepatitis C virus, and human immunodeficiency virus (HIV). The World Health Organization methods for modeling the global burden of disease from unsafe medical injections are reproduced, correcting for the concentrated structure of the HIV epidemic in India. A systematic review of risk factor analyses in India that investigate injection risks is used in the uncertainty analysis. The median population attributable fraction for hepatitis B carriage associated with recent injections is 46%, the median fraction of hepatitis C infections attributed to unsafe medical injections is 38%, and the median fraction of incident HIV infections attributed to medical injections is 12% in India. The modeled incidence of blood-borne viruses suggests that introducing the auto-disable syringe will impose an incremental cost of $46-48 per disability adjusted life year (DALY) averted. The epidemiological evidence suggests that the incremental cost of introducing the auto-disable syringe for all medical injections is between $39 and $79 per DALY averted. The auto-disable syringe is a cost-effective alternative to the reuse of syringes in a country with low prevalence of blood-borne viruses.


Identification, localization and differentiation of erosions and physiological bone channels by ultrasound in rheumatoid arthritis patients.
Ultrasound (US) can detect cortical bone lesions in RA. However, not all cortical bone lesions are erosions. Herein, we aimed to define whether US can differentiate between physiological bone channels and pathological erosions in RA and to provide topographic description of their differential localization. RA patients and healthy controls (HC) received US examination of the metacarpophalangeal (MCPJ) and proximal inter-phalangeal (PIPJ) joints adjudicating cortical bone lesions as physiological bone channels or pathological erosions. In a subset of RA patients and HC, high-resolution peripheral quantitative computed tomography (HR-pQCT) of the hand was performed to validate the classification of lesions. A total of 40 RA patients and 43 HC were enrolled and totally 771 MCPJ and 638 PIPJ were examined by US, and 94 and 51, respectively, by HR-pQCT. US-defined cortical bone lesions clustered in the lateral part of the MCP (50%) and the dorsal part of the PIPJ (66.7%) in RA. US-defined physiological bone channels clustered in the palmar parts of the MCPJ and PIPJ in both RA (78.8% and 100%, respectively) and HC (51.8% and 80%, respectively). HR-pQCT data confirmed US data with respect to adjudication of physiological bone channels and pathological erosions. Erosions were significantly (all P <0.000001) larger than physiological channels and preferentially localized at radial and ulnar sites, while physiological channels were clustered at palmar sites. Specificity of US was excellent for erosions in RA and for physiological bone channels in HC and RA. US allows differentiation between physiological channels and bone erosions in RA.


Leptomycin B inhibits equine infectious anemia virus Rev and feline immunodeficiency virus rev function but not the function of the hepatitis B virus posttranscriptional regulatory element.
Human immunodeficiency virus type 1 Rev export depends upon the presence of the nuclear export signal (NES), a leucine-rich stretch of hydrophobic amino acids. Recently, the nuclear NES-binding receptor has been identified as CRM1 or exportin 1. Rev export has been shown to be CRM1 dependent. The function of the atypical NES-containing Rev-like proteins of equine infectious anemia virus (EIAV) and feline immunodeficiency virus (FIV) is inhibited by leptomycin B, a drug that specifically blocks NES-CRM1 interactions. These data suggest that the function of atypical NES-containing proteins is CRM1 dependent. In contrast to the inhibition of EIAV Rev and FIV Rev, the cytoplasmic accumulation of hepatitis B virus (HBV) posttranscriptional regulatory element (PRE)-containing and Mason-Pfizer monkey virus (MPMV) constitutive transport element (CTE)-containing RNAs is not inhibited by leptomycin B treatment. We conclude that the HBV PRE, like the MPMV CTE, functions independently of an NES receptor-exportin 1 interaction.


[THE PROTEOME OF SALIVA AND ITS DIAGNOSTIC POSSIBILITIES].
By the present time, a number of articles has been published testifying an extremely high potential of proteome of saliva for diagnostic of many diseases. At the same time, the conclusions can be made from these publications. In particular, to the effect that studies of proteome of saliva are at the stage of data accumulation only. Then, lacking of standardization in collection of samples, techniques of analysis and requirements to representativeness of samplings used as basis for conclusions carry in discrepancies into results acquired by different researchers. Furthermore, physiology and biochemistry of saliva are studied insufficiently as well as characteristics of interaction of proteins of saliva with micro-organisms of oral cavity. All of this establishes obstacles for implementations of achievements in studying of proteome of saliva in diagnostic practice. The solution of these problems will permit making saliva an ideal biological medium for both detection of diseases and prognosis of their course.


Surface passivation effect on the photoluminescence of ZnO nanorods.
We report an investigation of the impact of surface passivation on the optical properties of ZnO nanorods. Al2O3 coating and hydrogen plasma treatment were used to passivate the surface states. It was found that Al2O3 coating led to the suppression of the deep level emissions, while hydrogen plasma treatment completely quenched the deep level emissions. It was confirmed that the surface states of the as-grown ZnO nanorod arrays indeed contributed to the deep level emissions. Evidence was also provided that shows surface states have a greater impact on the green emission than the orange emission and may cause the negative thermal quenching behavior. Moreover, the passivation effect was confirmed by the changes of the O 1s and Zn 2p spectra.


Spleen: Reparative Regeneration and Influence on Liver.
This review considers experimental findings on splenic repair, obtained in two types of small animal (mouse, rat, and rabbit) models: splenic resections and autologous transplantations of splenic tissue. Resection experiments indicate that the spleen is able to regenerate, though not necessarily to the initial volume. The recovery lasts one month and preserves the architecture, albeit with an increase in the relative volume of lymphoid follicles. The renovated tissues, however, exhibit skewed functional profiles; notably, the decreased production of antibodies and the low cytotoxic activity of T cells, consistent with the decline of T-dependent zones and prolonged reduction in T cell numbers. Species-specific differences are evident as well, with the post-repair organ mass deficiency most pronounced in rabbit models. Autotransplantations of splenic material are of particular clinical interest, as the procedure can possibly mitigate the development of post-splenectomy syndrome. Under these conditions, regeneration lasts 1-2 months, depending on the species. The transplants effectively destroy senescent erythrocytes, assist in microbial clearance, and produce antibodies, thus averting sepsis and bacterial pneumonia. Meanwhile, cellular sources of splenic recovery in such models remain obscure, as well as the time required for T and B cell number reconstitution.


COVID-19 Vaccines: Current Status and Implication for Use in Indonesia.
The coronavirus disease 2019 (COVID-19) has inflicted catastrophic damages in public health, economic and social stability-putting life globally on hold in 2020 and presumably a year more. Indonesia bears a heavy burden of the pandemic, counting the highest case prevalence and fatality rate in all of Southeast Asia. One hope remains in the groundbreaking universal effort in search of a vaccine against the causative virus SARS-CoV-2, which has shown success unparalleled in human vaccine development thus far. An array of modalities including novel techniques are being utilized as vaccine platforms, with the closest to phase III clinical trial completion being mRNA (manufactured by Moderna and BioNTech/Pfizer), inactivated virus (Sinovac, Sinopharm), viral vector (Oxford/AstraZeneca, Gamaleya, Janssen/Johnson&Johnson, CanSino), and protein subunit (Novavax). The vaccine produced by BioNTech/Pfizer has been deployed to the public as the first ever licensed COVID-19 vaccine. In this review, we will review all of these modalities on their safety and immunogenicity, phase II/III trial results of the nine vaccine candidates and current situation as of 29 December 2020, as well as the implication for use and distribution in Indonesia. COVID-19 vaccine progress, however, is moving exceedingly fast and new advances are unfolding on a daily basis, to which we hope an update to this review can be published in early 2021.


Long-term follow-up of the postoperative patient with congenital heart disease. General concerns.
There are an estimated 400,000 adults with postoperative congenital heart disease (CHD) in the United States. The majority of these patients require long-term follow-up for management of persistent problems. These problems are related to electrophysiologic sequelae, myocardial changes, ventricular failure, prosthetic materials, and infective endocarditis. The goal for adults with postoperative CHD is to achieve not only long-term survival, but the best possible quality of life.


Exploring the role of lexis and grammar for the stable identification of register in an unrestricted corpus of web documents.
The Internet offers great possibilities for many scientific disciplines that utilize text data. However, the potential of online data can be limited by the lack of information on the genre or register of the documents, as register-whether a text is, e.g., a news article or a recipe-is arguably the most important predictor of linguistic variation (see Biber in Corpus Linguist Linguist Theory 8:9-37, 2012). Despite having received significant attention in recent years, the modeling of online registers has faced a number of challenges, and previous studies have presented contradictory results. In particular, these have concerned (1) the extent to which registers can be automatically identified in a large, unrestricted corpus of web documents and (2) the stability of the models, specifically the kinds of linguistic features that achieve the best performance while reflecting the registers instead of corpus idiosyncrasies. Furthermore, although the linguistic properties of registers vary importantly in a number of ways that may affect their modeling, this variation is often bypassed. In this article, we tackle these issues. We model online registers in the largest available corpus of online registers, the Corpus of Online Registers of English (CORE). Additionally, we evaluate the stability of the models towards corpus idiosyncrasies, analyze the role of different linguistic features in them, and examine how individual registers differ in these two aspects. We show that (1) competitive classification performance on a large-scale, unrestricted corpus can be achieved through a combination of lexico-grammatical features, (2) the inclusion of grammatical information improves the stability of the model, whereas many of the previously best-performing feature sets are less stable, and that (3) registers can be placed in a continuum based on the discriminative importance of lexis and grammar. These register-specific characteristics can explain the variation observed in previous studies concerning the automatic identification of online registers and the importance of different linguistic features for them. Thus, our results offer explanations for the jungle-likeness of online data and provide essential information on online registers for all studies using online data.


Socially Inclusive Development: The Foundations for Decent Societies in East and Southern Africa.
This article is concerned with how social processes and social provision are conceptualised and measured in societies in order to offer guidance on how to improve developmental progress. Significant advances have been made in developing multidimensional measures of development, but they provide little guidance to governments on how to build sustainable societies. We argue for the need to develop a theoretically informed social and policy framework that permits the foundations for building decent societies to be put in place by governments. In our view the recently developed Decent Society Model provides such a framework. Our example is the assessment of government provision, by function, within fourteen countries of East and Southern Africa. The context is the current debates about socially inclusive development, but we argue that it is necessary to range more widely, as social processes of different kinds are multiply interrelated. Social inclusion is recognised by governments as well as international agencies, including the World Bank and the United Nations, as not only an ethical imperative but smart economics; socially inclusive societies are more stable and have greater potential for economic growth. Societies that can develop sustainably need not only to be inclusive, however, but to provide economic security for all, to be socially cohesive and to empower citizens so that as individuals and communities they can take control over their own lives.


The effect of aging on the spatial frequency selectivity of the human visual system.
Changes in the physiological properties of senescent V1 neurons suggest that the mechanisms encoding spatial frequency in primate cortex may become more broadly tuned in old age (Zhang et al., European Journal of Neuroscience, 2008, 28, 201-207). We examined this possibility in two psychophysical experiments that used masking to estimate the bandwidth of spatial frequency-selective mechanisms in younger (age approximately 22years) and older (age approximately 65years) human adults. Contrary to predictions from physiological studies, in both experiments, the spatial frequency selectivity of masking was essentially identical in younger and older subjects.


Micromanufactured Tactile Samples for Characterization of Rough and Dry Tactile Perception.
The quantitative characterization of tactile perception, which is crucial in the design of tactile devices, requires the tested samples to have individually and precisely controlled properties associated with the senses. In this work, we microfabricated such tactile samples and then quantitatively characterized tactile perception with a focus on roughness and dryness. In the roughness perception experiments, the tactile samples had a stripe pattern with ridge and groove widths that were individually controlled. The experimental results revealed that the feeling of roughness was more dominated by the width of the groove than that of the ridge and that conventionally used roughness parameters such as Sa and Sq were not sufficient for predicting roughness perception. In the dryness perception experiments, the tactile samples had a micropattern formed by dry etching and an array of squares. The experimental results revealed that dry perception had different properties when the feature sizes were below and above 30 µm, which may have been due to the effect of adhesion on friction. The proposed tactile samples were suitable for the quantitative and precise characterization of tactile perception.


Inferior vena cava thrombosis: an unusual complication of a large simple non-parasitic liver cyst requiring an integrated approach.
Most of the simple hepatic cysts are asymptomatic and have a benign course. However, some exceptional life-threatening complications may occur. We herein report the successful management of a case who suffered from a cystic compression of the inferior vena cava complicated by thrombosis of the inferior vena cava itself. To our knowledge this is the first report of such a complication and diagnostic and therapeutic aspects are discussed. This case is paradigmatic of the possible complexity of the diagnosis and treatment of cystic lesions of the liver and should induce physicians to consider a therapeutic approach if a clear tendency to enlarge can be recognized.


Seek for Success: A Visualization Approach for Understanding the Dynamics of Academic Careers.
How to achieve academic career success has been a long-standing research question in social science research. With the growing availability of large-scale well-documented academic profiles and career trajectories, scholarly interest in career success has been reinvigorated, which has emerged to be an active research domain called the Science of Science (i.e., SciSci). In this study, we adopt an innovative dynamic perspective to examine how individual and social factors will influence career success over time. We propose ACSeeker, an interactive visual analytics approach to explore the potential factors of success and how the influence of multiple factors changes at different stages of academic careers. We first applied a Multi-factor Impact Analysis framework to estimate the effect of different factors on academic career success over time. We then developed a visual analytics system to understand the dynamic effects interactively. A novel timeline is designed to reveal and compare the factor impacts based on the whole population. A customized career line showing the individual career development is provided to allow a detailed inspection. To validate the effectiveness and usability of ACSeeker, we report two case studies and interviews with a social scientist and general researchers.


Development of a Chlamydia trachomatis T cell Vaccine.
The immune correlates of protection for most of the currently used vaccines are based on long-lived humoral immunity. Vaccines based on humoral immunity alone are unlikely to protect against infections caused by intracellular pathogens and today's most pressing infectious diseases of public health importance are caused by intracellular infections that not only include Chlamydia trachomatis but also tuberculosis, malaria, and HIV/AIDS. For these infections, vaccines that induce cellular immune responses are essential. Major impediments in developing such vaccines include difficulty in identifying relevant T cell antigens and delivering them in ways that elicit protective cellular immunity. In turn this is compounded by the complexity and plasticity of T cell developmental pathways that often correlate with specific aspects of protective immunity. Genomics and proteomics now provide tools to allow unbiased selection of candidate T cell antigens. This review mainly focuses on an immunoproteomic approach used in our laboratory to identify Chlamydia T cell antigens and how these T cell antigens can be developed into a future human Chlamydia vaccine.


Conjunctival Kaposi's sarcoma in a patient with acquired immune deficiency syndrome.
A patient with confirmed acquired immune deficiency syndrome (AIDS) and disseminated Kaposi's sarcoma was seen in the Eye Clinic, Kenyatta National Hospital, and was found to have involvement of the conjunctiva and lids, confirmed by biopsy. He also had retinal haemorrhages and cotton-wool spots. Kaposi's sarcoma of the conjunctiva may be confused with a subconjunctival haemorrhage.


Expression of the thrombin receptor mRNA in rat brain.
Thrombin activates its receptor in a number of cultured cells of neural origin, but the functional significance of this activation in the nervous system is unknown. It is also not known which cells in brain express the thrombin receptor and whether the level of its expression is developmentally regulated. In the present study, Northern blot analysis showed that thrombin receptor mRNA was expressed at higher levels in brain compared to some other tissues, such as skeletal muscle, liver or kidney. The level of expression is substantially higher in the brain of newborn rats compared to that of postnatal day 28 (P28). At embryonic day 18, thrombin receptor mRNA is present throughout in the brain and in dorsal root ganglia as detected by in situ hybridization. The regions of the P28 brain in which the thrombin receptor mRNA was present include the substantia nigra and the ventral tegmental area, the pretectal area, some hypothalamic nuclei and some cells of the cerebral cortex. These results represent one of the first steps needed to understand the role played by the thrombin receptor in the development and function of the nervous system.


Differential affinity of mammalian histone H1 somatic subtypes for DNA and chromatin.
Histone H1 is involved in the formation and maintenance of chromatin higher order structure. H1 has multiple isoforms; the subtypes differ in timing of expression, extent of phosphorylation and turnover rate. In vertebrates, the amino acid substitution rates differ among subtypes by almost one order of magnitude, suggesting that each subtype might have acquired a unique function. We have devised a competitive assay to estimate the relative binding affinities of histone H1 mammalian somatic subtypes H1a-e and H1 degrees for long chromatin fragments (30-35 nucleosomes) in physiological salt (0.14 M NaCl) at constant stoichiometry. The H1 complement of native chromatin was perturbed by adding an additional amount of one of the subtypes. A certain amount of SAR (scaffold-associated region) DNA was present in the mixture to avoid precipitation of chromatin by excess H1. SAR DNA also provided a set of reference relative affinities, which were needed to estimate the relative affinities of the subtypes for chromatin from the distribution of the subtypes between the SAR and the chromatin. The amounts of chromatin, SAR and additional H1 were adjusted so as to keep the stoichiometry of perturbed chromatin similar to that of native chromatin. H1 molecules freely exchanged between the chromatin and SAR binding sites. In conditions of free exchange, H1a was the subtype of lowest affinity, H1b and H1c had intermediate affinities and H1d, H1e and H1 degrees the highest affinities. Subtype affinities for chromatin differed by up to 19-fold. The relative affinities of the subtypes for chromatin were equivalent to those estimated for a SAR DNA fragment and a pUC19 fragment of similar length. Avian H5 had an affinity ~12-fold higher than H1e for both DNA and chromatin. H1 subtypes freely exchange in vitro between chromatin binding sites in physiological salt (0.14 M NaCl). The large differences in relative affinity of the H1 subtypes for chromatin suggest that differential affinity could be functionally relevant and thus contribute to the functional differentiation of the subtypes. The conservation of the relative affinities for SAR and non-SAR DNA, in spite of a strong preference for SAR sequences, indicates that differential affinity alone cannot be responsible for the heterogeneous distribution of some subtypes in cell nuclei.


Microbial genotoxicity as an environmental indicator for near-coastal sediment pore waters.
The genotoxic potential of sediment pore water collected from coastal areas in the Gulf of Mexico has not been reported frequently in the literature. This report summarizes a study of the microbial mutagenicity of 31 pore water samples obtained from sediment affected by non-point source runoff and compares the results with those for more traditional chemical and biological indicators of sediment quality. Genotoxicity was determined pre- and post-enzyme activation using a proprietary short-term microbial assay for pore water centrifuged from sediment collected adjacent to a Florida coastal golf complex and from an urbanized bayou-estuary. Sediment and the associated pore water also were analyzed for acute toxicity to Hyallela azteca, Palaemonetes pugio, or Americamysis bahia and for benthic macroinvertebrate diversity (sediment only). Genotoxicity (direct and enzyme-activated) was detected in 4 of 17 (golf complex) and in 10 of 14 (urbanized bayou) pore water samples. The lowest toxic pore water concentrations were between 1.8% and 44.4% (direct) and between 2.6% and 25% (enzyme-activated). The results of the genotoxic assay paralleled those based on exceedance of proposed sediment quality guidelines, pore water acute toxicity and Shannon-Wiener diversity index values for 81%, 58%, and 65% of the comparisons, respectively.


Heavy metal staining, a comparative assessment of gadolinium chloride and osmium tetroxide for inner ear labyrinthine contrast enhancement using X-ray microtomography.
The use of both gadolinium chloride (GdCl(3)) and osmium tetroxide (OsO(4)) allowed for the visualization of the membranous labyrinth and other intralabyrinthine structures, at different intensities, as compared with the control sample. This initial comparison shows the advantages of GdCl(3) in radiological assessments and OsO(4) in more detailed anatomical studies and pathways of labyrinthine pathogenesis using X-ray microtomography (microCT). To assess an improved OsO(4) staining protocol and compare the staining affinities against GdCl(3). Guinea pig temporal bones were stained with either GdCl(3) (2% w/v) for 7 days or OsO(4) (2% w/v) for 3 days, and scanned in a microCT system. The post-scanned datasets were then assessed in a 3D rendering program. The enhanced soft tissue contrast as presented in the temporal bones stained with either GdCl(3) or OsO(4) allowed for the membranous labyrinth to be visualized throughout the whole specimen. GdCl(3)-stained specimens presented more defined contours of the bone profile in the radiographs, while OsO(4)-stained specimens provided more anatomical detail of individual intralabyrinthine structures, hence allowing spatial relationships to be visualized with ease in a 3D rendering context and 2D axial slice images.


The Role of Regional versus General Anesthesia on Arteriovenous Fistula and Graft Outcomes: A Single-Institution Experience and Literature Review.
Multiple studies have demonstrated the benefits of creating arteriovenous fistulas (AVFs) under regional anesthesia. This is most likely because of the avoidance of hemodynamic instability and stress response of general anesthesia, as well as the sympathectomy associated with brachial plexus blockade. As vein diameter is the major limiting factor for primary AVF creation and maturation, our aim is to investigate if the vasodilation that accompanies regional anesthesia leads to improved patency and maturation rate of autologous AVF and improved patency of arteriovenous graft (AVG) compared with those placed under general anesthesia. This retrospective study was approved by the institutional review board. A total of 238 patients who had either an AVF or an AVG placed at the Mayo Clinic, Florida, between 2012 and 2017 were analyzed. Demographics, access type, preoperative vein diameter, anesthesia type, change of plan after regional versus general anesthesia, and outcomes were assessed. All statistical tests were 2 sided, with the alpha level set at 0.05 for statistical significance. Among 238 patients, 120 (50.4%) had regional anesthesia. Differences between the 2 groups in risk factors and 30-day or long-term outcomes (failure, abandonment, or reoperation) were not statistically significant. Of the accesses placed under general anesthesia, 58.5% were abandoned compared with 45.2% of those placed under regional anesthesia. Owing to loss of patency, 25.8% of accesses placed under general anesthesia were abandoned compared with 19.2% of those placed under regional anesthesia. Two-month failure was higher in the general anesthesia group than that in the regional anesthesia group (P = 0.076). After preoperative vein mapping, 22 patients were originally intended to have an AVG placed under regional anesthesia. After brachial plexus blockade, 9 of these patients (41%) were successfully switched to AVF, while the other 13 followed the original surgical plan and received an AVG. Of these, 0 failed and 0 were abandoned because of loss of patency. This study showed possible improvements in failure rates for vascular accesses placed under regional anesthesia compared with those placed under general anesthesia. In addition, we showed an impact of regional anesthesia on the surgical plan by transitioning from a planned AVG to an AVF, intraoperatively. Giving patients with originally inadequate vein diameter the chance to have the preferred hemodialysis access method by simply switching anesthesia type could reduce the number of grafts placed in favor of fistulas.


Propensity for fugitive gas migration in glaciofluvial deposits: An assessment of near-surface hydrofacies in the Peace Region, Northeastern British Columbia.
Petroleum resource development has generated a global legacy of millions of active and decommissioned energy wells. Associated with this legacy are concerns about wellbore integrity failure and leakage of fugitive gas into groundwater and atmosphere. The fate of fugitive gas in the shallow subsurface is controlled by sediment heterogeneity, hydrostratigraphy and hydraulic connectivity. We characterized the shallow subsurface at a site in northeastern British Columbia, Canada; a region of extensive petroleum resource development. We collected 13 core profiles, 9 cone-penetrometer profiles, 58 sediment samples and 4 electrical resistivity profiles. At the site, a ~ 12 m thick layer of low-permeability diamict (10-8 m/s) overlays a more permeable (10-6 - 10-4 m/s) but highly heterogeneous sequence of glacigenic sand, clay and silt. We develop a conceptual hydrostratigraphic model for fluid flow in this system in the context of fugitive-gas migration. Driven by buoyancy forces, free-phase gas will move upward through discontinuous permeable zones within the Quaternary sediments, until it encounters lower permeability interbeds where it will pool, flow laterally or become trapped and dissolve into flowing groundwater. The vertical extent of gas migration will be significantly limited by the relatively continuous overlying diamict, a feature common across the Western Canadian Sedimentary Basin. However, intra-till lenses observed embedded within the diamict may provide pathways for gas to move vertically towards ground surface and into the atmosphere. This study provides one of the few investigations examining geological and hydrogeological heterogeneity in the shallow subsurface at scales relevant to gas migration. For glaciated regions with similar surficial geology, such as Western Canada Sedimentary Basin, gas that is released into the subsurface from an energy wellbore, below a surface diamict, will likely migrate laterally away from the wellbore, and be inhibited from reaching ground surface and emitting to atmosphere.


Growth arrest-specific gene 6 (Gas6) levels are elevated in patients with chronic renal failure.
The TAM receptors (tyro3, axl and mer) and their ligands (vitamin K-dependent proteins-Gas6 and Protein S) are crucial modulators of inflammation, which may be relevant in chronic kidney disease (CKD). Gas6 and axl have multiple roles in mediating vascular atherosclerosis and injury, thrombosis and inflammation, yet nothing is known about the Gas6-axl pathway in humans with CKD. Given the prevalence of chronic inflammation and vascular disease in this population, we measured TAM ligands in patients with various levels of renal function. Gas6 and protein S were quantified in the plasma by ELISA in three patient groups: end-stage renal disease on chronic hemodialysis (HD), CKD and normal controls. Significantly increased levels of Gas6 and protein S were found in CKD patients compared with normal controls (P < 0.01 and <0.001, respectively). In HD patients, Gas6 levels were elevated compared with controls (P < 0.001) and positively associated with low albumin (r = 0.33; P = 0.01), dialysis vintage (r = 0.36; P = 0.008) and IV iron administration (r = 0.33; P = 0.01). The levels of Gas6 rose with CKD stage and were inversely associated with estimated GFR (P < 0.0001). Dysregulation of circulating Gas6 is associated with renal disease and inversely proportional to renal function. Low albumin and higher IV iron administration were associated with higher Gas6 levels, suggesting a possible connection between inflammation and oxidative stress mediated by iron. Protein S levels were also elevated in CKD patients, but the relevance of this finding needs to be further investigated.


Industrial Food Animal Production and Community Health.
Industrial food animal production (IFAP) is a source of environmental microbial and chemical hazards. A growing body of literature suggests that populations living near these operations and manure-applied crop fields are at elevated risk for several health outcomes. We reviewed the literature published since 2000 and identified four health outcomes consistently and positively associated with living near IFAP: respiratory outcomes, methicillin-resistant Staphylococcus aureus (MRSA), Q fever, and stress/mood. We found moderate evidence of an association of IFAP with quality of life and limited evidence of an association with cognitive impairment, Clostridium difficile, Enterococcus, birth outcomes, and hypertension. Distance-based exposure metrics were used by 17/33 studies reviewed. Future work should investigate exposure through drinking water and must improve exposure assessment with direct environmental sampling, modeling, and high-resolution DNA typing methods. Investigators should not limit study to high-profile pathogens like MRSA but include a broader range of pathogens, as well as other disease outcomes.


Global allocation rules for patterns of biomass partitioning in seed plants.
A general allometric model has been derived to predict intraspecific and interspecific scaling relationships among seed plant leaf, stem, and root biomass. Analysis of a large compendium of standing organ biomass sampled across a broad sampling of taxa inhabiting diverse ecological habitats supports the relations predicted by the model and defines the boundary conditions for above- and below-ground biomass partitioning. These canonical biomass relations are insensitive to phyletic affiliation (conifers versus angiosperms) and variation in averaged local environmental conditions. The model thus identifies and defines the limits that have guided the diversification of seed plant biomass allocation strategies.


Alcohol intake and risk of non-Hodgkin lymphoma in men and women.
The effect of alcohol intake on risk of NHL is unclear. We therefore conducted a population-based case-control study to examine the association between alcohol and NHL risk. 613 NHL cases and 480 population controls in Sweden reported their average consumption of beer, wine, and liquor 2 years before the study. Unconditional logistic regression was used to estimate the odds ratios (OR) and corresponding 95% confidence intervals (CI) for associations between alcohol intake and NHL risk. Intake of total alcohol, beer, wine, or liquor was not associated with risk of overall NHL. There was no difference in risk of NHL among those who habitually consumed above 19.1 g of ethanol per day, compared to those who consumed on average 0-2.2 g of ethanol per day (OR = 1.2 (95% CI: 0.8, 1.7); Ptrend = 0.29). However, the association was significantly positive among males (OR = 1.8 (95% CI: 1.1, 2.9); Ptrend = 0.06). Total alcohol, beer, wine, or liquor intake was not associated with any major histopathologic subtype of NHL examined, apart from an association between high wine consumption and increased risk of chronic lymphocytic leukemia. Alcohol does not appear to be a major etiologic factor for overall NHL, nor its common subtypes.


Individuals seeking gender reassignment: marked increase in demand for services.
Aims and methodTo describe the pattern of referrals and characteristics of people aged over 18 seeking gender reassignment in Oxfordshire over a 6-year period (2011-2016). A total of 153 individuals attended for assessment (of 162 referred); 97 (63.4%) were natal males and 56 (36.6%) were natal females. Mean age at referral was markedly different between the two groups, with females being younger. The number of referral significantly increased over the time period, by an average of 18% per year (95% CI 1.08-1.30). Eighty-seven patients sought transition from male to female, and 46 from female to male, while a smaller group (n = 13) had non-binary presentations. Twelve patients (7.8%) had autism spectrum disorder.Clinical implicationsThere are various possible reasons for the increased demand for services for people with gender dysphoria, which we discuss here. When planning services in the UK, both the increase in overall referral rates and the apparent earlier age at referral should be taken into account.Declaration of interestNone.


Immune responses to complex protein antigens I. MHC control of immune responses to bovine albumin.
Murine T cell proliferative and antibody responses to the multi-determinant protein bovine serum albumin (BSA) are controlled by Ir genes mapping within the H-2 gene complex. Strains possessing the H-2k, H-2a, and H-2d haplotypes are classified as high responders to BSA. In contrast, H-2b strains are low responders to BSA. Genetic mapping experiments employing strains with recombinant H-2 haplotypes indicate that both T cell proliferative and antibody responses are at least in part regulated by genes within the I-A subregion. Studies on the inhibition of T cell proliferation by monoclonal anti-Ia antibodies are consistent with the assignment of an Ir gene for BSA to the I-A subregion and strongly suggest a role for genes within the I-E/C subregions as well. The MHC-mediated control of antibody responses did not affect the affinity or the isotype of the antibody produced. The relative quantities of antibody specific for each of the three domains of BSA appears to be regulated by H-2-linked BSA Ir genes, and domain III antigenic determinants were found to be dominant in the responses of low-responder mice and in the early response of high-responder mice. This domain III epitope dominance essentially disappears by the tertiary response of high-responder mice.


Combination of PEG-decorated black phosphorus nanosheets and immunoadjuvant for photoimmunotherapy of melanoma.
Photoimmunotherapy, which combines local photothermal therapy (PTT) with immunological stimulation, is a promising modality for cancer treatment. Herein, we have reported a photothermal-immunotherapy of melanoma using pegylated black phosphorus nanosheets (BP-PEG NSs) and imiquimod (R837) as the photothermal conversion agent and the immunoadjuvant, respectively. The photothermal stability of BP NSs was remarkably enhanced after the modification of poly(ethylene glycol) (PEG) by electrostatic interactions. The in situ generation of tumor-associated antigens by PTT elicited a strong immune response in the presence of R837, achieving a photoimmunotherapy of B16 melanoma. This photoimmunotherapy stimulated a stronger immune response both in vitro and in vivo than monotherapy, inducing a much greater release of cytokines such as IL-6, IL-12, and TNF-α. In vivo antitumor studies in B16 tumor-bearing mice demonstrated that photoimmunotherapy showed the best tumor inhibition effects. Our study suggested that BP-PEG NS-based PTT primed with an immunoadjuvant can be used for synergistic photoimmunotherapy of melanomas.


Culling in 50 dairy herds in England.
A survey of 50 Friesian/Holstein dairy herds (average size 178 cows) in England investigated the rate of culling and the reasons for disposal and death over three years from 1990 to 1992. The average total annual culling rate was 23.8 per cent (22.0 per cent sold and 1.8 per cent died). Of the disposals, 54 per cent were culled by the end of their fourth lactation. Poor fertility was the most important reason for culling (36.5 per cent of disposals), followed by management policy (11.5 per cent), mastitis (10.1 per cent), bovine spongiform encephalopathy (BSE) (7.4 per cent) and lameness (5.6 per cent). The most common causes of death were mastitis (8.9 per cent) and BSE (11.5 per cent), but 46 per cent died for unknown reasons.


Magnesium-dependent adenosine triphosphatase as a marker enzyme for the plasma membrane of human polymorphonuclear leukocytes.
The adenosine triphosphatase (ATPase) activities of human polymorphonuclear leukocytes (PMNL) were studied with an assay that monitored the release of 32P-labeled inorganic pyrophosphate (32P1) from gamma-[32P]adenosine 5'-triphosphate (ATP). In cell homogenates, (Na+ + K+)-sensitive, ouabain-inhibitable ATPase comprised an insignificant fraction of the total ATPase activity. Additions of p-nitrophenyl phosphate and beta-glycerophosphate (substrates for nonspecific acid and alkaline phosphatases) and of tartrate (inhibitor of acid phosphatase) gave no indication of inhibition. This suggested that the assay was relatively specific for ATP hydrolysis. The activity was found to have a pH optimum of 8.7 and a Km for ATP of 0.6 mM. There was an absolute requirement for Mg2+, with other divalent cations substituting less efficiently. When the Mg2+-dependent ATPase activity of intact cells was compared with that in homogenized cells, no significant difference was observed. The activity in intact cells was linear with respect to incubation time up to at least l0 min. Trypan blue staining and lactate dehydrogenase assays revealed that greater than 92% of the PMNL remained intact and viable during the assay. No soluble ATPase was released from the cells under assay conditions. In following the distribution of gamma[32P]ATP and 32P2 counts became cell associated. Since the experimental evidence supports the observation that PMNL remain intact and viable and that ATP does not penetrate the cell under assay conditions, it is proposed that greater than 90% of the Mg2+-dependent ATPase of the human PMNL is associated with a plasma membrnae enzyme. This would qualify the enzyme for the role of a plasma membrane marker for future fractionation and isolation attempts.


Biomaterial-host interactions: consequences, determined by implant retrieval analysis.
Prosthetic biomaterials have had a profound impact on reconstructive surgery but complete biocompatability remains illusive. This review considers the retrieval analysis of four common prosthetic structures: the hip, the knee, heart valves, and blood vessels. We show that despite a fine record of early success, deterioration due to mechanical failure or deleterious host responses to the implant may compromise long term function. The eventual retrieval and detailed analysis of implanted structures provides an invaluable opportunity to determine the characteristics of implant success or failure and to provoke the development of still better materials.


Downregulation of the antioxidant defence during glucocorticoid-mediated apoptosis.
Recent studies implicate oxidative stress in the mechanism of apoptosis. We have examined the expression of genes, whose products counteract oxidative stress, during glucocorticoid-mediated apoptosis of a murine thymoma-derived cell line. Using Northern blot hybridisation analyses, we observed a progressive decline over a 24 h period in the transcript levels for catalase, manganese superoxide dismutase, copper, zinc-superoxide dismutase, DT-diaphorase and thioredoxin. The changes were first seen within 2-8 h of the addition of the hormone which is well in advance of appreciable apoptosis. Using Western blot hybridisation analyses we found that a dexamethasone-mediated increase in glutathione S-transferase message level was followed closely by an increase in glutathione S-transferase mu class protein and a 20% decrease in reduced glutathione levels. Our findings suggest that the downregulation of cellular oxidant defense enzymes with a consequent increase in oxidant damage could contribute to the molecular mechanism of apoptosis.