Prognostic impact of pleural invasion in 1488 patients with surgically resected non-small cell lung carcinoma.
This study aimed to verify the prognostic impact of pleural invasion according to the revised TNM classification, seventh edition. The study consisted of 1488 patients with surgically resected non-small cell carcinoma. The degree (pl0-3) and location of pleural invasion were examined using hematoxylin and eosin- and elastica van Gieson-stained slides, and outcome was compared with stratification by several clinicopathological factors. The 5-year overall survival rates of 1008, 260, 85 and 135 patients with pl0, pl1, pl2 and pl3 tumours were 80, 60, 55 and 52%, respectively. Overall survival differed significantly between patients with pl0 tumours and those with pl1 tumours (P < 0.0001). The difference was significant for patients with 1<≤ 2 cm (P = 0.004), 2<≤ 3 cm (P = 0.003) and 3<≤ 5 cm (P = 0.02) tumours. The overall survival of pl0 patients was also significantly better in patients with adenocarcinoma (P < 0.0001) than squamous cell carcinoma (P = 0.043). The overall survival of pl0 patients was significantly better in patients without lymph node metastasis (P < 0.0001) than in those with lymph node metastasis. The 5-year overall survival rates of patients with interlobar, lateral, mediastinal and diaphragmatic pl3 tumours were 65, 51, 51 and 40%, respectively. Overall survival did not differ significantly among these four groups. Outcome differs between patients with pl0 tumours and those with pl1-3 tumours, particularly among patients with 1<≤ 2 cm, 2 <≤ 3 cm and 3<≤ 5 cm tumours, adenocarcinoma histology and no lymph node metastasis. The location of pl3 pleural invasion did not affect outcome significantly.


Hormonal signaling and pituitary adenomas.
In recent years the demonstration that human pituitary adenomas are monoclonal in origin provides further evidence that pituitary neoplasia arise from the replication of a single mutated cell in which growth advantage results from either activation of proto-oncogenes or inactivation of tumor suppressor genes. Mutations in common oncogenes and tumor suppressor genes are only exceptionally involved in pituitary tumors. Since pituicytes may proliferate in response to hypothalamic neurohormones, locally produced growth factors and peripheral hormones, it has been speculated that dysregulation of the signaling molecules that constitute these pathways may confer growth advantage to the target cell, finally resulting in tumor formation. The only mutational change so far recognized to be unequivocally associated with pituitary tumors occur in the Gs alpha gene (GNAS1) and cause constitutive activation of the cAMP-dependent pathway. However, other components of pituitary-specific pathways are frequently altered in their expression and activity. This review will focus on the possible impact of G proteins and other components of hormone signaling on pituitary tumorigenesis.


BIT/SHPS-1 promotes antiapoptotic effect of BDNF on low potassium-induced cell death of cultured cerebellar granule neurons.
Brain immunoglobulin-like molecule with tyrosine-based activation motifs/SHP substrate 1 (BIT/SHPS-1) is a neuronal adhesion molecule that is highly expressed in cerebellar granule neurons (CGNs); however its function in CGNs remains unclear. Our previous studies indicated that BIT/SHPS-1 is able to modulate the antiapoptotic effect of brain-derived neurotrophic factor (BDNF) on CNS neurons by cell type-specific mechanisms. In this article, we have studied the role of BIT/SHPS-1 in the antiapoptotic function of BDNF on low potassium (LK)-induced cell death of cultured CGNs which is an in vitro model system of neuronal apoptosis during brain development. Cultured rat CGNs were transduced with wild-type rat BIT/SHPS-1 (BIT/SHPS-1(WT)), its 4F-mutant (BIT/SHPS-1(4F), in which all cytoplasmic tyrosine residues were substituted with phenylalanine), or nuclear localization signal-attached beta-galactosidase (NLS-LacZ, as control)-expressing adenoviruses. Expression of BIT/SHPS-1(WT) and BIT/SHPS-1(4F) alone did not affect steady-state cell viability. Tyrosine phosphorylation of BIT/SHPS-1 was only detected in BIT/SHPS-1(WT)-expressing cultures in the presence and the absence of BDNF. When subjected to LK in the presence of BDNF, BIT/SHPS-1(WT)- and BIT/SHPS-1(4F)-expressing cultures showed a significant resistance to cell death, while the control virus-transfected culture did not. In addition, a phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002, attenuated the antiapoptotic effect of BDNF on BIT/SHPS-1(WT)-, and BIT/SHPS-1(4F)-expressing cultures. These results demonstrated that in both tyrosine phosphorylation-independent and PI3-K-dependent manners, BIT/SHPS-1 promotes the antiapoptotic effect of BDNF on the LK-induced cell death of CGNs.


Human Error Prediction Using Heart Rate Variability and Electroencephalography.
As human's simple tasks are being increasingly replaced by autonomous systems and robots, it is likely that the responsibility of handling more complex tasks will be more often placed on human workers. Thus, situations in which workplace tasks change before human workers become proficient at those tasks will arise more frequently due to rapid changes in business trends. Based on this background, the importance of preventing human error will become increasingly crucial. Existing studies on human error reveal how task errors are related to heart rate variability (HRV) indexes and electroencephalograph (EEG) indexes. However, in terms of preventing human error, analysis on their relationship with conditions before human error occurs (i.e., the human pre-error state) is still insufficient. This study aims at identifying biological indexes potentially useful for the detection of high-risk psychological states. As a result of correlation analysis between the number of errors in a Stroop task and the multiple HRV and EEG indexes obtained before and during the task, significant correlations were obtained with respect to several biological indexes. Specifically, we confirmed that conditions before the task are important for predicting the human error risk in high-cognitive-load tasks while conditions both before and during tasks are important in low-cognitive-load tasks.


Prognostic implication of left atrial sphericity in atrial fibrillation patients undergoing radiofrequency catheter ablation.
Left atrial (LA) sphericity can predict recurrence of atrial fibrillation (AF) after radiofrequency catheter ablation (RFCA). We sought to reconfirm the prognostic role of atrial sphericity after RFCA of atrial fibrillation (AF), assess any relationship between the atrial pressure and sphericity, and determine the characteristics of the patients for whom atrial sphericity was most highly predictive. All 148 nonvalvular AF patients (57 ± 11 years, 121 men, 95 paroxysmal AF [PaAF]) who underwent RFCA were enrolled. The LA volume (LAV) was determined and LA sphericity assessed from three-dimensional computed tomographic images. The preprocedural mean LA pressure (mLAP) was measured. After a 3-month blanking period, AF/atrial tachycardia (AT) recurrences within 1 year were documented in 38 patients (26%). Patients with recurrence had a greater LAV (124 ± 35 mL vs 151 ± 45 mL, P < 0.001) and LA sphericity (0.669 ± 0.040 vs 0.684 ± 0.038, P = 0.041). In patients with smaller LAs (LAV < 125 mL), LA sphericity predicted AF/AT recurrences (odds ratio [OR]: 1.030 [for each 0.001 increase], 95% confidence interval [CI]: 1.008-1.053, P = 0.007), whereas the LAV did not. In patients with larger LAs (LAV ≥ 125 mL), the LAV could predict recurrence (OR: 1.021, 95% CI: 1.001-1.041, P = 0.036), while the LA sphericity could not. The LA sphericity and mLAP are linearly correlated (r = 0.345, P < 0.022) in persistent AF, but not PaAF. LA spherical change precedes severe LA enlargement in AF. It predicts 1-year AF/AT recurrence after RFCA and is more important than the LA size in patients with less severe LA enlargement.


[Brazilian National Registry of Healthcare Establishments as a tool for the analysis of decentralization of tuberculosis treatment to basic care services].
This study aimed to validate a method for classification of healthcare services in Brazil (basic care vs. other levels) and describe the decentralization of tuberculosis (TB) care to basic services (2002 to 2016). The healthcare services that reported and followed TB cases were classified as either "basic care" or "other levels" based on the type of establishment registered in the Brazilian National Registry of Healthcare Establishments (CNES, in Portuguese). The study estimated the agreement between this classification with a previous classification performed in 2013 by Brazil's state and local tuberculosis programs. Using the CNES registry, the authors then calculated the percentage of TB patients treated in basic care from 2002 to 2016. Agreement was 94.4%, and overall kappa index was 0.86. There was a relative increment of 31.2% in TB care provided by basic services (from 50.9% in 2002 to 66.8% in 2016). All regions of Brazil showed an increase in this percentage, except the South. The classification based on the CNES registry allowed analyzing the trend in decentralization of TB treatment to basic healthcare services in Brazil.


Adaptive Graph Convolutional Networks for Medical Image Segmentation.
Medical image segmentation is very essential for computer-aided diagnosis in the field of medical imaging. In the last decade, Deep Learning-based frameworks (e.g., UNet) have been widely used in medical applications such as image segmentation tasks. Recently, numerous Transformer-based frameworks are presented for the image segmentation tasks as their design can utilize long-range dependencies. Transformer's design has a weak inductive bias since it does not take advantage of local relationships between pixels and lacks scale invariance. Consequently, Transformers require large datasets for convergence whereas the availability of massive medical datasets is challenging. In this paper, we present a graph-based approach replacing Transformer design to capture long-range dependencies and reduce computational cost. Our proposed framework achieves competitive performance using publicly available dataset Synapse.


Identification of potential pharmacological and toxicological targets differentiating structural analogs by a combination of transcriptional profiling and promoter analysis in LS-180 and Caco-2 adenocarcinoma cell lines.
Detecting and understanding the potential for off-target pharmacological effects is critical in the optimization of lead compounds in drug discovery programs. Compound-mediated activation of the pregnane X receptor (PXR; NR1I2), a key regulator for drug metabolism genes, is often monitored to avoid potential drug-drug interactions. Two structural analogs, MRL-1 and MRL-2, were determined to be equivalent PXR activators in trans-activation assays. To differentiate these two PXR activators, their transcriptional effects were examined in PXR-sufficient (LS180) and PXR-deficient (Caco-2) adenocarcinoma cell lines. Both compounds regulated drug-management genes (e.g. CYP3A4, CYP2B6, UGT1A1 and ABCB1) in LS180 cells, but not in PXR-deficient Caco-2 cells. The potency of MRL-1 and MRL-2 on PXR activation was again equivalent as revealed by a set of 113 genes that were regulated by four prototypical PXR agonists (rifampicin, ritonavir, troglitazone and dexamethasone) in the LS180 cells. The specificity of the PXR signature genes was supported by the enrichment of putative PXR binding sites uncovered by sequence-based promoter analyses. Interestingly, an additional off-target activity of MRL-2 was suggested where sterol response element binding protein binding sites were found enriched in a subset of PXR signature genes. These genes, involved in cholesterol and fatty acid synthesis, were significantly regulated by ritonavir, chlorpromazine and MRL-2, which were linked to the manifestation of phospholipidosis. The present study demonstrates the utility of our approach in the differentiation and selection of lead compounds for drug development.


Defibrination in obstetrics. Modern concepts.
Coagulation profiles of serum fibrinogen, factors V and VIII and haemoglobin in normal pregnancies during labour, delivery and the early puerperium are presented. These factors were also studied in patients with abruptio placentae, in intra-uterine death, and in patients whose pregnancies were terminated with intra-amniotic saline and prostaglandin F2alpha. An assessment of fibrinolytic activity in these patients was made using qualitative (euglobulin lysis time) and quantitative (FR-antigen) tests. The coagulation findings presented form a basis for the rational management of defibrination in obstetrics.


Piperlongumine induces apoptosis and reduces bortezomib resistance by inhibiting STAT3 in multiple myeloma cells.
Effective new therapies are urgently needed for the treatment of multiple myeloma (MM), an incurable hematological malignancy. In this study, we evaluated the effects of piperlongumine on MM cell proliferation both in vivo and in vitro. Piperlongumine inhibited the proliferation of MM cells by inducing cell apoptosis and blocking osteoclastogenesis. Notably, piperlongumine also reduced bortezomib resistance in MM cells. In a disseminated MM mouse model, piperlongumine prolonged the survival of tumor-bearing mice without causing any obvious toxicity. Mechanistically, piperlongumine inhibited the STAT3 signal pathway in MM cells by binding directly to the STAT3 Cys712 residue. These findings suggest that the clinical use of piperlongumine to overcome bortezomib resistance in MM should be evaluated.


Role of astrocytes in the control of developing retinal vessels.
To assess the role of astrocytes in controlling the growth of developing retinal vessels. Growth of retinal vessels in the neonatal rat retina was examined in three conditions: normal development, cyclic hyperoxia, and normoxia (1 day 70% to 75% oxygen, 1 day room air for up to seven cycles from birth, and room air for up to 16 days), and direct hypoxia (10% oxygen from postnatal day 3 [P3]). Retinas were examined as wholemounts labeled for astrocytes, microglia, and blood vessels and in some experiments for the fragmentation of DNA characteristic of apoptosis. In normoxia, superficial retinal vessels formed to the processes of astrocytes. In cyclic hyperoxia, the depletion of superficial retinal vessels and subsequent neovascularization described by others were confirmed. The neovascularization was preceded by the depletion by apoptotic death of the astrocyte population, first between vessels but eventually breaching the glia limitans along vessels. The earliest forms of neovascularization resembled microaneurysms, each protruding through a defect in the glia limitans of a capillary. Neurons of the ganglion cell layer survived. Direct hypoxia from P3 caused hypertrophy of superficial vessels. Between P3 and P6, some vessels accelerated past the still-spreading astrocytes, often growing out of the retina into the vitreous humor. Direct hypoxia also caused astrocyte degeneration, but capillaries retained astrocyte investment and were not the site of vascular damage. By P8, breaches in the astrocytic glia limitans became prominent but were restricted to large veins. At such breaches, bleeding into the vitreous humor was common. Retinal vessels normally develop in close association with astrocytes. Where that association is broken, preretinal vessels may grow or bleed into the vitreous humor. Astrocytes play important roles in constraining retinal vessels to the retina and in maintaining their integrity.


Diagnostic accuracy of endometrial biopsy in relation to the amount of tissue.
For the diagnostic workup of postmenopausal bleeding, histological examination of the endometrium is frequently performed. Failure of endometrial sampling due to insufficient material is often reported but objective criteria for quality assessment of endometrial biopsies are lacking. The aim of the present study is to evaluate the association between the amount of tissue obtained by endometrial sampling and the diagnostic accuracy, and to establish a cut-off level for a minimal amount of tissue required for a conclusive diagnosis. For this retrospective cohort study, clinicopathological data and Pipelle endometrial sampling slides of 139 patients who were treated with hysterectomy were collected. The surface of evaluable endometrial tissue was measured by means of structured digital assessment. The correlation between the predictive values in relation to the endometrial tissue surface was calculated for different cut-off values. The median endometrial tissue surface was 4.7 mm2 (range 0.4-156.4) for benign endometrium, 27.8 mm2 (range 0.0-208.4) for premalignant endometrium and 43.8 mm2 (range 0.0-223.6) for malignant endometrium. There was a significant association between the endometrial tissue surface and the correctness of diagnosis. A minimal endometrial tissue surface of 35 mm2 could be defined, for positive and negative predictive values of 92.6% and 85.7%, respectively. The diagnostic accuracy of Pipelle endometrial sampling is associated with the amount of endometrial tissue surface, with a minimal cut-off value of 35 mm2 required to classify an endometrial sample as conclusive. Quantification of endometrial tissue can contribute to standardisation of quality assessment of endometrial samplings.


Treatment of osteonecrosis of the jaw (ONJ) by medical ozone gas insufflation. A case report.
Osteonecrosis of the jaw (ONJ) is an adverse event reported in patients receiving cancer treatment, especially bisphosphonates and denosumab. A patient with multiple myeloma who underwent up to 22 intravenous zoledronic acid infusions without previous dental examination developed a devastating ONJ lesion in the right horizontal mandibular ramus. He was treated with local ozone gas applications every third day by means of a special bell to avoid O(3) diffusion. Azithromycin 500 mg/day was administered for 10 days prior to the O(3) applications. O(3) therapy resulted in sequestration of the necrotic bone after a median of 15 applications, following which surgery was necessary to remove it. Interestingly, removal was possible without the resection of the healthy mandible edge because of the presence of the bone sequestrum. Medical O(3) gas administration was effective and safe in a patient treated with bisphosphonates who developed a >2.5 cm ONJ lesion. Future research is needed to demonstrate the efficacy and tolerability of such treatment in a larger number of patients.


Investigating Alkylated Prodigiosenes and Their Cu(II)-Dependent Biological Activity: Interactions with DNA, Antimicrobial and Photoinduced Anticancer Activity.
Prodigiosenes are a family of red pigments with versatile biological activity. Their tripyrrolic core structure has been modified many times in order to manipulate the spectrum of activity. We have been looking systematically at prodigiosenes substituted at the C ring with alkyl chains of different lengths, in order to assess the relevance of this substituent in a context that has not been investigated before for these derivatives: Cu(II) complexation, DNA binding, self-activated DNA cleavage, photoinduced cytotoxicity and antimicrobial activity. Our results indicate that the hydrophobic substituent has a clear influence on the different aspects of their biological activity. The cytotoxicity study of the Cu(II) complexes of these prodigiosenes shows that they exhibit a strong cytotoxic effect towards the tested tumor cell lines. The Cu(II) complex of a prodigiosene lacking any alkyl chain excelled in its photoinduced anticancer activity, thus demonstrating the potential of prodigiosenes and their metal complexes for an application in photodynamic therapy (PDT). Two derivatives along with their Cu(II) complexes showed also antimicrobial activity against Staphylococcus aureus strains.


Protein export in malaria parasites: an update.
Symptomatic malaria is caused by the infection of human red blood cells (RBCs) with Plasmodium parasites. The RBC is a peculiar environment for parasites to thrive in as they lack many of the normal cellular processes and resources present in other cells. Because of this, Plasmodium spp. have adapted to extensively remodel the host cell through the export of hundreds of proteins that have a range of functions, the best known of which are virulence-associated. Many exported parasite proteins are themselves involved in generating a novel trafficking system in the RBC that further promotes export. In this review we provide an overview of the parasite synthesized export machinery as well as recent developments in how different classes of exported proteins are recognized by this machinery.


Interactions of ascorbic acid with prostaglandins.
Samples of blood, urine and ovarian tissues of non-pregnant cycling guinea-pigs were obtained from day 3 before until day 2 after oestrus. In addition placental specimens were obtained from 49- to 62-day pregnant guinea-pigs. In a separate series of experiments blood samples of normally menstruating and dysmenorrhoeic women were collected daily during the last one week preceding and the first two days of the menstrual cycle. Plasma and tissue samples were analyzed simultaneously for ascorbic acid (AA) and prostaglandins (PGs) E2 and F2 alpha. The urine and leukocyte samples were estimated for AA only. The results demonstrate that the ovarian AA depletion at ovulation is not associated with a rise in urinary, plasma or leukocyte levels. From about the 8th week of pregnancy in the guinea-pig the placental levels of AA start to decline, while the concentrations of PGs start to rise. During the late luteal phase, the plasma of normally cycling women has a PGD2 alpha/PGE2 ratio of about 0.6. In the dysmenorrhoeic women this ratio varies from 0.9 to 1.3. In addition, the plasma and leukocyte levels of AA in the dysmenorrhoeic women are lower than the levels found in the normally cycling women. The results of both animal and human studies indicate that an inverse relationship exists between the levels of AA and the amount of PGF2 alpha synthesized and/or released in the body tissues. It is suggested that AA acts to control the ratio between PGF2 alpha and PGE2 and therefore forms an integral part of the adenyl/guanylate cyclase system. The mechanism for the fall in tissue ascorbic acid is however not known. The results suggest that this is due to increased break-down and/or rapid consumption of AA in the body tissues. In addition the reduction in placental tissue levels of AA near term could be due to its redistribution from maternal to foetal tissues.


[Photography as analysis document, body and medicine: theory, method and criticism--the experience of Museo Nacional de Medicina Enrique Laval].
This article is an experimental methodological reflection on the use of medical images as useful documents for constructing the history of medicine. A method is used that is based on guidelines or analysis topics that include different ways of viewing documents, from aesthetic, technical, social and political theories to historical and medical thinking. Some exercises are also included that enhance the proposal for the reader: rediscovering the worlds in society that harbor these medical photographical archives to obtain a new theoretical approach to the construction of the history of medical science.


[Ultrastructural features of virus infected hepatocytes in patients with pathology of the hepatobiliary organs].
In electron-microscopic study of the puncture biopsy material in 52 patients with diseases of the hepatobiliary organs in 22% of cases, the liver contamination with the viruses was revealed. They caused destruction of hepatocytes and induced their appearance in the cytoplasma and mitochondria of the protein crystalline inclusions. This was of certain diagnostic and, perhaps, lithogenic importance.


Paraxial T-box genes, Tbx6 and Tbx1, are required for cranial chondrogenesis and myogenesis.
We previously reported that Tbx6, a T-box transcription factor, is required for the differentiation of ventral body wall muscle and for segment formation and somitic muscle differentiation. Here, we show that Tbx6 is also involved, at later stages, in cartilage differentiation from the cranial neural crest and head muscle development. In Tbx6 knockdown embryos, the cranial neural crest was shown to be correctly induced at the border of the neural plate and migrated in a slightly delayed manner, but finally reached positions in the pharyngeal arches nearly similar to those in the normal embryos as revealed by in situ hybridization and the neural crest-transplantation experiments. However, the neural crest cells failed to maintain Sox9 expression. Tbx6 knockdown also reduced the expression of Tbx1, another T-box gene expressed in more anterior paraxial structures. Tbx1 knockdown caused phenotypes milder but similar to those of Tbx6 morphants, including reduced formation of head muscles and cartilages, and attenuated Sox9 expression. Furthermore, the phenotypes caused by Tbx6 knockdown were partially rescued by Tbx1 plasmid injection. These results suggest that Tbx6 is involved in the cranial cartilage and head muscle development by regulating anterior paraxial genes such as Tbx1 and Sox9.


[Role of IPS-1 in type I IFN induction].
Type I interferons (IFNalpha/beta) are central mediators for antiviral responses. Using a functional cloning strategy, we have identified a molecule designated IPS-1. IPS-1 overexpression caused antiviral responses by producing type I IFN and IFN-inducible genes through activation of IRF3, IRF7 and NF-kappaB. TBK1 and IKKi protein kinases were required for the IPS-1-mediated IFN induction. IPS-1 contains an N-terminal caspase recruiting domain (CARD)-like structure that mediates interaction with the CARD of RIG-I and Mda5, cytoplasmic RNA helicases sensing RNA viruses. Reduction of IPS-1 by siRNA blocked IFN induction by virus infection. Thus, IPS-1 is an adapter that mediates RIG-I- and Mda5-dependent antiviral responses.


Arabinosyl-5-azacytosine: mechanisms of native and acquired resistance.
Factors influencing the activity of the nucleoside analogue arabinosyl-5-azacytosine (ara-AC) were studied in P388 murine lymphoblasts in vitro and in vivo, in variants of these cells with artificially acquired resistance, in the naturally resistant colon 38 carcinoma in vivo, and in a panel of six human tumors maintained in continuous culture. Differences were noted not only between the sensitive and artificially developed resistant variants of P388, but also between the naturally sensitive (P388) and naturally resistant (colon 38) tumors. The artificially developed resistant P388 cell lines showed an inhibited capacity to accumulate nucleotides derived from ara-AC and deoxycytidine, whereas the accumulation of cytidine nucleotides remained unchanged. Studies of the initial velocity of facilitated diffusion of ara-AC showed only minor differences between parental and resistant lines, while the nucleotide formation rates from both ara-AC and deoxycytidine were markedly depressed in the latter cells. It is concluded, therefore, that the failure of resistant P388 cells to accumulate these compounds results not from a transport deficit per se but rather from a failure to convert the nucleosides to nondiffusible (i.e., phosphorylated) species inside the cell. This failure was accompanied by a substantial reduction in the incorporation of a radiolabeled product derived from deoxycytidine into the nucleic acids of the resistant clones. The common factor responsible for the resistance of P388 variants toward ara-AC appears to be a markedly decreased level of deoxycytidine kinase activity. The naturally resistant colon 38 carcinoma, on the other hand, in addition to a decrease in the activity of its deoxycytidine kinase, showed a lower level of activity of all its purine and pyrimidine kinases, along with a notably elevated nucleoside triphosphatase activity (with ATP as substrate) when compared to P388. These differences were reflected in lower endogenous nucleoside triphosphate pool sizes in colon 38, and in a lower level of ara-AC-5'-triphosphate accumulation in colon 38 than in P388 after comparable drug exposure. In the six human tumor lines, a positive correlation was established between sensitivity to ara-AC (as determined by its median inhibitory concentration) and cellular content of deoxycytidine kinase. It is concluded that this latter enzyme is a generally important determinant of sensitivity to arabinosyl-5-azacytosine.


Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset.
Type 1 diabetes is characterized by the loss of insulin production caused by β-cell dysfunction and/or destruction. The hypothesis that β-cell loss occurs early during the prediabetic phase has recently been challenged. Here we show, for the first time in situ, that in pancreas sections from autoantibody-positive (Ab+) donors, insulin area and β-cell mass are maintained before disease onset and that production of proinsulin increases. This suggests that β-cell destruction occurs more precipitously than previously assumed. Indeed, the pancreatic proinsulin-to-insulin area ratio was also increased in these donors with prediabetes. Using high-resolution confocal microscopy, we found a high accumulation of vesicles containing proinsulin in β-cells from Ab+ donors, suggesting a defect in proinsulin conversion or an accumulation of immature vesicles caused by an increase in insulin demand and/or a dysfunction in vesicular trafficking. In addition, islets from Ab+ donors were larger and contained a higher number of β-cells per islet. Our data indicate that β-cell mass (and function) is maintained until shortly before diagnosis and declines rapidly at the time of clinical onset of disease. This suggests that secondary prevention before onset, when β-cell mass is still intact, could be a successful therapeutic strategy.


[Effect of discontinuation of long-term preventive lithium therapy].
The development of manic-depressive psychoses (15 cases) and attack-like schizophrenia (20 cases) was studied, following a withdrawal of a durable and successful prophylactic intake of lithium preparations. A comparison with a control group selected according to the double method, not suspending the administration of lithium salts, demonstrated a statistically significant increase of phases-attacks, their aggravation as well as an increased amount of hospitalizations due to lithium withdrawal. The conclusion is made that there is a necessity for durable and continuous lithium prophylaxis even after obtaining complete remissions.


Improved Stability of Butterfly Pea Anthocyanins with Biopolymeric Walls.
Butterfly pea (Clitoria ternatea) anthocyanins are important natural food colorants. However, the instability hinders industrial applications. The butterfly pea anthocyanin extract was prepared and mixed with biopolymeric wall systems such as maltodextrin (MD) and gum arabic (GA), MD and gelatin (GE), and MD and guar gum at 1/4 and 1/5 ratios with or without acidified condition, and assessed using the accelerated stability test. The total anthocyanin content (TAC) and color were reassessed. The biopolymeric walls of MD and GA (1/5) under acidified condition exhibited best stability enhancement in comparison with the unprotected one (12.04% ± 4.49% and 85.37% ± 0.22% TAC reduction, respectively). a* and b shifts of the protected system were 4.76% ± 0.00% and 0.28% ± 0.00%, respectively. The particle size of this system was 95.44 ± 1.57 µm. This stabilized anthocyanin extract can, therefore, be used in food, pharmaceutical, and cosmetic industries.


Transmural coronary flow reserve patterns in dogs.
To investigate transmural variations in coronary flow reserve, we studied 20 anesthetized dogs with a Gregg cannula in the left main coronary artery. In 11 dogs, radionuclide-labeled microspheres were injected over a range of perfusion pressures in the control state and during maximal coronary vasodilation produced with chromonar or adenosine. In another nine dogs, control, reactive hyperemic, and adenosine-vasodilated flows were compared at the same perfusion pressures. Adenosine dilated vessels more than did reactive hyperemia, which in turn vasodilated more than did hypoperfusion. Adenosine or chromonar vasodilated more than did hypoperfusion alone in all layers of the heart at perfusion pressures as low as 30 mmHg (P less than 0.05). This effect was greatest in the subepicardium and least in the subendocardium and varied with perfusion pressure (P less than 0.05). Subendocardial-to-subepicardial flow ratios declined with diminishing perfusion pressure despite the fact that flow reserve was present in all layers. We conclude that exhaustion of flow reserve is not the mechanism by which subendocardial ischemia occurs.


The fatty acid site is coupled to functional motifs in the SARS-CoV-2 spike protein and modulates spike allosteric behaviour.
The SARS-CoV-2 spike protein is the first contact point between the SARS-CoV-2 virus and host cells and mediates membrane fusion. Recently, a fatty acid binding site was identified in the spike (Toelzer et al. Science 2020). The presence of linoleic acid at this site modulates binding of the spike to the human ACE2 receptor, stabilizing a locked conformation of the protein. Here, dynamical-nonequilibrium molecular dynamics simulations reveal that this fatty acid site is coupled to functionally relevant regions of the spike, some of them far from the fatty acid binding pocket. Removal of a ligand from the fatty acid binding site significantly affects the dynamics of distant, functionally important regions of the spike, including the receptor-binding motif, furin cleavage site and fusion-peptide-adjacent regions. Simulations of the D614G mutant show differences in behaviour between these clinical variants of the spike: the D614G mutant shows a significantly different conformational response for some structural motifs relevant for binding and fusion. The simulations identify structural networks through which changes at the fatty acid binding site are transmitted within the protein. These communication networks significantly involve positions that are prone to mutation, indicating that observed genetic variation in the spike may alter its response to linoleate binding and associated allosteric communication.


Determining the 2-Dimensional Threshold for Perception of Artificial-Appearing Lips.
Recognizing the perceptual threshold for artificial-appearing lips is important to avoid an undesirable outcome of treatment. To characterize the quantitative measurements for the perceptual threshold of artificial- and unnatural-appearing lips. Photographs of a female model's lips were digitally altered incrementally in 5 sets of features (the upper lip, lower lip, upper and lower lips, and shape of the Cupid's bow). From December 1, 2013, to January 30, 2014, participants viewed the photographs in random sequence using an online survey and responded to 2 questionnaires after each photograph. The participants were prompted to respond whether each altered photograph of the lips appeared to have received any cosmetic treatment, and whether the lips looked attractive and natural or artificial and unnatural. The measurement of each lip at which 50% of the observers perceived the lips as being treated and 50% of the observers perceived the lips as being artificial was determined. The difference in these 2 measurements was defined as dTA50, which represents the threshold differential between the perception of treated lips and artificial lips for 50% of the observers. Survey responses of the participants to the appearance of the lips in the photographs. A total of 98 participants (76 females and 22 males; mean age, 42 years) provided usable responses to the survey. Each area of the lips had a unique quantitative measurement at which the observers perceived the lips as being treated and artificial. Enhancement of the upper lip alone had a narrower margin for artificial appearance (dTA50, 0.9 mm) compared with enhancement of both the upper and lower lips (dTA50, 1.5 mm). Any alteration to the Cupid's bow resulted in the narrowest margin for artificial appearance (dTA50, 0.3 mm). The difference in the perceptual threshold between the age of the observers was the most significant for the upper lip. The perceptual threshold for treated and/or artificial appearance is unique for each area of the lips. NA.


Mitochondrially Targeted Gene Therapy Rescues Visual Loss in a Mouse Model of Leber's Hereditary Optic Neuropathy.
Leber's hereditary optic neuropathy (LHON) is a common mitochondrial genetic disease, causing irreversible blindness in young individuals. Current treatments are inadequate, and there is no definitive cure. This study evaluates the effectiveness of delivering wildtype human NADH ubiquinone oxidoreductase subunit 4 (hND4) gene using mito-targeted AAV(MTSAAV) to rescue LHOH mice. We observed a declining pattern in electroretinograms amplitudes as mice aged across all groups (p < 0.001), with significant differences among groups (p = 0.023; Control vs. LHON, p = 0.008; Control vs. Rescue, p = 0.228). Inner retinal thickness and intraocular pressure did not change significantly with age or groups. Compared to LHON mice, those rescued with wildtype hND4 exhibited improved retinal visual acuity (0.29 ± 0.1 cy/deg vs. 0.15 ± 0.1 cy/deg) and increased functional hyperemia response (effect of flicker, p < 0.001, effect of Group, p = 0.004; Interaction Flicker × Group, p < 0.001). Postmortem analysis shows a marked reduction in retinal ganglion cell density in the LHON group compared to the other groups (Effect of Group, p < 0.001, Control vs. LHON, p < 0.001, Control vs. Rescue, p = 0.106). These results suggest that MTSAAV-delivered wildtype hND4 gene rescues, at least in part, visual impairment in an LHON mouse model and has the therapeutic potential to treat this disease.


[Mapping of the yellow inhibitor gene I in silkworm Bombyx mori using SSR markers].
The yellow color of silkworm (Bombyx mori) cocoon is mainly controlled by three genes, Y (yellow blood), I (yellow inhibitor) and C (out-layer yellow cocoon) genes. I gene locates on the 9th chromosome of silkworm and prevents the transport of carotenoid from epithelia of midgut into hemolymph. Owning to a lack of crossing over in females, reciprocal backcrossed F1(BC1) progenies were used for linkage analysis and mapping of the I gene based on the SSR linkage map using silkworm strains Baghdad (Ba), which express white hemolymph (II+Y+Y), and KY, which express yellow hemolymph (+I+IYY). The gene of interest was linked to three (S0904, S0905, and S0906) SSR markers. All the individuals with white hemolymph in the BC1F (BC1 was generated using F1 as female) showed heterozygous profile of (BaxKY) F1, and the yellow ones in BC1F showed the homozygous profile of the strain KY. Using a reciprocal BC1M cross, we con-structed a linkage map of 38.4 cM, and the distance between I gene and the nearest marker S0904 is 7.4 cM.


[Laws that ban smoking in indoor places in Mexico].
Recently Mexico passed federal and state-level laws banning smoking in indoor spaces. These actions are totally in accordance with measures proposed in the WHO-FCTCs article 8, ratified by Mexico in 2004. This essay reviews scientific evidence that secondhand smoke causes both chronic and acute diseases among non smokers, children and adults. There is no safe level of exposure to secondhand smoke, so the only effective intervention to protect Mexican people from such harmful exposure is by promoting 100% smoke free indoor air, as the two new laws do. Total banning of smoking is associated with reduction in smoking prevalence, amount of cigarette smoked per day, and an increase in cessation rates. Reductions in acute respiratory symptoms and hospitalization of acute myocardial infarction have been also reported. Well documented examples show that main tobacco industry arguments against smoke free policy: negative economic impact and lack of support from the public, are unjustified. These two laws strengthen the Mexican tobacco control program. Next steps include their implementation, evaluation, enforcement of compliance and encouragement for similar laws at state level.


Mobilization studies in mice deficient in sphingosine kinase 2 support a crucial role of the plasma level of sphingosine-1-phosphate in the egress of hematopoietic stem progenitor cells.
Sphingosine-1-phosphate (S1P) is a bioactive lipid involved in cell signaling and, if released from cells, also plays a crucial role in regulating the trafficking of lympho-hematopoietic cells, including primitive hematopoietic stem/progenitor cells (HSPCs). It has been demonstrated that S1P chemoattracts HSPCs, and its level in peripheral blood creates a gradient directing egress of these cells during mobilization. In this paper we analyzed hematopoiesis in mice deficient in sphingosine kinase 2 (Sphk2-KO mice) and studied the effect of this mutation on plasma S1P levels. We found that Sphk2-KO mice have normal hematopoiesis, and, in contrast to Sphk1-KO mice, the circulating S1P level is highly elevated in these animals and correlates with the fact that HSPCs in Sphk2-KO animals, also in contrast to Sphk1-KO animals, show enhanced mobilization. These results were recapitulated in wild type (WT) animals employing an Sphk2 inhibitor. We also administered an inhibitor of the S1P-degrading enzyme S1P lyase, known as tetrahydroxybutylimidazole (THI), to WT mice and observed that this resulted in an increase in S1P level in PB and enhanced mobilization of HSPCs. In sum, our results support a crucial role for S1P gradients in blood plasma in the mobilization process and indicate that small-molecule inhibitors of Sphk2 and Sgpl1 could be employed as mobilization-facilitating compounds. At the same time, further studies are needed to explain the unexpected effect of Sphk2 inhibition on increasing S1P levels in plasma.


A systematic review of pediatric adherence to antiretroviral therapy in low- and middle-income countries.
Sustaining antiretroviral therapy (ART) adherence requires accurate, consistent monitoring, a particular challenge for low-income countries. The optimal strategy to measure pediatric adherence remains unclear. To conduct a systematic review of pediatric ART adherence measurement techniques, adherence estimates, and clinical correlates in low- and middle-income countries to inform ART adherence monitoring. We searched online bibliographic databases, including MEDLINE and EMBASE, using systematic criteria. Two reviewers selected all descriptive or interventional studies involving nonpregnant, HIV-positive individuals < or =18 years old that measured ART adherence in low- or middle-income countries as defined by World Bank criteria. Data were extracted regarding sample characteristics, study setting, measurement strategy, adherence estimate, and adherence correlates. The search yielded 1566 titles, of which 17 met selection criteria. Adherence measurement strategies included self- or proxy-report measures (14 studies), pill counts (4 studies), pharmacy records, drug levels, clinic adherence, and directly observed therapy (1 study each). The self- or proxy-report measures were heterogeneous, and few employed validation strategies. Caregiver-reported adherence was generally higher than self-report estimates. Pill counts revealed lower adherence estimates. Estimates of ART adherence ranged from 49% to 100%, with 76% of articles reporting >75% adherence. Factors related to family structure, socioeconomic status, disclosure, and medication regimen were all significantly associated with ART adherence. Pediatric HIV care programs in low- and middle-income countries use heterogeneous methods to measure ART adherence. Adherence estimates vary substantially, but most studies from low- and middle-income countries report >75% adherence, whereas most studies from high-income countries report <75% adherence.


Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.
Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy. We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10-10. Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10-4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample. In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.


Adult systemic lupus erythematosus in Egypt: The nation-wide spectrum of 3661 patients and world-wide standpoint.
The aim of this study was to present the epidemiology, clinical manifestations and treatment pattern of systemic lupus erythematosus (SLE) in Egyptian patients over the country and compare the findings to large cohorts worldwide. Objectives were extended to focus on the age at onset and gender driven influence on the disease characteristics. This population-based, multicenter, cross-sectional study included 3661 adult SLE patients from Egyptian rheumatology departments across the nation. Demographic, clinical, and therapeutic data were assessed for all patients. The study included 3661 patients; 3296 females and 365 males (9.03:1) and the median age was 30 years (17-79 years), disease duration 4 years (0-75 years) while the median age at disease onset was 25 years (4-75 years). The overall estimated prevalence of adult SLE in Egypt was 6.1/100,000 population (1.2/100,000 males and 11.3/100,000 females).There were 316 (8.6%) juvenile-onset (Jo-SLE) and 3345 adult-onset (Ao-SLE). Age at onset was highest in South and lowest in Cairo (p < 0.0001). SLE in Egypt had a wide variety of clinical and immunological manifestations, with some similarities with that in other nations and differences within the same country. The clinical characteristics, autoantibodies and comorbidities are comparable between Ao-SLE and Jo-SLE. The frequency of various clinical and immunological manifestations varied between gender. Additional studies are needed to determine the underlying factors contributing to gender and age of onset differences.


Abnormal coronary microvascular endothelial function in humans with asymptomatic left ventricular dysfunction.
Coronary endothelial dysfunction may potentially lead to myocardial ischemia and to the progression of heart failure. Though endothelial dysfunction is associated with advanced heart failure in humans, relatively little is known regarding their temporal relationship. Thus, the current study was designed to test the hypothesis that coronary endothelial dysfunction is present in patients with asymptomatic left ventricular dysfunction. Three hundred patients without symptoms of heart failure, with normal or mildly diseased coronary arteries at angiography underwent coronary vascular reactivity evaluation using intracoronary adenosine, acetylcholine (ACH) and nitroglycerin. Patients were divided into 2 groups based on the left ventricular ejection fraction (EF): patients with asymptomatic left ventricular dysfunction (ALVD), EF <45% (n = 11); and patients with EF > or =45% (n = 289, controls). Except for a lower high-density lipoprotein level in patients with ALVD, there were no significant differences between the groups in regards to conventional cardiovascular risk factors. There was no difference in the change (mean +/- SE) in epicardial diameter in response to ACH (-21.7% +/- 7.2% vs -13.8% +/- 1.5%, P =.3). The change in coronary blood flow in response to ACH was significantly attenuated in the patients with ALVD when compared to the controls (-18.5% +/- 14.9% vs 74.0% +/- 7.2%, P <.013). By multivariate analysis, EF was an independent predictor of coronary microvascular dilation with ACH (P <.001). The current study demonstrates that coronary microvascular endothelial dysfunction is present in ALVD. Thus, coronary endothelial dysfunction may be an early event in the pathophysiology of heart failure.


Analysis of cell movements in zebrafish embryos: morphometrics and measuring movement of labeled cell populations in vivo.
Cell movements occur in all phases of animal life from embryogenesis, to maintaining adult organs, to comprising a critical component of pathology. During gastrulation, cells demonstrate a repertoire of morphogenetic movements coordinated with fate inductions to sculpt the embryonic body. The morphogenetic behaviors, underlying mechanisms, and their control, are the subject of much current study. External development of the transparent zebrafish embryo, the abundance of mutations influencing cell movements, as well as a range of observation and manipulation methods, make the zebrafish valuable for cell movement studies. This chapter offers a conceptual background for analysis of gastrulation cell movements by reviewing how region specific cell movements shape the wild-type zebrafish embryo, and how defective morphogenetic movements alone or in combination with altered cell fate specification distort the body plans of known zebrafish mutants. We furnish methods for the morphometric analysis of embryonic shape and organ rudiments in live and fixed embryos, and present data collected from live wild-type, dorsoventral patterning (somitabun and chordino) and convergence and extension (knypek and trilobite) classes of mutants. We provide a method for quantitative assessment of the movements of cell populations in vivo, and a method for determining whether cell fate and/or movement are disturbed.


Affect Balance and Relationship With Well-Being in Nursing Home Residents With Dementia.
The purpose of this exploratory study was to determine whether the balance of positive to negative affect can discriminate states of well-being in nursing home residents with dementia and whether affect balance is associated with activity engagement. Baseline data from a randomized clinical trial were used in this secondary analysis. Participants were 128 residents recruited from 9 nursing homes located in Pennsylvania. Participants were primarily female, Caucasian, and had a mean age of 86 years. Measures of agitation and affect were taken from video recordings of 10 observational sessions. Measures of engagement and self-reported mood were taken in real time. Ten percent of participants were categorized as having high well-being. These participants had a mean ratio of positive-negative affect of 2.21 (±0.50), a ratio significantly different than that of participants with moderate or low well-being. Affect balance was related to greater engagement in activity (r= .23;P= .008).


Escalating impacts of climate extremes on critical infrastructures in Europe.
Extreme climatic events are likely to become more frequent owing to global warming. This may put additional stress on critical infrastructures with typically long life spans. However, little is known about the risks of multiple climate extremes on critical infrastructures at regional to continental scales. Here we show how single- and multi-hazard damage to energy, transport, industrial, and social critical infrastructures in Europe are likely to develop until the year 2100 under the influence of climate change. We combine a set of high-resolution climate hazard projections, a detailed representation of physical assets in various sectors and their sensitivity to the hazards, and more than 1100 records of losses from climate extremes in a prognostic modelling framework. We find that damages could triple by the 2020s, multiply six-fold by mid-century, and amount to more than 10 times present damage of €3.4 billion per year by the end of the century due only to climate change. Damage from heatwaves, droughts in southern Europe, and coastal floods shows the most dramatic rise, but the risks of inland flooding, windstorms, and forest fires will also increase in Europe, with varying degrees of change across regions. Economic losses are highest for the industry, transport, and energy sectors. Future losses will not be incurred equally across Europe. Southern and south-eastern European countries will be most affected and, as a result, will probably require higher costs of adaptation. The findings of this study could aid in prioritizing regional investments to address the unequal burden of impacts and differences in adaptation capacities across Europe.


Therapeutic approaches to polyglutamine diseases: combating protein misfolding and aggregation.
Polyglutamine diseases are autosomal dominant, late-onset neurodegenerative disorders. Expansion of a polyglutamine (polyQ) tract above a threshold size leads to misfolding and aggregation and eventual intracellular accumulation of the disease-specific protein. To date, only symptomatic treatments of limited effectiveness are available. Various research strategies aim to interfere with known steps in the pathomechanism. Protein misfolding and aggregation probably occur very early in the cascade of pathogenic events and are therefore attractive targets for potential drug treatment. Misfolding of polyQ proteins may either be prevented by drugs that stabilize the native conformation or via induction of cellular chaperones. Several amyloid-binding dyes as well as small molecules that inhibit polyQ protein aggregation have been identified in compound screens and may be entered into drug development. Small molecule inhibitors of further pathogenic phenomena like transcriptional repression, excitotoxicity, mitochondrial dysfunction, and neuronal cell death have been tested in vitro and in vivo. The first drugs have now reached clinical trial stage. More general studies of how putative steps in the pathomechanism can be modulated will yield further insights into the pathogenesis of polyQ disorders.


Sustained efficacy and safety of infliximab in psoriasis: a retrospective study of 73 patients.
Infliximab inhibits T-cell activation by binding tumor necrosis factor-alpha (TNF-alpha). This medication is widely used in the US for treatment of psoriasis as an off-label indication. The durability of its effect is largely unknown. To assess the proportion of patients still on infliximab 12 months after initiation of therapy for psoriasis. Retrospective chart review analysis of 73 patients with psoriasis treated with infliximab for at least 12 months or those who experienced treatment failure in less than 12 months. The point where infusions were deemed to no longer be efficacious was determined by physician's global assessment (PGA). Of 73 patients who started infliximab at least 12 months prior to this chart review, 22 (30.1%) had discontinued treatment secondary to loss of efficacy. Thirty seven patients (50.7%) had no loss of efficacy and continued to receive infusions. Two patients (2.7%) discontinued due to loss of efficacy after greater than 12 months. Of the 22 patients who discontinued treatment due to loss of efficacy, 2 were on concomitant methotrexate (5-7.5 mg/wk) therapy. Of the 37 patients still receiving treatment with no loss of efficacy at 12 months, 3 patients were on concomitant methotrexate therapy. Five patients (6.8%) discontinued secondary to minor adverse events: sinus infection (1), acne (1), fever (1), arthralgia (1), and transient rash (1). Three patients (4.1%) discontinued due to major adverse events: reactivation of tuberculosis (1), breast cancer (1), and gastrointestinal bleeding (1). One patient discontinued infliximab secondary to concerns of possible lymphoma risk (though there were no signs of symptoms of disease on examination), and 3 patients discontinued due to insurance concerns. Infliximab treatment resulted in significant improvement in psoriasis, with 37 out of 73 patients (50.7%) experiencing no loss of efficacy. This longitudinal retrospective chart review demonstrates continued benefit of infliximab infusions in about half of patients after 1 year, though a notable percentage (30.1%) experienced loss of efficacy as determined by physician's global assessment (PGA) and a number of others discontinued due to adverse events or insurance difficulty.


Butyrate stimulates the secretion of apolipoprotein (apo) A-I and apo B100 by the human hepatoma cell line Hep G2. Induction of apo A-I mRNA with no change of apo B100 mRNA.
Addition of sodium butyrate to the culture medium of the human hepatoma cell line Hep G2 resulted in a time- and dose-dependent increase in the secretion of apolipoprotein A-I (apo A-I) and apolipoprotein B100 (apo B100). After a 24 h preincubation period, a 2.4- and 2.2-fold increase in the secretion of apo A-I and apo B100 respectively was obtained during the next 24 h in the presence of 2 mM-sodium butyrate. Secretion of albumin, fibrinogen or [35S]methionine-labelled newly synthesized proteins was unaffected or only marginally affected, indicating that the effect of butyrate on apo A-I and apo B100 is not part of a general effect on protein synthesis and secretion. In structure-function studies, butyrate was found to be the most potent inducer among various straight-chain carboxylic acids. Hydroxylated, aminated and otherwise modified butyrate derivatives were inactive. The enhanced accumulation of apo A-I and apo B100 in the culture medium could not be explained by changes in the uptake and degradation of the synthesized apolipoproteins or by alterations in the secretion of possible intracellular pools. In addition, [35S]methionine incorporation studies indicated that synthesis and/or secretion of newly synthesized apo A-I and apo B100 is enhanced in the presence of butyrate. The apo A-I mRNA level was increased 2.3-fold upon treatment with 2 mM-butyrate for 48 h, suggesting regulation at (post-)transcriptional level. In contrast, no change in the level of apo B100 mRNA in butyrate-treated cells was observed, indicating regulation at translational or co- or post-translational level. We propose that the effect of butyrate on the secretion of apo A-I and apo B100 by Hep G2 results from two different regulatory mechanisms.


Magnetic characterization of isolated candidate vertebrate magnetoreceptor cells.
Over the past 50 y, behavioral experiments have produced a large body of evidence for the existence of a magnetic sense in a wide range of animals. However, the underlying sensory physiology remains poorly understood due to the elusiveness of the magnetosensory structures. Here we present an effective method for isolating and characterizing potential magnetite-based magnetoreceptor cells. In essence, a rotating magnetic field is employed to visually identify, within a dissociated tissue preparation, cells that contain magnetic material by their rotational behavior. As a tissue of choice, we selected trout olfactory epithelium that has been previously suggested to host candidate magnetoreceptor cells. We were able to reproducibly detect magnetic cells and to determine their magnetic dipole moment. The obtained values (4 to 100 fAm(2)) greatly exceed previous estimates (0.5 fAm(2)). The magnetism of the cells is due to a μm-sized intracellular structure of iron-rich crystals, most likely single-domain magnetite. In confocal reflectance imaging, these produce bright reflective spots close to the cell membrane. The magnetic inclusions are found to be firmly coupled to the cell membrane, enabling a direct transduction of mechanical stress produced by magnetic torque acting on the cellular dipole in situ. Our results show that the magnetically identified cells clearly meet the physical requirements for a magnetoreceptor capable of rapidly detecting small changes in the external magnetic field. This would also explain interference of ac powerline magnetic fields with magnetoreception, as reported in cattle.


Cardiac effects of beta-2 adrenoceptor stimulation with intracoronary procaterol in the absence and presence of regional myocardial ischemia in dogs.
To evaluate consequences of cardiac beta-2 adrenoceptor stimulation on coronary hemodynamics and regional myocardial function assessed by sonomicrometry in the normal and regionally ischemic heart, the effects of administration of procaterol, a selective beta-2 adrenoceptor agonist, into the left circumflex coronary artery (LCX) were examined in the absence and presence of a stenosis of the LCX in anesthetized open-chest dogs. The stenosis of the LCX was made sufficient to decrease percent segment shortening in the LCX-perfused region to around 2 to 3%. When coronary stenosis was absent, intracoronary infusion of procaterol (6.7 ng/min for 15 min) produced significant increases in LCX flow and myocardial segment shortening in the infused region without changes in global hemodynamics. During coronary stenosis, on the contrary, intracoronary procaterol at the same dose significantly deteriorated regional myocardial dysfunction without changing LCX flow, global hemodynamics and cardiac lactate metabolism. These changes induced by procaterol were not observed in the dogs treated with a selective beta-2 antagonist, erythro-(+/-)-1-(7-methylindan-4-yloxy)-3-isopropylaminob utan-2-ol. These results suggest the presence of functional beta-2 adrenoceptors in the canine heart both with and without myocardial ischemia.


[Nutritional status of children ten years of age or under in a settlement organized by the "Landless Peasants' Movement" in Porto Calvo, Alagoas, Brazil]
This study describes the nutritional status of 357 children (0-10 years) living in Fazenda Conceição, an area occupied by the "Landless Peasants' Movement" and recently expropriated for land reform purposes by the Brazilian National Institute for Land Settlement and Agrarian Reform. The prevalence of nutritional deficits (Z < -2 standard deviations from the NCHS median anthropometric standard) relating to body- weight-for-age, height-for-age, and body-weight-for-height were the following, respectively: 19.6%, 39.8%, and 2%, thus higher than the figures published recently for the rural areas of the State of Alagoas as a whole (8.4%, 22.7%, and 1.3%). These findings suggest that children are these affected by dwarfism. Despite this condition being widely acknowledged as one of the most visible manifestations of malnutrtion in developing countries, it is important to stress that the concentration of land tenure, an integral part of the income-concentrating development model adopted by Brazil, is also a major factor in determining such a health profile. There is thus an urgent need for policy-makers to reallocate resources for immediate intervention in such farm communities, in order to reduce the dire consequences of a situation of this magnitude.


Balance between solitude and socializing: everyday solitude time both benefits and harms well-being.
Two literatures argue that time alone is harmful (i.e., isolation) and valuable (i.e., positive solitude). We explored whether people benefit from a balance between their daily solitude and social time, such that having 'right' quantities of both maximizes well-being. Participants (n = 178) completed a 21-day diary study, which quantified solitude time in hours through reconstructing daily events. This procedure minimized retrospective bias and tested natural variations across time. There was no evidence for a one-size-fits-all 'optimal balance' between solitude and social time. Linear effects suggested that people were lonelier and less satisfied on days in which they spent more hours in solitude. These detrimental relations were nullified or reduced when daily solitude was autonomous (choiceful) and did not accumulate across days; those who were generally alone more were not, on the whole, lonelier. On days in which people spent more time alone they felt less stress and greater autonomy satisfaction (volitional, authentic, and free from pressure). These benefits were cumulative; those who spent more time alone across the span of the study were less stressed and more autonomy satisfied overall. Solitude time risks lowering well-being on some metrics but may hold key advantages to other aspects of well-being. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on June 1, 2022. The protocol, as accepted by the journal, can be found at: https://doi.org/10.17605/OSF.IO/5KXQ3 .


Recent advances in mesenchymal stem cell immunomodulation: the role of microvesicles.
Mesenchymal stem cells are the most widely used cell phenotype for therapeutic applications, the main reasons being their well-established abilities to promote regeneration of injured tissues and to modulate immune responses. Efficacy was reported in the treatment of several animal models of inflammatory and autoimmune diseases and, in clinical settings, for the management of disorders such as GVHD, systemic lupus erythematosus, multiple sclerosis, and inflammatory bowel disease. The effects of mesenchymal stem cells are believed to be largely mediated by paracrine signals, and several secreted molecules have been identified as contributors to the net biological effect. Recently, it has been recognized that bioactive molecules can be shuttled from cell to cell packed in microvesicles, tiny portions of cytoplasm surrounded by a membrane. Coding and noncoding RNAs are also carried in such microvesicles, transferring relevant biological activity to target cells. Several reports indicate that the regenerative effect of mesenchymal stem cells can be reproduced by microvesicles isolated from their culture medium. More recent evidence suggests that the immunomodulatory effects of mesenchymal stem cells are also at least partially mediated by secreted microvesicles. These findings allow better understanding of the mechanisms involved in cell-to-cell interaction and may have interesting implications for the development of novel therapeutic tools in place of the parent cells.


Double-Wire versus Single-Wire Sternal Closure in Obese Patients: a Randomized Prospective Study.
Background Sternal instability after coronary artery bypass grafting (CABG) is a serious complication. Obese patients are at high risk for sternal instability after CABG. This study was conducted to assess the positive impact of double-wire sternal closure on sternal instability. Methods A total of 200 obese patients with a body mass index ≥ 30 kg/m2 undergoing isolated CABG with left internal mammary artery (LIMA) graft were randomly assigned to sternal closure either by eight single wires (n = 100) or by a combination of four double wires and four single wires. Results There was a total of 21 cases with sternal instability: 5 cases (i.e., 5%) in the double-wire group versus 16 cases (16%) in the single-wire group (p = 0.019). Logistic regression analysis showed sternal closure via double wires as an independent protection factor (odds ratio [OR]: 0.276; p = 0.029). Smoking (OR: 5.5; p = 0.006) and postoperative delirium (OR: 3.5; p = 0.033) turned out to be independent risk factors for the development of sternal instability. Conclusion Double-wire sternal closure significantly reduces postoperative sternal instability in obese patients undergoing isolated CABG with LIMA graft.


How men and women with heart disease seek care: the delay experience.
Coronary heart disease (CHD) is the leading cause of death among American men and women. Much research has focused on CHD in men while less is known about the disease in women. Traditionally, research protocols have excluded women or have not addressed gender differences in the experience of the disease. A major factor contributing to morbidity and mortality is delay in seeking medical care when experiencing symptoms of CHD. The purpose of this study was to examine the experiences of men and women with symptoms of CHD in seeking care. A sample of 121 men and women admitted to one of two cardiac units in an urban hospital were interviewed using a questionnaire concerning demographics and factors related to delay. The study demonstrated that women were more likely than men to contact a family member when experiencing symptoms. Smokers and previous smokers with symptoms were less likely to delay seeking care. The findings suggest important differences in the experience of CHD among men and women. Implications for practice and directions for further research are discussed. The information gained can be used to develop interventions that reduce delay and improve health care for men and women with CHD.


Molecular Comparison of Bacterial Communities on Peripheral Intravenous Catheters and Matched Skin Swabs.
Skin bacteria at peripheral intravenous catheter (PIVC) insertion sites pose a serious risk of microbial migration and subsequent colonisation of PIVCs, and the development of catheter related bloodstream infections (CRBSIs). Common skin bacteria are often associated with CRBSIs, therefore the bacterial communities at PIVC skin sites are likely to have major implications for PIVC colonisation. This study aimed to determine the bacterial community structures on skin at PIVC insertion sites and to compare the diversity with associated PIVCs. A total of 10 PIVC skin site swabs and matching PIVC tips were collected by a research nurse from 10 hospitalised medical/surgical patients at catheter removal. All swabs and PIVCs underwent traditional culture and high-throughput sequencing. The bacterial communities on PIVC skin swabs and matching PIVCs were diverse and significantly associated (correlation coefficient = 0.7, p<0.001). Methylobacterium spp. was the dominant genus in all PIVC tip samples, but not so for skin swabs. Sixty-one percent of all reads from the PIVC tips and 36% of all reads from the skin swabs belonged to this genus. Staphylococcus spp., (26%), Pseudomonas spp., (10%) and Acinetobacter spp. (10%) were detected from skin swabs but not from PIVC tips. Most skin associated bacteria commonly associated with CRBSIs were observed on skin sites, but not on PIVCs. Diverse bacterial communities were observed at skin sites despite skin decolonization at PIVC insertion. The positive association of skin and PIVC tip communities provides further evidence that skin is a major source of PIVC colonisation via bacterial migration but microbes present may be different to those traditionally identified via culture methods. The results provide new insights into the colonisation of catheters and potential pathogenesis of bacteria associated with CRBSI, and may assist in developing new strategies designed to reduce the risk of CRBSI.


The anticancer effect of phospho-tyrosol-indomethacin (MPI-621), a novel phosphoderivative of indomethacin: in vitro and in vivo studies.
We have synthesized a novel derivative of indomethacin, phospho-tyrosol-indomethacin (PTI; MPI-621), and evaluated its anticancer efficacy in vitro and in vivo. PTI inhibited the growth of human colon, breast and lung cancer cell lines 6-30-fold more potently than indomethacin. In vivo, in contrast to indomethacin that was unable to inhibit colon cancer xenograft growth, PTI inhibited the growth of colon (69% at 10mg/kg/day, P < 0.01) and lung (91% at 15mg/kg/day, P < 0.01) subcutaneous cancer xenografts in immunodeficient mice, suppressing cell proliferation by 33% and inducing apoptosis by 75% (P < 0.05, for both). Regarding its pharmacokinetics in mice, after a single intraperitoneal injection of PTI, its plasma levels reached the maximum concentration (Cmax = 46 μM) at 2h (Tmax) and became undetectable at 4h. Indomethacin is the major metabolite of PTI, with plasma Cmax = 378 μM and Tmax = 2.5h; it became undetectable 24h postadministration. The cellular uptake of PTI (50-200 μM) at 6h was about 200-fold greater than that of indomethacin. Regarding its safety, PTI had no significant genotoxicity, showed less gastrointestinal toxicity than indomethacin and presented no cardiac toxicity. Mechanistically, PTI suppressed prostaglandin E2 production in A549 human lung cancer cells and strongly inhibited nuclear factor-κB activation in A549 xenografts. These findings indicate that PTI merits further evaluation as an anticancer agent.


Cobalt-catalyzed asymmetric hydroboration of aryl ketones with pinacolborane.
The highly enantioselective cobalt-catalyzed hydroboration reaction of aryl ketones with HBpin was developed using iminopyridine oxazoline ligands. Halides, amines, ethers, sulfides, esters and amides are well tolerated under the mild reaction conditions, demonstrating its synthetic advantage. Substituted diaryl ketones could also be hydroborated with high enantioselectivity.


Immunosuppressive activity of staphylococcal enterotoxin B. I. Characterization of staphylococcal enterotoxin-B-induced suppressor cells.
Staphylococcal enterotoxin B (SEB) binds specifically to major histocompatibility complex class II molecules on the surface of accessory cells and stimulates virtually all T cells bearing certain, but not all, T cell-receptor V beta alleles. We have previously shown that this superantigen is a potent inducer of multiple regulatory T cell populations. In the present report we show that SEB induces a population of suppressor T cells which inhibits the generation of alloantigen-induced cytotoxic T cell activity. Using both negative- and positive-selection analysis, we found that this suppressor population is a CD4- CD8- CD5+ IL-2R+ T cell. This cell population inhibited both syngeneic and allogeneic cytotoxic T lymphocyte activity, but the cell population which inhibited allogeneic CTL activity was radiation sensitive. In addition, allogeneic SEB-primed cells appeared to develop cytolytic activity as a result of the additional stimulation in the mixed-lymphocyte reaction culture. The relationship of the SEB-primed CD4- CD8- CD5+ T cells to related regulatory T cell populations is discussed.


Cholangitis Definition and Treatment after Kasai Hepatoportoenterostomy for Biliary Atresia: A Delphi Process and International Expert Panel.
(1) Background: Acute cholangitis during the first year after Kasai hepatoportoenterostomy (HPE) has a negative impact on patient and native liver survival. There are no consistent guidelines for the definition, treatment, and prophylaxis of cholangitis after HPE. The aim of this study was to develop definition, treatment, and prophylaxis guidelines to allow for expeditious management and for standardization in reporting. (2) Methods: the Delphi method, an extensive literature review, iterative rounds of surveys, and expert panel discussions were used to establish definition, treatment, and prophylaxis guidelines for cholangitis in the first year after HPE. (3) Results: Eight elements (pooled into two groups: clinical and laboratory/imaging) were identified to define cholangitis after HPE. The final proposed definitions for suspected and confirmed cholangitis are a combination of one element, respectively, two elements from each group; furthermore, the finding of a positive blood culture was added to the definition of confirmed cholangitis. The durations for prophylaxis and treatment of suspected and confirmed cholangitis were uniformly agreed upon by the experts. (4) Conclusions: for the first time, an international consensus was found for guidelines for definition, treatment, and prophylaxis for cholangitis during the first year after Kasai HPE. Applicability will need further prospective multicentered studies.


Deletion of the activating NKG2C receptor and a functional polymorphism in its ligand HLA-E in psoriasis susceptibility.
Psoriasis is an inflammatory, immune-mediated disease of the skin. Several studies have suggested that natural killer (NK) cells and their receptors may be important for its pathogenesis. Here, we examined whether deletion of the activating natural killer receptor gene NKG2C, which has a frequency of 20% in the European population, was associated with psoriasis susceptibility. The NKG2C deletion and a functional polymorphism in its ligand HLA-E were genotyped in a Caucasian cohort of 611 psoriasis cases and 493 controls. We found that the NKG2C deletion was significantly increased in cases compared with controls [0.258 vs 0.200, P = 0.0012, OR = 1.43 (1.15-1.79)]. The low-expressing HLA-E*01:01 allele was associated with psoriasis (P = 0.0018), although this association was dependent on HLA-C. Our findings support a potential immunoregulatory role for NK cells in psoriasis and suggest the importance of future studies to investigate the contribution of NK cells and their regulatory receptors to the pathogenesis of psoriasis.


Screening of Drug Repositioning Candidates for Castration Resistant Prostate Cancer.
Purpose: Most prostate cancers (PCs) initially respond to androgen deprivation therapy (ADT), but eventually many PC patients develop castration resistant PC (CRPC). Currently, available drugs that have been approved for the treatment of CRPC patients are limited. Computational drug repositioning methods using public databases represent a promising and efficient tool for discovering new uses for existing drugs. The purpose of the present study is to predict drug candidates that can treat CRPC using a computational method that integrates publicly available gene expression data of tumors from CRPC patients, drug-induced gene expression data and drug response activity data. Methods: Gene expression data from tumoral and normal or benign prostate tissue samples in CRPC patients were downloaded from the Gene Expression Omnibus (GEO) and differentially expressed genes (DEGs) in CRPC were determined with a meta-signature analysis by a metaDE R package. Additionally, drug activity data were downloaded from the ChEMBL database. Furthermore, the drug-induced gene expression data were downloaded from the LINCS database. The reversal relationship between the CRPC and drug gene expression signatures as the Reverse Gene Expression Scores (RGES) were computed. Drug candidates to treat CRPC were predicted using summarized scores (sRGES). Additionally, synergic effects of drug combinations were predicted with a Target Inhibition interaction using the Minimization and Maximization Averaging (TIMMA) algorithm. Results: The drug candidates of sorafenib, olaparib, elesclomol, tanespimycin, and ponatinib were predicted to be active for the treatment of CRPC. Meanwhile, CRPC-related genes, in this case MYL9, E2F2, APOE, and ZFP36, were identified as having gene expression data that can be reversed by these drugs. Additionally, lenalidomide in combination with pazopanib was predicted to be most potent for CRPC. Conclusion: These findings support the use of a computational reversal gene expression approach to identify new drug and drug combination candidates that can be used to treat CRPC.


Large Spin Perturbation Theory for Conformal Field Theories.
We consider conformal field theories around points of large twist degeneracy. Examples of this are theories with weakly broken higher spin symmetry and perturbations around generalized free fields. At the degenerate point we introduce twist conformal blocks. These are eigenfunctions of certain quartic operators and encode the contribution, to a given four-point correlator, of the whole tower of intermediate operators with a given twist. As we perturb around the degenerate point, the twist degeneracy is lifted. In many situations this breaking is controlled by inverse powers of the spin. In such cases the twist conformal blocks can be decomposed into a sequence of functions which we systematically construct. Decomposing the four-point correlator in this basis turns crossing symmetry into an algebraic problem. Our method can be applied to a wide spectrum of conformal field theories in any number of dimensions and at any order in the breaking parameter. As an example, we compute the spectrum of various theories around generalized free fields.


Extrahepatic expression of the N-acetylation polymorphism toward arylamine carcinogens in tumor target organs of an inbred rat model.
An N-acetylation polymorphism is described that is expressed toward arylamine carcinogens in tumor target organs of an inbred rat model. High levels (rapid acetylator phenotype) of arylamine carcinogen N-acetyltransferase activity were observed in kidney, colon, prostate and urinary bladder cytosols derived from Fischer (F-344) inbred rats, the strain most commonly used for tumor bioassay studies and the strain most particularly used in arylamine-induced colon and prostate cancer studies. Significantly lower (slow acetylator phenotype) levels of arylamine carcinogen N-acetyltransferase activity were observed in corresponding tissue cytosols derived from Wistar-Kyoto inbred rats. Intermediate levels of arylamine carcinogen N-acetyltransferase activity significantly different from both the parental strains were observed in F1 hybrids of the parental strains, consistent with codominant expression of two alleles at a single gene locus. The arylamine substrates exhibiting the acetylator phenotype-dependent N-acetyltransferase activities included p-aminobenzoic acid, p-aminosalicylic acid, p-phenetidine, p-aminophenol, 2-aminofluorene, 3,2'-dimethyl-4-aminobiphenyl, beta-naphthylamine and 4-aminobiphenyl, but not procainamide. Highest levels of arylamine carcinogen N-acetyltransferase were expressed consistently in colon cytosol, but expression of the N-acetylation polymorphism toward arylamine carcinogens was observed in each (kidney, colon, prostate and urinary bladder) of the tumor target organs. The expression of the N-acetylation polymorphism in tumor target organs suggests that the inbred rat model will be useful in assessing the role of acetylator phenotype in arylamine-induced cancers of the colon and prostate.


How patients with depressive symptoms view their condition: a qualitative study.
Depressive symptoms are common in primary care, yet considerable professional controversy exists about appropriate management including the effectiveness of treatments. In addition, avoiding prescribing antidepressants at least initially is recommended. Views of patients themselves should therefore be particularly important in agreeing management strategies. To examine lay beliefs about depressive symptoms in primary care. A total of 23 semi-structured interviews were conducted with patients scoring positively for depression on the Hospital Anxiety and Depression Score in a primary care setting. Differentiating 'depression' from understandable reactions to adversity was difficult for patients. The wide range of consequences discussed included adverse effects on others, difficulties coping with feeling out of control and loss of self-identity. Negative images of depression, such as depression being a 20th century phenomenon, were pervasive. Views about medication varied. Various management strategies described included strategies of detachment, engagement in activities and 'blotting out' symptoms. Patients' views about depressive symptoms are significantly different from conventional medical views. A 'disease management approach' fits uncomfortably with patients' experiences. Acknowledging feelings of loss of control and loss of self-identity in consultations may be useful. The wide employment of techniques patients use to control their disorders, such as support from others, engagement in activities and working at relationships, may be useful to encourage in consultations as alternatives to the use of antidepressant medication.


Risk factors for premature termination of treatment at a child and family mental health clinic.
Premature termination of treatment amongst children and families attending mental health services is a significant problem for both outcomes research and clinical practice in South Africa and elsewhere. This study investigated factors that are associated with premature termination of treatment at a public service child and family clinic in Cape Town. A retrospective archival analysis of clinic files from 2002-2009 was conducted. Administrative, child and family factors, and type of treatment were explored as risk factors for premature termination. A single-parent household and the presence of a child or oppositional defiant disorder were risk factors for premature termination of treatment, while the presence of a maternal psychiatric diagnosis was associated with a lower likelihood of terminating treatment prematurely. Conducting a scholastic assessment with the child was associated with a lower risk of premature termination, while there was a trend towards a higher risk of premature termination when individual child therapy was the recommended treatment. This study offers recommendations for how these findings could assist South African clinicians to enhance client retention in child and family mental health services, and suggestions for future research.


High temperature-induced sterility in the female Nile tilapia, Oreochromis niloticus.
High temperature treatments induce germ cell loss in gonads of vertebrate animals, including fish. It could be a reliable source for induction of sterility if the treatments led to a permanent loss of germ cells. Here we report that heat treatment at 37 °C for 45-60 days caused a complete loss of germ cells in female Nile tilapia, Oreochromis niloticus, and that sterility was achieved in fish at all stages of their life cycle. Unlike previous observations, germ cells did not repopulate even after returning them to the water at control conditions suggesting permanent depletion of germ cells. Gonadal somatic cells immunopositive for 3β-hydroxysteroid dehydrogenase (3β-HSD) were clustered at one end of the germ cell depleted gonads close to the blood vessel. Serum level of testosterone, 11-ketotestosterone, and 17β-estradiol was significantly decreased in sterile fish compared to control. Body weight of sterile fish was higher than control fish at the end of experiment. Our observations of increased growth and permanent sterilization in the high temperature-treated fish suggest that this method could be an appropriate and eco-friendly tool for inducing sterility in fish with a higher thermal tolerance.


Information flow and information production in a population system.
An approach aiming to quantify the dynamics of information within a population is developed based on the mapping of the processes underlying the system's evolution into a birth and death type stochastic process and the derivation of a balance equation for the information entropy. Information entropy flux and information entropy production are identified and their time-dependent properties, as well as their dependence on the parameters present in the problem, are analyzed. States of minimum information entropy production are shown to exist for appropriate parameter values. Furthermore, uncertainty and information production are transiently intensified when the population traverses the inflexion point stage of the logisticlike growth process.


Relationship of Performance Measures and Muscle Activity between a 180° Change of Direction Task and Different Countermovement Jumps.
The ability to rapidly perform change of direction (COD) is crucial for performance in Soccer. COD speed is thought to share similarities with countermovement jumps in kinematics and muscle activation. Thus, the objective of the current study was to investigate the relationship between muscle activities in performance measures of a modified 505-agility test and different countermovement jumps. Twenty-one experienced soccer players performed a COD test including the 505-agility test and uni- and bi-lateral horizontal and vertical countermovement jumps. The main findings were that the vertical bilateral and horizontal unilateral countermovement jump were able to predict total time to complete the COD, but not 505-agility time. Muscle activity in the COD and countermovement jumps was only distinguished by a higher peak muscle activity for the adductor longus, semitendinosus and biceps femoris in the COD to stabilize the hip and decelerate knee joint movements when turning compared with the jumps. Conclusively, the relationship between performance in countermovement jumps and total time to complete the COD test was due to longer sprint distances, which makes the distinction between performances bigger. Peak muscle activity of most muscles is similar between the jumps and the COD step, indicating similar muscular demands between these activities.


Low-dose eplerenone decreases left ventricular mass in treatment-resistant hypertension.
Mineralocorticoid receptor antagonists are increasingly used in patients with treatment-resistant hypertension (TRH). There is experimental evidence for blood pressure (BP) independent effects of mineralocorticoid receptor blockade on cardiovascular target organ damage. We hypothesized that low-dose eplerenone (50 mg) will reduce left ventricular mass (LVM) beyond its BP-lowering effects. We performed a randomized, double-blind, placebo-controlled, parallel group study in 51 patients with TRH. Patients were allocated to receive either eplerenone 50 mg or placebo for 6 months, while other antihypertensive agents could be added in both groups to achieve a BP target of less than 140/90 mmHg. LVM was assessed by MRI before and after treatment. Baseline office BP was similar in the eplerenone and the placebo group (166 ± 21/91 ± 15 versus 159 ± 19/94 ± 8 mmHg, n.s.). BP was similarly reduced in the eplerenone versus the placebo group (-35 ± 20/-15 ± 11 versus -30 ± 19/-13 ± 7 mmHg, n.s.). However, LVM was reduced only in the eplerenone group (from 155 ± 33 to 136 ± 33 g, P < 0.001), but not in the placebo group (152 ± 32 versus 148 ± 38 g, P = 0.45). Despite similar BP-lowering, only patients with TRH who were allocated to eplerenone experienced a reduction of LVM. Thus, our data suggest that in patients with TRH, mineralocorticoid receptor antagonists should be used preferentially in order to achieve an effective reduction of LVM along with the improvement of BP control.


Neurocognitive functioning in overweight and obese patients with bipolar disorder: data from the Systematic Treatment Optimization Program for Early Mania (STOP-EM).
Obesity is frequent in people with bipolar I disorder (BD I) and has a major impact on the course of the illness. Although obesity negatively influences cognitive function in patients with BD, its impact in the early phase of the disorder is unknown. We investigated the impact of overweight and obesity on cognitive functioning in clinically stable patients with BD recently recovered from their first manic episode. Sixty-five patients with BD (25 overweight or obese and 40 normal weight) recently remitted from a first episode of mania and 37 age- and sex-matched healthy control. subjects (9 overweight or obese and 28 normal weight) were included in this analysis from the Systematic Treatment Optimization Program for Early Mania (commonly referred to as STOP-EM). All subjects had their cognitive function assessed using a standard neurocognitive battery. We compared cognitive function between normal weight patients, overweight-obese patients, and normal weight healthy control subjects. There was a negative affect of BD diagnosis on the domains of attention, verbal memory, nonverbal memory, working memory, and executive function, but we were unable to find an additional effect of weight on cognitive functioning in patients. There was a trend for a negative correlation between body mass index and nonverbal memory in the patient group. These data suggest that overweight-obesity does not negatively influence cognitive function early in the course of BD. Given that there is evidence for a negative impact of obesity later in the course of illness, there may be an opportunity to address obesity early in the course of BD.


Best Splinting Methods in Case of Dental Injury-A Literature Review.
The objective of this manuscript was to review the literature on dental trauma splints and discuss materials used for splinting injured teeth in terms of their properties and conditions that are required for optimal stabilization. A literature search was conducted in the PubMed database with the keywords: "trauma splints", "dental trauma" and "traumatic dental injuries". The search was limited to English language publications. 42 publications fulfilled the inclusion criteria and were in accordance with the current recommendations. Optimal splinting of the teeth after trauma is one of the main predictors for pulpal and periodontal healing. The splints stabilize and protect the teeth, creating favorable conditions for the regeneration of the supporting tissues. Their application and removal should be easy and fast without any additional irritating of the surrounding tissues. The materials used to stabilize the injured teeth should keep the tooth in the original position, allowing for its physiological mobility.


Solution structure of TbTFIIS2-2 PWWP domain from Trypanosoma brucei and its binding to H4K17me3 and H3K32me3.
Posttranslational modifications (PTMs) of core histones, such as histone methylation, play critical roles in a variety of biological processes including transcription regulation, chromatin condensation and DNA repair. In T. brucei, no domain recognizing methylated histone has been identified so far. TbTFIIS2-2, as a potential transcription elongation factors in T. brucei, contains a PWWP domain in the N-terminus which shares low sequence similarity compared with other PWWP domains and is absent from other TFIIS factors. In the present study, the solution structure of TbTFIIS2-2 PWWP domain was determined by NMR spectroscopy. TbTFIIS2-2 PWWP domain adopts a global fold containing a five-strand β-barrel and two C-terminal α-helices similar to other PWWP domains. Moreover, through systematic screening, we revealed that TbTFIIS2-2 PWWP domain is able to bind H4K17me3 and H3K32me3. Meanwhile, we identified the critical residues responsible for the binding ability of TbTFIIS2-2 PWWP domain. The conserved cage formed by the aromatic amino acids in TbTFIIS2-2 PWWP domain is essential for its binding to methylated histones.


Association between deliberate self-harm-related Internet searches and the mental states and lifetime suicidal behaviors of Japanese young adults.
This study aimed to clarify the association between the experience of searching for deliberate self-harm (DSH)-related Internet content and the mental states and lifetime suicidal behaviors of Japanese young adults (n = 1000) using an online questionnaire. The results were assessed using χ(2) and t-tests, which revealed that the experience of DSH-related Internet searches may be significantly associated with lifetime suicidal behaviors (including DSH), suicidal ideation, and tendencies towards depression/anxiety. We discussed the possibility of using search engines to increase the motivation of Japanese young adults who deliberately harmed themselves with regard to seeking help.


Transcriptional regulation of genes encoding the acute-phase proteins CRP, SAA, and C3.
Inflammation or acute tissue injury results in a programmed change in the concentration of several plasma proteins. Among these proteins, two--C-reactive protein (CRP) and serum amyloid A protein (SAA)--increase up to 1000-fold after an acute-phase stimulus in humans and rabbits. To determine the mechanism for regulation of acute-phase gene expression, we examined changes in the rates of transcription and specific hepatic mRNA content for rabbit CRP, SAA, and some complement protein mRNA during an acute-phase response. Induction of a sterile inflammatory reaction with intramuscular injection of turpentine resulted in an increase in the hepatocellular content of CRP, SAA, C3, and factor B mRNA and the transcription of CRP, SAA, and C3 genes. These data suggest that the increase in CRP, SAA, and C3 serum concentrations observed during an acute-phase reaction is due to an increase in biosynthesis and is, at least in part, under transcriptional control.