Quantitative mass spectrometry for human melanocortin peptides in vitro and in vivo suggests prominent roles for β-MSH and desacetyl α-MSH in energy homeostasis.
The lack of pro-opiomelanocortin (POMC)-derived melanocortin peptides results in hypoadrenalism and severe obesity in both humans and rodents that is treatable with synthetic melanocortins. However, there are significant differences in POMC processing between humans and rodents, and little is known about the relative physiological importance of POMC products in the human brain. The aim of this study was to determine which POMC-derived peptides are present in the human brain, to establish their relative concentrations, and to test if their production is dynamically regulated. We analysed both fresh post-mortem human hypothalamic tissue and hypothalamic neurons derived from human pluripotent stem cells (hPSCs) using liquid chromatography tandem mass spectrometry (LC-MS/MS) to determine the sequence and quantify the production of hypothalamic neuropeptides, including those derived from POMC. In both in vitro and in vivo hypothalamic cells, LC-MS/MS revealed the sequence of hundreds of neuropeptides as a resource for the field. Although the existence of β-melanocyte stimulating hormone (MSH) is controversial, we found that both this peptide and desacetyl α-MSH (d-α-MSH) were produced in considerable excess of acetylated α-MSH. In hPSC-derived hypothalamic neurons, these POMC derivatives were appropriately trafficked, secreted, and their production was significantly (P < 0.0001) increased in response to the hormone leptin. Our findings challenge the assumed pre-eminence of α-MSH and suggest that in humans, d-α-MSH and β-MSH are likely to be the predominant physiological products acting on melanocortin receptors.


Cannabis use, abuse and dependence during the COVID-19 pandemic: a scoping review.
The interaction between cannabis use or addiction and SARS-COV-2 infection rates and COVID-19 outcomes is obscure. As of 08/01/2022 among 57 evaluated epidemiological/clinical studies found in Pubmed-database, most evidence for how cannabis use patterns were influenced by the pandemic was given by two systematic reviews and 17 prospective studies, mostly involving adolescents. In this age group, cannabis use patterns have not changed markedly. For adults, several cross-sectional studies reported mixed results with cannabis use having increased, decreased or remained unchanged. Two cross-sectional studies demonstrated that the severity of adults´ cannabis dependence was either increased as a consequence of increasing cannabis use during the pandemic or not changed. Regarding the effect of cannabis use on COVID-19 outcomes, we found only five retrospective/cross-sectional studies. Accordingly, (i) cannabis use did not impact mild COVID-19 symptoms; (ii) cannabis using individuals experienced more COVID-19-related hospitalizations; (iii) cannabis using veterans were associated with reduced SARS-COV-2 infection rates; (iv) frequent cannabis use was significantly associated with COVID-19 mortality, and (v) cannabis dependents were at higher risk of COVID-19 breakthrough after vaccination. It should be outlined that the validity of these retrospective/cross-sectional studies (all self-reports or register/e-health-records) is rather low. Future prospective studies on the effects of cannabis use on SARS-COV-2 infection rates and COVID-19 outcomes are clearly required for conclusive risk-benefit assessments of the role of cannabis on users' health during the pandemic. Moreover, substance dependence (including cannabis) is associated with (often untreated) somatic comorbidity, which severity is a proven key risk factor for worse COVID-19 outcomes.


[Familial hypobetalipoproteinemia. Familial study of 4 cases].
A familial study of four cases with hypobetalipoproteinemia is reported. Three members are heterozygous and one is homozygous. This congenital fat malabsorption in homozygous state is commonly associated with an absence of serum apoprotein B and LDL. Neuromuscular and ophthalmological signs are absent in this case. The major role of upper digestive endoscopy in the diagnostic procedure is emphasized. Histochemical and immunoenzymatic stains of enterocytes and intestinal organ culture show defective synthesis apo B in the homozygous patient. Studies of DNA polymorphism in the homozygous patient have shown that the apo B gene doesn't certain major insertions or deletions. These results are discussed.


Suicidal ideation among Canadian adults during the COVID-19 pandemic: the role of psychosocial factors and substance use behaviours.
Suicide is one of the most important and increasing public health agenda around the world. Since the COVID-19 pandemic, concerns have been raised about the potential adverse impacts of the pandemic on suicide-related outcomes. The main objective of this study was to examine the association of psychosocial risk factors (mental health illnesses and social isolation) and substance use behaviors (cannabis and alcohol consumption) with suicidal ideation during the COVID-19 pandemic among Canadian adults. The study was conducted based on a total of 4005 persons 18 years of age or older, living in Canada's ten provinces. The data used in this study were collected during April 20-28, 2021, by Mental Health Research Canada. Multivariable logistic regression was used to determine the association of mental health conditions (anxiety, depression, and other mood disorder) before and since COVID-19 outbreaks, social isolation and living arrangement, as well as cannabis and alcohol consumption with suicidal ideation during COVID-19. The results of adjusted logistic regression showed that the odds of suicidal ideation were 1.526 times higher (95% CI:1.082-2.152) among those who reported continued negative impacts of social isolation. The odds of suicidal ideation were also higher for those who were diagnosed as having depression before (OR = 3.136, 95% CI: 2.376-4.138) and since the COVID-19 pandemic (OR = 3.019, 95% CI:1.929-4.726) and 1.627 times higher (95% CI: 1.225-2.163) for those who were diagnosed as having anxiety before the COVID-19 pandemic. Those who reported having increased and those who were consuming cannabis during the pandemic were 1.970 (95% CI: 1.463-2.653) and 1.509 times (95% CI: 1.158-1.966) more likely to have thought of suicide than non-takers, respectively. Given the significant associations of psychosocial factors (mental health illnesses and social isolation) and cannabis use with suicidal ideation, more attention and support need to be given to adults who had mental health conditions before and since COVID-19, those who were negatively impacted by social isolation, and those are exposed to substance use (cannabis).


The use of RNAs complementary to specific mRNAs to regulate the expression of individual bacterial genes.
A naturally occurring small RNA molecule ( micF RNA), complementary to the region encompassing the Shine-Dalgarno sequence and initiation codon of the ompF mRNA, is known to block the expression of that mRNA in E. coli. We have constructed a plasmid that produces a complementary RNA to the E. coli lpp mRNA (mic[Ipp] RNA). Induction of the mic(Ipp) gene efficiently blocked lipoprotein production and reduced the amount of lpp mRNA. Two mic(ompC) genes were similarly engineered and their expression was found to inhibit drastically production of OmpC. Analysis of several types of mic(ompA) genes suggests that micRNAs complementary to regions of the mRNA likely to come in contact with ribosomes were most effective. The novel capabilities of this artificial mic system provide great potential for application in both procaryotic and eucaryotic cells.


Patterns and predictors of comorbidity of DSM-IV anxiety disorders in a clinical sample of children and adolescents.
This study examined the comorbidity of anxiety disorders and its predictors in a large, clinically referred sample of children and adolescents. Participants were 608 youth aged 4-18 years presenting at a large anxiety clinic for assessment and treatment of anxiety or mood related problems. The diagnoses were determined using the Anxiety Disorder Interview Schedule, Child/Parent versions. Sixty three percent of the participants had an additional diagnosis of an anxiety or depressive disorder. Comorbidity patterns differed based on the principal diagnostic category. Older children and females with anxiety were more likely to have a comorbid anxiety disorder. The presence of a medical condition increased the odds of having a comorbid anxiety disorder as well. This is the largest clinical sample of children and adolescents in which comorbidity of emotional disorders has been examined. Understanding the common patterns of comorbidity has important implications for future classification and treatment planning of childhood anxiety disorders.


Studying Autophagy In Vivo in the Mammary Gland and in Xenograft Samples.
Autophagy is a dynamic process that can be monitored in multiple ways, both in vitro and in vivo. Studies in mice are a widely used tool to understand multiple diseases and conditions where autophagy plays a role, and therefore autophagic flux measurement in tissues of rodent models are of utmost importance. Here, we present some assays successfully used in determining the autophagy status in the mice mammary gland as well as in xenografts.


Conjugation of the CRM197-inulin conjugate significantly increases the immunogenicity of Mycobacterium tuberculosis CFP10-TB10.4 fusion protein.
Mycobacterium tuberculosis (Mtb) is a serious fatal pathogen that causes tuberculosis (TB). Effective vaccination is urgently needed to deal with the serious threat from TB. Mtb-secreted protein antigens are important virulence determinants of Mtb with poor immunogenicity. Adjuvants and antigen delivery systems are thus highly desired to improve the immunogenicity of protein antigens. Inulin is a biocompatible polysaccharide (PS) adjuvant that can stimulate a strong cellular and humoral immunity. Bacterial capsular PS and haptens have been conjugated with cross-reacting material 197 (CRM197) to improve their immunogenicity. CFP10 and TB10.4 were two Mtb-secreted immunodominant protein antigens. A CFP10-TB10.4 fusion protein (CT) was used as the antigen for covalent conjugation with the CRM197-inulin conjugate (CRM-inu). The resultant conjugate (CT-CRM-inu) elicited high CT-specific IgG titers, stimulated splenocyte proliferation and provoked the secretion of Th1-type and Th2-type cytokines. Conjugation with CRM-inu significantly prolonged the systemic circulation of CT and exposure to the immune system. Moreover, CT-CRM-inu showed no apparent toxicity to cardiac, hepatic and renal functions. Thus, conjugation of CT with CRM-inu provided an effective strategy for development of protein-based vaccines against Mtb infection.


Expression of ASIC3 in the Trigeminal Nucleus Caudalis Plays a Role in a Rat Model of Recurrent Migraine.
Acid-sensing ion channel 3 (ASIC3) is abundant in the trigeminal nervous system and is most sensitive to a slight pH decrease. Recent studies have indicated that ASIC3 in the peripheral trigeminal ganglia is likely involved in the pathogenesis of migraine pain. However, it is unclear whether this receptor plays a role in recurrent migraine, namely, migraine chronicity. Here, we aimed to investigate the role of ASIC3 in an animal model of recurrent migraine (RM). In this study, we established a rat model of RM through repeated administration of inflammatory soup (IS) onto the dura. Then, we tested the mechanical pain thresholds of the face and hindpaws by von Frey filaments. qRT-PCR, Western blot and immunofluorescence labelling were used to detect the expression and localization of ASIC3 in the trigeminal nucleus caudalis (TNC). The protein levels of calcitonin gene-related peptide (CGRP), its receptor component receptor activity modifying protein 1 (RAMP1) and c-Fos were analysed following treatment with the ASIC3 inhibitor APETx2 and activator 2-guanidine-4-methylquinazoline (GMQ). We found decreased pain thresholds after repeated dural inflammatory stimulation, which suggested the establishment of an RM model. Based on this model, we observed elevated expression of ASIC3 in the TNC group compared to that in the Sham group. ASIC3 was primarily expressed in neurons but not in astrocytes of the TNC. Moreover, APETx2 attenuated tactile allodynia and significantly decreased the expression of c-Fos, CGRP and RAMP1, while GMQ aggravated these effects compared to those observed in the IS + vehicle group. These findings indicate a critical role of ASIC3 channels in the pathophysiology of RM, and ASIC3 might represent a potential therapeutic target to prevent the progression of migraine.


Coevolution of actin and associated proteins: an alpha-actinin-like protein in a cyanobacterium (Spirulina platensis).
Actin, together with associated proteins, such as myosin, cross-linking or capping proteins, has been observed in all eukaryotic cells. Presence of actin or actin-like proteins has also been reported in prokaryotic organisms belonging to the cyanobacteria. Our aim was first to extend the characterization of an actin-like protein to another prokaryotic cell, i.e. Spirulina, then to compare the antigenic reactivity of this new protein with that of Synechocystis and skeletal actins. We observed that some of the conserved antigenic epitopes corresponded to actin regions known to interact with cross-linking proteins. We also report for the first time that alpha-actinin and filamin purified from chicken gizzard both interact with a prokaryotic actin-like protein. Finally, we searched for the occurrence of a cross-linking protein in these cyanobacteria and identified a 105-kDa protein as an alpha-actinin-like protein using specific antibodies.


Ethnic minorities and weight control research priorities: where are we now and where do we need to be?
Within the overall obesity epidemic, the burden of obesity and related health problems is particularly high among African Americans, Hispanic/Latino Americans, American Indians, and Pacific Islanders--both children and adults. The often asked question of what types of obesity interventions work in these populations reflects uncertainty about how applicable standard interventions are to diverse socio-cultural groups and socio-environmental contexts. A meta-analysis in this issue of Preventive Medicine (Seo and Sa, 2008. A meta-analysis of psycho-behavioral obesity interventions among US multiethnic and minority adults) includes selected multi-ethnic and minority-focused studies that in total had 40% minority participants. Although the authors' conclusions were congruent with current general guidance for weight loss programs, insights about how to intervene with minority populations were limited by the small amount and nature of the available evidence. Ethnic minorities in the aggregate are now a third of the U.S. population. We should be purposeful in identifying research needs and quality standards for conducting and reporting studies with these populations and in motivating related research. Improving the relevance to and quality of evidence on obesity prevention and treatment for a more diverse set of populations will also improve the weight control literature as a whole.


Overexpression of the c-myc oncogene inhibits nonsense-mediated RNA decay in B lymphocytes.
The Myc transcription factor plays a vital role in both normal cellular physiology and in many human cancers. We have recently demonstrated that nonsense-mediated RNA decay (NMD), a mechanism that rapidly degrades select mRNAs, is inhibited by the stress-induced phosphorylation of translation initiation factor eIF2α, and this inhibition stabilizes many transcripts necessary for tumorigenesis. Here, we demonstrate that NMD is inhibited by high Myc expression. We show that the phosphorylation of eIF2α, likely due to the ability of Myc to generate reactive oxygen species and augment endoplasmic reticulum stress, is necessary for the inhibition of NMD by Myc. The inhibition of NMD both stabilizes and up-regulates multiple Myc targets, suggesting that the inhibition of NMD may play an important role in the dynamic regulation of genes by Myc.


Effect of interleukin-2 on the expression of cell cycle genes in human T lymphocytes.
We have studied the expression of seven cell cycle-dependent genes in phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells, in macrophage-depleted cultures and in macrophage-depleted cultures plus Interleukin-2 (IL-2). The expression of all seven genes is increased in PHA stimulated peripheral cells. Only two (2F1 and the IL-2 receptor) are increased in PHA-stimulated macrophage depleted cultures. Addition of IL-2 to these cultures increased the RNA levels of four genes (KC-1, c-myc, beta-actin and IL-2R), but has no effect on three others (4F1, 2F1, and JE-3). The results indicate that the expression of these cell cycle genes is regulated by different components of the mitogenic stimulus.


On the associations of body cholesterol pool size with age, HDL cholesterol and plasma total cholesterol concentration in humans.
Data from 17 subjects, in whom cholesterol kinetics had been measured by two-pool analysis of medium-term plasma cholesterol specific activity-time curves, were examined by multiple linear regression to explore the determinants of the size of the slowly exchanging cholesterol pool (MBmin) in humans. Pool size was independently and positively related to body weight (regression coefficient, 0.94 g per kg; P = 0.05) and age (1.77 g per year; P = 0.02). After allowance for these effects, MBmin retained a significant negative association with the plasma high density lipoprotein (HDL) cholesterol concentration (-0.56 g per mg/dl; P = 0.03), but was unrelated to plasma total cholesterol. This result is consistent with published data on the composition of those human tissues whose cholesterol is known to be largely a component of the slowly exchanging pool. It differs, however, from that of a recent study of cholesterol turnover [Blum et al, J. Lipid Res., 1985; 26: 1079-1088] in which pool size, measured by three-pool analysis of long-term decay curves, was unrelated to HDL and directly related to plasma total cholesterol. On the basis of other published data, it is considered that this discrepancy is unlikely to be a consequence of the difference between our respective studies in the duration and method of analysis of the specific activity decay curves. Differences in the variances of HDL cholesterol and plasma total cholesterol concentration that were examined, and in the biochemical-genetic factors underlying these variances, provide a more likely explanation. The overall weight of evidence favours the view that the pool of slowly exchangeable cholesterol in many human tissues expands during ageing at a rate which is increased in the presence of severe hypercholesterolemia, and which under some, but not all, circumstances also varies inversely with HDL cholesterol. The critical components of HDL metabolism which affect this process remain to be identified.


Modeling and optimizing in vitro percentage and speed callus induction of carrot via Multilayer Perceptron-Single point discrete GA and radial basis function.
Callus induction is the first step in optimizing plant regeneration. Fit embryogenesis and shooting rely on callus induction. In addition, using artificial intelligence models in combination with an algorithm can be helpful in the optimization of in vitro culture. The present study aimed to evaluate the percentage and speed of callus induction optimization in carrot with a Multilayer Perceptron-Single point discrete genetic algorithm (GA). In this study, the outputs included callus induction percentage and speed, while inputs were different types and concentrations of plant growth regulator (0. 5, 0.2 mg/l 2,4-D, 0.3, 0.2, 0.5 mg/l BAP, 1, 0.2 mg/l Kin, and 2 mg/l NAA), different explants (shoot, root, leaf, and nodal), a different concentration compound of MS medium (1 × MS, 4× MS, and 8× MS) and time of sampling. The data were obtained in the laboratory, and multilayer perceptron (MLP) and radial basis function (RBF), two well-known ANNs, were employed to model. Then, GA was used for optimization, and sensitivity analysis was performed to indicate the inputs' importance. The results showed that MLP had better prediction efficiency than RBF. Based on the results, R2 in training and testing data was 95 and 95% for the percentage of callus induction, while it was 94 and 95% for the speed of callus induction, respectively. In addition, a concentration compound of MS had high sensitivity, while times of sampling had low sensitivity. Based on the MLP-Single point discrete GA, the best results were obtained for shoot explants, 1× MS media, and 0.5 mg/l 2, 4-D + 0.5 mg/l BAP. Further, a non-significant difference was observed between the test result and predicted MLP. Generally, MLP-Single point discrete GA is considered a potent tool for predicting treatment and fit model results used in plant tissue culture and selecting the best medium for callus induction.


Antiviral activity in interferon-treated bovine tracheal organ cultures.
The effect of bovine interferon on the replication of infectious bovine rhinotracheitis virus and vesicular stomatitis virus in bovine tracheal organ cultures was studied. After treatment of tracheal organ cultures with interferon, inhibition of infectious bovine rhinotracheitis virus and vesicular stomatitis virus replication was observed. This tracheal organ system may be useful in determining the in vivo response to interferon for viral infections of the bovine respiratory tract.


Synthesis of Selective Estrogen Receptor Degrader GDC-0810 via Stereocontrolled Assembly of a Tetrasubstituted All-Carbon Olefin.
We report an efficient synthesis of GDC-0810 on the basis of a sequence involving a highly stereoselective lithium tert-butoxide-mediated enolization-tosylation (≥95:5 E: Z) and a Pd-catalyzed Suzuki-Miyaura cross-coupling as key steps. Global deprotection, pyrrolidine salt formation, and final active pharmaceutical ingredient (API) form control/isolation produced GDC-0810 free acid in a 40% overall yield with >99.0% purity as ascertained by HPLC analysis.


Identification and analysis of multimode guided waves in tibia cortical bone.
The hollow cylinder model filled with viscous-liquid is performed to simulate tibial bone shape in this paper. Short time Fourier transform (STFT) was applied to identify and analyze guided wave modes of a series of ultrasonic signals acquired at various transmitter-receiver positions for a fixed transmitter. Experimental results were compared with theoretical simulation. The high correlation values for group velocity were obtained between results of experiment and theory for L(0,2) (r=0.89, p<10(-5)), and L(0,3) (r=0.87, p<10(-5)). The experimental group velocities correlated strongly with cortical thickness (cortTh) for L(0,2) (r(2)=0.79, p<10(-5)) and L(0,3) (r(2)=0.74, p<10(-5)) at 0.5 MHz center frequency. The results showed that the STFT is an effective method to identify the propagating modes and derive dispersion information. The experimental results were in good agreement with theoretical predictions. This study suggests that the guided wave L(0,2) mode is a promising mode to assess change in cortical thickness.


Hydrophilic surface modification of metallic endoluminal stents.
Stainless steel endovascular stents are inherently thrombogenic so that thrombus accumulates on these devices, leading to acute vessel occlusion. A potential solution to this problem is stent surface modification with hydrophilic polymers, which might limit platelet adhesion and reactivity. N-vinylpyrrolidone (NVP) and potassium sulfopropyl acrylate (KSPA) hydrophilic monomers were gamma graft polymerized onto 1 cm2 stainless steel slabs and 4 mm Palmaz stainless steel stents. Surface characteristics of modified and plain stainless steel stents were then investigated with contact angle and x-ray photoelectron spectroscopy measurements, and in vitro and in vivo platelet reactivity was assessed as 111Indium platelet accumulation expressed as counts/min/cm2. Surface modification of stainless steel slabs and stents with both NVP and KSPA hydrophilic polymers significantly reduced in vitro platelet adhesion (plain = 2249 +/- 723 counts/min/cm2, NVP = 428 +/- 156 counts/min/cm2, KSPA = 958 +/- 223 counts/min/cm2) and in vivo platelet accumulation after 1 hour of blood flow exposure (plain = 1407 +/- 796 counts/min/cm2, NVP = 426 +/- 175 counts/min/cm2, KSPA = 399 +/- 124 counts/min/cm2. In addition, platelet accumulation on modified stents indexed to plain stents was lowest in KSPA-modified stents (NVP = 79.3% +/- 31.7% of plain, KSPA = 51.2% +/- 36.2% of plain). Surface analysis confirmed surface grafting with both monomers, and SEM documented smoothing of the irregular surfaces of the stainless steel stents after grafting. Hydrophilic polymer surface modification of stainless steel stents decreases initial stent surface platelet accumulation, which may decrease the risk of vessel thrombosis associated with the use of these devices.


Regulation of calcium transport in pancreatic acinar plasma membranes from guinea pig.
The regulation of the guinea-pig pancreatic acinar plasma membrane Ca2+ pump by protein kinase A, protein kinase C and calmodulin was investigated. The results were compared with the effects of these regulators on the high affinity Ca(2+)-ATPase found in this membrane preparation. The catalytic subunit of cyclic AMP-dependent protein kinase stimulated Ca2+ transport 2-fold, but had no effect on Ca(2+)-dependent ATPase activity. Purified protein kinase C, the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate and diacylglycerol derivative, 1-stearoyl-2-arachidonoyl-sn-glycerol, failed to stimulate the Ca(2+)-uptake but augmented the Ca(2+)-dependent ATPase activity. Exogenously added calmodulin failed to stimulate either activity. In addition, two antagonists of calmodulin activity, trifluoperazine and compound 48/80 produced a concentration-dependent inhibition of Ca(2+)-transport. These data suggest the presence of endogenous calmodulin within guinea-pig pancreatic acinar plasma membranes. Both calmodulin antagonists failed to influence the Ca(2+)-dependent ATPase activity. The ability of boiled extracts from guinea-pig pancreatic acinar plasma membranes to stimulate the Ca(2+)-ATPase activity in calmodulin-depleted erythrocyte plasma membranes confirmed the presence of endogenous calmodulin. Our results imply a role for calmodulin and cAMP-dependent protein kinase, but not protein kinase C, in the regulation of Ca2+ efflux from pancreatic acinar cells. These results also provide further evidence suggesting that the high affinity Ca(2+)-ATPase does not catalyze the plasma membrane Ca(2+)-transport activity observed in pancreatic acini.


The YbgC protein encoded by the ybgC gene of the tol-pal gene cluster of Haemophilus influenzae catalyzes acyl-coenzyme A thioester hydrolysis.
This paper examines the catalytic function of the protein YbgC, encoded by the ybgC gene of the tol-pal gene cluster in Haemophilus influenzae. The YbgC protein, a homologue of the Pseudomonas sp. strain CBS3 4-hydroxybenzoyl-coenzyme A thioesterase, conserves the active site Asp residue associated with thioesterase activity. The H. influenzae ybgC gene was cloned and overexpressed in Escherichia coli. The recombinant protein was purified and tested for thioesterase activity towards acyl-CoA and acyl-N-acetylcysteamine thioesters. The YbgC protein catalyzes the hydrolysis of short chain aliphatic acyl-CoA thioesters, while the D18N YbgC mutant protein (prepared to serve as a control) does not.


Microbially-reduced graphene scaffolds to facilitate extracellular electron transfer in microbial fuel cells.
A one-pot method is exploited by adding graphene oxide (GO) and acetate into an microbial fuel cell (MFC) in which GO is microbially reduced, leading to in situ construction of a bacteria/graphene network in the anode. The obtained microbially reduced graphene (MRG) exhibits comparable conductivity and physical characteristics to the chemically reduced graphene. Electrochemical measurements reveal that the number of exoelectrogens involved in extracellular electron transfer (EET) to the solid electrode, increases due to the presence of graphene scaffolds, and the EET is facilitated in terms of electron transfer kinetics. As a result, the maximum power density of the MFC is enhanced by 32% (from 1440 to 1905 mW m(-2)) and the coulombic efficiency is improved by 80% (from 30 to 54%). The results demonstrate that the construction of the bacteria/graphene network is an effective alternative to improve the MFC performance.


Contribution of CD4+ T cell-mediated inflammation to diarrhea in patients with COVID-19.
This study aimed to explore the role of CD4+ T cells in the mechanisms of COVID-19 related diarrhea. We analyzed lymphocyte subsets in patients with COVID-19 and the expression of angiotensin-converting enzyme 2 (ACE2), the transmembrane protease serine 2, and CD4+ T cell-related indicators in the colon were compared between patients with and without diarrhea. Correlation analyses were performed for ACE2 and other indicators to identify the relationship between SARS-CoV-2 infection and CD4+ mediated inflammation. The expression and distribution of CD4+ T cell-associated chemokines and their receptors were detected to determine the possibility of migration of CD4+ T cells to inflammation sites. The CD4+ T cell counts and percentages and CD4/CD8 ratio showed the most significant differences between the 2 groups. The diarrhea group expressed higher levels of ACE2, T-box expressed in T cells (Tbet), and tumor necrosis factor-alpha (TNFα) at both the mRNA and protein levels, with no difference from the nondiarrhea group for the percentage of ACE2+TNFα+ cells, indicating an indirect association between ACE2 and TNFα. The mRNA expression of CXCL10, CXCL11, and CXCR3 and the number of CD4+CXCR3+T cells were increased in the diarrhea group. CD4+ T cell-mediated inflammation may contribute to COVID-19 related diarrhea. CXCR3+ mediated migration of CD4+ T cells into the gut may perpetuate inflammation.


[Use of Freiburg monosyllabic test words in the contemporary German language : Currentness of the test words].
The Freiburg monosyllabic test has a word inventory based on the word frequency in written sources from the 19th century, the distribution of which is not even between the test lists. The median distributions of word frequency ranking in contemporary language of nine test lists deviate significantly from the overall median of all 400 monosyllables. Lists 1, 6, 9, 10, and 17 include significantly more very rarely used words; lists 2, 3, 5, and 15, include significantly more very frequently used words. Compared with the word frequency in the contemporary spoken German language, about 45 % of the test words are practically no longer used. Due to this high proportion of extremely rarely or no longer used words, the word inventory is no longer representative of the contemporary German language-neither for the written, nor for the spoken language. Highly educated persons with a large vocabulary are thereby favored. The reference values for normal-hearing persons should therefore be reevaluated.


Astrocytic plasticity at the dorsal dentate gyrus on an animal model of recurrent depression.
Astrocytes are now known to play crucial roles in the central nervous system, supporting and closely interacting with neurons and therefore able to modulate brain function. Both human postmortem studies in brain samples from patients diagnosed with Major Depressive Disorder and from animal models of depression reported numerical and morphological astrocytic changes specifically in the hippocampus. In particular, these studies revealed significant reductions in glial cell density denoted by a decreased number of S100B-positive cells and a decrease in GFAP expression in several brain regions including the hippocampus. To reveal plastic astrocytic changes in the context of recurrent depression, we longitudinally assessed dynamic astrocytic alterations (gene expression, cell densities and morphologic variations) in the hippocampal dentate gyrus under repeated exposure to unpredictable chronic mild stress (uCMS) and upon treatment with two antidepressants, fluoxetine and imipramine. Both antidepressants decreased astrocytic complexity immediately after stress exposure. Moreover, we show that astrocytic alterations, particularly an increased number of S100B-positive cells, are observed after recurrent stress exposure. Interestingly, these alterations were prevented at the long-term by either fluoxetine or imipramine treatment.


Effect of tributylphenyltetraethoxylate on enzyme production of Pleurotus ostreatus.
The effect of the addition of the nonionic surfactant tributylphenyltetraethoxylate to culture media on pH and extracellular protein content, and on production of beta-glucosidase, xylanase, laccase, and manganese-dependent and -independent peroxidases by the edible fungus Pleurotus ostreatus was determined. The relationship between fermentation parameters and concentration of surfactant was assessed by multiple linear regression analysis, and the similarities and differences among the fermentation parameters were elucidated by principal component analysis. Calculations proved that except for xylanase all other cultivation parameters were significantly influenced by the surfactant, with the effect higher at higher surfactant concentrations. Surfactant increased the production of beta-glucosidase and inhibited laccase and manganese-dependent and -independent peroxidase activities.


Association of a home-based nursing service during chemotherapy with the transfer to home care immediately after the last chemotherapy treatment in patients with advanced cancer.
The appropriate timing of introducing the home-based nursing service to patients with advanced cancer has not been clarified. This study conducted a retrospective cohort study to investigate the associations of the early utilization of the home-based nursing service during chemotherapy with the place of care immediately after the last chemotherapy treatment in patients with advanced cancer. Among the patients referred to the palliative care team of the University of Tsukuba Hospital between January 2018 and December 2019, patients with advanced cancer undergoing chemotherapy or before the start of chemotherapy at referral were included. The study patients who utilized the home-based nursing service during chemotherapy were classified into the early utilization group. The primary endpoint was the place of care immediately after the last chemotherapy treatment. Of the 1154 patients referred to the palliative care team during the study period, 261 were eligible for this study. Of these patients, 15.3% of patients (n = 40) received the home-based nursing service during chemotherapy. The proportion of patients transferred to home care after the last chemotherapy treatment was 17.5% in the early utilization group and 7.2% in the control group. The multivariate analysis revealed that the early utilization of the home-based nursing service during chemotherapy was significantly associated with the transfer to home care (odds ratio = 3.077; 95% confidence interval, 1.113-8.502). The early utilization of the home-based nursing service during chemotherapy might be associated with the transfer to home care immediately after the last chemotherapy treatment.


The selection of appropriate health education topics for publication in the press.
To compare the perceptions of patients, doctors, and journalists concerning the priority of health education topics in the media. A cross sectional Knowledge, Attitude, and Practice (K.A.P.) study. A self-administered questionnaire was used during 2 weeks in September 1990; it included questions on sociodemographic characteristics and on each group's perceived opinion of priority health topics for discussion in the media. Two university hospitals and six newspapers offices in Riyadh Saudi Arabia. 300 randomly selected outpatients aged 12 years and over, and 77 doctors. 31 journalists from six local newspapers also participated. The ratio of respondents in the three study groups who believed there was a need for health education in 22 topics. For most of these topics, statistically significant differences were found between the perceptions of the three groups. Doctors put more emphasis on preventive issues, while patients perceived new therapeutic and diagnostic methods as important more commonly than the other two groups. A team consisting of doctors, journalists, and patients should be formed to select health education topics in the media. Priority should be given to topic preferences shared by both doctors and the public.


Expression of protease-activated receptors and tissue factor in human liver.
Thrombin, acting via protease-activated receptors (PARs), and tissue factor (TF) are involved in inflammation, tissue repair and tumorigenesis. Hepatocellular carcinomas (HCCs) usually complicate chronic liver diseases characterised by inflammation and fibrosis. The aim of this study was to describe the expression of PARs and TF in normal liver, cirrhosis and HCCs. We performed an immunohistochemical detection of PAR-1, PAR-3, PAR-4 and human TF in human tissue samples from 19 subnormal livers, 33 cirrhosis and 30 HCCs. PAR-1 was found on endothelial cells of sinusoids and larger vessels. In cirrhosis, spindle-shaped cells within septa and T lymphocytes were PAR-1 positive. A few PAR-1-positive tumour cells were found in 10% of HCCs. PAR-4 expression was restricted to macrophages, B lymphocytes and nerves. PAR-3 expression was rare. Unexpectedly, TF was expressed in 95% of normal livers and in 94% of cirrhosis but only in 50% of HCCs (p<0.001). Staining was mostly hepatocellular. No association existed between TF labelling and clinicopathological characteristics of HCCs. In conclusion, the pattern of expression of PARs is compatible with its role in chronic liver disease by promoting inflammation via immune cells and neurogenic stimulation. However, our data do not support a role for PARs or TF in HCC progression.


Comparison of firing patterns and sensory responsiveness between supraoptic and other hypothalamic neurons in the unanesthetized sheep.
Adult Southdown ewes were surgically prepared with pituitary stimulating electrodes, carotid and jugular cannulae, and a cranial platform-cylinder arrangement for chronic single unit recording. Isolated neurons (n = 112) in the region of the supraoptic nucleus (SON) were identified by pituitary stalk stimulastion as AD + (antidromically invaded) SON neuroendocrine cells (n = 75) or AD--(not antidromically invaded) SON neurons (n = 37). Spontaneous firing pattern distribution and sensory evoked behavior of these SON region neurons were compared with activity recorded from 112 randomly located non-identified neurons of extra-SON areas of the hypothalamus. Spontaneous discharge activity was categorized into six distinct firing pattern types: continuously active slow (CAS), continuously active fast (CAF), continuously active bursting (CAB), continuously active regular (CAR), low frequency bursting (LFB), and high frequency bursting (HFB). These 6 firing pattern types were characterized by computer analysis and their mean order independent statistical parameters compared. Bursting discharge patterns (LFB, HFB, and CAB) were compared with respect to mean burst duration, burst mean firing rate, and interburst interavls. Ninety-three per cent of all neurons maintained a stable discharge pattern in the absence of apparent stimuli. Occasionally CAS and CAF neurons spontaneously generated spike clusters sufficient to give the transient appearance of a bursting discharge pattern and LFB neurons lapsed spontaneously into CAS acitivity. All 6 firing pattern types recorded from non-identified extra-SON neurons were also recorded in the SON region. However, spontaneously discharging AD+ SON neurons exhibited only continuously active slow (CAS), continuously active fast (CAF), and low frequency bursting (LFB) activity. The total absence of high frequency bursting (HFB), continuously active regular (CAR), and continuously active bursting (CAB) patterns of discharge from AD+ SON neurons suggests that AD- SON neurons exhibiting these firing patterns may function as interneurons, pacemaker neurons, or receptor neurons. A significant number of LFB discharging neurons were recorded in widespread extra-SON regions of the hypothalamus, indicating this discharge pattern may not be unique to magnocellular neuroendocrine cells. AD+ SON LFB neurons sampled in this study demonstrated a significantly longer mean interburst interval (20.86 sec) compared to extra-SON LFB neurons (12.43 sec). No AD+ SON neuron tested was significantly sensitive to non-specific sensory arousal or sleep-waking state changes. In extra-SON areas of the hypothalamus, 11 of 75 neurons tested to sensory arousal and 6 of 19 neurons tested to sleep-waking changes responded with significant changes in mean firing rate (MFR); no significant difference between firing pattern types was demonstrated in arousal or sleep-waking sensitivity...


Machine learning for the development of diagnostic models of decompensated heart failure or exacerbation of chronic obstructive pulmonary disease.
Heart failure (HF) and chronic obstructive pulmonary disease (COPD) are two chronic diseases with the greatest adverse impact on the general population, and early detection of their decompensation is an important objective. However, very few diagnostic models have achieved adequate diagnostic performance. The aim of this trial was to develop diagnostic models of decompensated heart failure or COPD exacerbation with machine learning techniques based on physiological parameters. A total of 135 patients hospitalized for decompensated heart failure and/or COPD exacerbation were recruited. Each patient underwent three evaluations: one in the decompensated phase (during hospital admission) and two more consecutively in the compensated phase (at home, 30 days after discharge). In each evaluation, heart rate (HR) and oxygen saturation (Ox) were recorded continuously (with a pulse oximeter) during a period of walking for 6 min, followed by a recovery period of 4 min. To develop the diagnostic models, predictive characteristics related to HR and Ox were initially selected through classification algorithms. Potential predictors included age, sex and baseline disease (heart failure or COPD). Next, diagnostic classification models (compensated vs. decompensated phase) were developed through different machine learning techniques. The diagnostic performance of the developed models was evaluated according to sensitivity (S), specificity (E) and accuracy (A). Data from 22 patients with decompensated heart failure, 25 with COPD exacerbation and 13 with both decompensated pathologies were included in the analyses. Of the 96 characteristics of HR and Ox initially evaluated, 19 were selected. Age, sex and baseline disease did not provide greater discriminative power to the models. The techniques with S and E values above 80% were the logistic regression (S: 80.83%; E: 86.25%; A: 83.61%) and support vector machine (S: 81.67%; E: 85%; A: 82.78%) techniques. The diagnostic models developed achieved good diagnostic performance for decompensated HF or COPD exacerbation. To our knowledge, this study is the first to report diagnostic models of decompensation potentially applicable to both COPD and HF patients. However, these results are preliminary and warrant further investigation to be confirmed.


Preliminary audiologic and peri-operative outcomes of the Sophono™ transcutaneous bone conduction device: A systematic review.
To delineate the auditory functional improvement and peri-operative outcomes of the Sophono™ transcutaneous bone conduction device. Eligible articles presenting patients implanted with the Sophono™ were identified through a comprehensive search of PubMed and Embase electronic databases. All relevant articles were reviewed to justify inclusion independently by 2 authors. Studies that successfully passed critical appraisal for directness of evidence and risk of bias were included. From a total of 125 articles, 8 studies encompassing 86 patients using 99 implants were selected. Most patients (79.1%) were children. Ear atresia (67.5%) was the most frequently reported indication for Sophono™ implantation. Overall pure tone average auditory improvement was 31.10 (±8.29) decibel. During a mean follow-up time of 12.48 months, 25 patients (29%) presented with post-operative complications from which 3 were deemed as serious implant-related adverse events (3.5%). The Sophono™ transcutaneous bone conduction device shows promising functional improvement, no intra-operative complications and minor post-operative skin related complications. If suitable, the device could be a proposed solution for the rehabilitation of hearing in children meeting eligibility criteria. A wearing schedule must be implemented in order to reduce magnet-related skin complications.


An 8-year-old boy with a Pott's puffy tumor.
An 8-year old boy with a history of trauma, sinusitis and a swelling of the frontal bone with somnolence was diagnosed with a Pott's puffy tumor (PPT). Minimal invasive surgical intervention was performed together with a strict regimen of antibiotic therapy. In this case debridement of the frontal bone was not necessary. Serial X-ray imaging of the skull showed complete ossification of the frontal bone lesion. Early diagnosis using thorough radiological evaluation is necessary to effectuate the proper therapeutic approach. For this reason, a patient with a forehead swelling and a history of trauma and/or sinusitis should be suspected for a PPT.


STB1, a mouse lymphocyte marker found on T cell and B cell subpopulations.
A set of monoclonal antibodies has been raised to cell surface markers which are either hyperexpressed, or exclusive to activated murine lymphocytes. One antigen is present on all B cells of the Ly1 lineage and defines a novel subpopulation of classical B cells, most of which are activated B cells. In Western blots, this antigen appears as a single glycoprotein of 95 kDa molecular weight but of greater interest, is its expression at high levels on all mature peripheral T cells but on only 30% of thymocytes. This marker is expressed at high levels on all CD4 and CD8 thymocytes, most double-negative (CD4-CD8-) thymocytes, and at low levels on double-positive (CD4+CD8+) thymocytes. It may prove useful as a developmental marker for subdividing the double-positive (CD4+CD8+) and double negative (CD4-CD8-) thymocyte populations. Taken together these results indicate that mab 3.17 recognises a novel lymphocyte antigen expressed on subsets of T and B cells, which is hyperexpressed on lymphocyte activation.


Host, viral, and vaccine factors that determine protective efficacy induced by rotavirus and virus-like particles (VLPs).
Critical factors that are important in protection from rotavirus infection have remained elusive. We demonstrate here that inbred mice (C57BL/6 and BALB/c) exhibit differences in: (1) susceptibility to and (2) VLP-induced protection from rotavirus infection. Comparing protection induced by 2/4/6/7-VLPs with inactivated and live rotavirus, intranasally induced protection was dependent on dsRNA or minor structural proteins and correlated with intestinal antibody, while orally induced protection required immunization with replicating virus. Combination oral/intranasal vaccination did not improve VLP protective efficacy. These studies indicate that host, viral, and vaccine factors determine the level of protective efficacy induced by VLPs.


Operating room ventilation systems: recovery degree, cleanliness recovery rate and air change effectiveness in an ultra-clean area.
Entrainment test methods are described in most European standards and guidelines to determine the protected area for ultra-clean ventilation (UCV) systems. New UCV systems, such as temperature-controlled airflow (TcAF) and controlled dilution ventilation (cDV) systems, claim the whole operating room (OR) to be ultra-clean. However, current test standards were not developed to assess ventilation effectiveness outside the standard protected area. To assess and compare the ventilation effectiveness of four types of OR ventilation systems in the ultra-clean area using a uniform test grid. Ventilation effectiveness of four ventilation systems was evaluated for three different ultra-clean (protected) areas: the standard protected area (A); the area outside the standard protected area (B); and a large protected area (AB). Ventilation effectiveness was assessed using recovery degree (RD), cleanliness recovery rate (CRR) and air change effectiveness (ACE). RD, CRR and ACE were significantly higher for the unidirectional air flow (UDAF) system compared with the other systems in area A. In area B, the UDAF and cDV systems were comparable for RD and CRR, and the UDAF and conventional ventilation (CV) systems were comparable for ACE. In area AB, the UDAF and cDV systems were comparable for CRR and ACE, but significant differences were found in RD. In area A, the ventilation effectiveness of the UDAF system outperformed other ventilation systems. In area B, the cDV system was best, followed by the UDAF, TcAF and CV systems. In area AB, the UDAF system was best, followed by the cDV, TcAF and CV systems.


Mature seed-derived callus of the model indica rice variety Kasalath is highly competent in Agrobacterium-mediated transformation.
We previously established an efficient Agrobacterium-mediated transformation system using primary calli derived from mature seeds of the model japonica rice variety Nipponbare. We expected that the shortened tissue culture period would reduce callus browning--a common problem with the indica transformation system during prolonged tissue culture in the undifferentiated state. In this study, we successfully applied our efficient transformation system to Kasalath--a model variety of indica rice. The Luc reporter system is sensitive enough to allow quantitative analysis of the competency of rice callus for Agrobacterium-mediated transformation. We unexpectedly discovered that primary callus of Kasalath exhibits a remarkably high competency for Agrobacterium-mediated transformation compared to Nipponbare. Southern blot analysis and Luc luminescence showed that independent transformation events in primary callus of Kasalath occurred successfully at ca. tenfold higher frequency than in Nipponbare, and single copy T-DNA integration was observed in ~40% of these events. We also compared the competency of secondary callus of Nipponbare and Kasalath and again found superior competency in Kasalath, although the identification and subsequent observation of independent transformation events in secondary callus is difficult due to the vigorous growth of both transformed and non-transformed cells. An efficient transformation system in Kasalath could facilitate the identification of QTL genes, since many QTL genes are analyzed in a Nipponbare × Kasalath genetic background. The higher transformation competency of Kasalath could be a useful trait in the establishment of highly efficient systems involving new transformation technologies such as gene targeting.


Drug discovery and amyotrophic lateral sclerosis: Emerging challenges and therapeutic opportunities.
Amyotrophic lateral sclerosis (ALS) is characterized by the degeneration of upper and lower motor neurons (MNs) leading to paralysis and, ultimately, death by respiratory failure 3-5 years after diagnosis. Edaravone and Riluzole, the only drugs currently approved for ALS treatment, only provide mild symptomatic relief to patients. Extraordinary progress in understanding the biology of ALS provided new grounds for drug discovery. Over the last two decades, mitochondria and oxidative stress (OS), iron metabolism and ferroptosis, and the major regulators of hypoxia and inflammation - HIF and NF-κB - emerged as promising targets for ALS therapeutic intervention. In this review, we focused our attention on these targets to outline and discuss current advances in ALS drug development. Based on the challenges and the roadblocks, we believe that the rational design of multi-target ligands able to modulate the complex network of events behind the disease can provide effective therapies in a foreseeable future.


Effect of sulfamethazine on surface characteristics of biochar colloids and its implications for transport in porous media.
Antibiotics are contaminants of emerging concern due to their potential effect on antibiotic resistance and human health. Antibiotics tend to sorb strongly to organic materials, and biochar, a high efficient agent for adsorbing and immobilizing pollutants, can thus be used for remediation of antibiotic-contaminated soil and water. The effect of ionizable antibiotics on surface characteristics and transport of biochar colloids (BC) in the environment is poorly studied. Column experiments of BC were conducted in 1 mM NaCl solution under three pH (5, 7, and 10) conditions in the presence of sulfamethazine (SMT). Additionally, the adsorption of SMT by BC and the zeta potential of BC were also studied. The experimental results showed that SMT sorption to BC was enhanced at pH 5 and 7, but reduced at pH 10. SMT sorption reduced the surface charge of BC at pH 5 and 7 due to charge shielding, but increased surface charge at pH 10 due to adsorption of the negatively charged SMT species. The mobility of BC was inhibited by SMT under acidic or neutral conditions, while enhanced by SMT under alkaline conditions, which can be well explained by the change of electrostatic repulsion between BC and sand grains. These findings imply that pH conditions played a crucial role in deciding whether the transport of BC would be promoted by SMT or not. Biochar for antibiotics remediation will be more effective under acidic and neutral soil conditions, and the mobility of BC will be less than in alkaline soils.


Engineered elastomer substrates for guided assembly of complex 3D mesostructures by spatially nonuniform compressive buckling.
Approaches capable of creating three-dimensional (3D) mesostructures in advanced materials (device-grade semiconductors, electroactive polymers etc.) are of increasing interest in modern materials research. A versatile set of approaches exploits transformation of planar precursors into 3D architectures through the action of compressive forces associated with release of prestrain in a supporting elastomer substrate. Although a diverse set of 3D structures can be realized in nearly any class of material in this way, all previously reported demonstrations lack the ability to vary the degree of compression imparted to different regions of the 2D precursor, thus constraining the diversity of 3D geometries. This paper presents a set of ideas in materials and mechanics in which elastomeric substrates with engineered distributions of thickness yield desired strain distributions for targeted control over resultant 3D mesostructures geometries. This approach is compatible with a broad range of advanced functional materials from device-grade semiconductors to commercially available thin films, over length scales from tens of microns to several millimeters. A wide range of 3D structures can be produced in this way, some of which have direct relevance to applications in tunable optics and stretchable electronics.


Lack of efficacy of 'weighted' radiographs in diagnosing acute acromioclavicular separation.
The efficacy of "weighted" films in diagnosing grade 3 acromioclavicular (AC) sprains not evident on plain (unweighted) films was evaluated. Eighty-three pairs of radiographs, taken with and without weights, of patients with suspected AC injury were studied. The films were read in a randomized and blinded manner by a staff radiologist. Criteria for classifying AC injuries were: grade 1, less than 3 mm (or less than 50%) difference between the AC widths with a normal coracoclavicular (CC) distance; grade 2, greater than or equal to 3 mm (or greater than or equal to 50%) difference between the AC widths with a normal CC distance; and grade 3, greater than or equal to 5 mm (or greater than or equal to 50%) difference in CC distance. In only three cases (4%) did weights cause the injured CC distance to increase and thereby unmask a grade 3 injury not evident on plain films. Further evidence that weights may not reliably elucidate the degree of AC joint injury is suggested by the fact that in several cases the weights actually caused the injured and uninjured CC distance to decrease. We conclude that the use of weighted radiographs lacks efficacy in unmasking grade 3 AC sprains on radiograph and we recommend that routine use of this technique be abandoned.


Direction and magnitude of displacement differ between slowly expanding and non-expanding multiple sclerosis lesions as compared to small vessel disease.
Differentiating between multiple sclerosis (MS) and small vessel disease (SVD) lesions represents a key challenge in the day-to-day management of patients. We aimed to distinguish between MS and SVD by identifying the dynamics of lesion movement patterns between enlarging and contracting foci from two MRI time points. Standardized 3-Tesla 3-dimensional brain magnetic resonance imaging (MRI) studies were performed at two time points on enrolled MS and SVD patients. Selected supratentorial lesions were segmented and longitudinal changes in the direction of lesion displacement and magnitude along with the evolution of contracting and expanding T1-weighted and T2-weighted MS lesions were quantified based on lesion centroid positioning. Bayesian linear mixed effects regression models were constructed to evaluate associations between changes in lesion transitions and disease state. A total of 420 lesions were analyzed from 35 MS (female (F):22 (62.9%); median age (range):38 years (y) (22-61), median disease duration:7.38y (0.38-20.99)) and 12 SVD patients (F:11 (100%); 54y (40-66)). MS T2-weighted lesions that increased in volume between MRI time points demonstrated movement toward the cortex (p = 0.01), whereas those that decreased in volume moved toward the center (p < 0.0001). Lesion volume changes related to SVD demonstrated no effect on movement direction over time. Both expanding (p = 0.03) and contracting (p = 0.01) MS lesions demonstrated greater distances between centroids when compared to SVD. Lesion dynamics may reveal distinct characteristics associated with the biology of disease while providing further insights into the behavior of inflammatory CNS disorders.


Physiological characteristics of environmental isolates of pathogenic dematiaceous fungi.
A total of 39 environmental isolates of pathogenic dematiaceous fungi (Fonsecaea pedrosoi: 14 isolates, Phialophora verrucosa: 6, Cladosporium carrionii: 9, Exophiala jeanselmei: 2, Ramichloridium subulatum: 6, Cladosporium tenuissimum: 1 and Phaeoisaria clematidis: 1) were evaluated for their various physiological characteristics including the ability to produce extracellular enzymes. Significant physiological characteristics included the ability of isolates of all the species except C. tenuissimum to decompose tyrosine, lyse human red blood cells, conversion of R. subulatum from filamentous to yeast form when cultured on Czapek-Dox agar and also on blood agar and the growth of C. tenuissimum on Sabouraud dextrose agar incorporating 3.6 M NaCl. Isolates of all the species except those of C. carrionii produced lipase, while only the isolates of P. verrucosa, E. jeanselmei and Ph. clematidis were positive for phospholipase.


Bidipyrrin AuIII Complex as a Helical Charged π-Electronic System.
A series of ion pairs based on a bidipyrrin-AuIII complex that acts as a stable helical π-electronic cation have been prepared via ion-pair metathesis. The helical cation, which exhibits NIR absorption and phosphorescence emission, formed solid-state ion-pairing assemblies, whose assembling modes depended on the properties of coexisting counteranions.


GFR ≤25 years postdonation in living kidney donors with (vs. without) a first-degree relative with ESRD.
An increased risk of ESRD has been reported for living kidney donors, and appears to be higher for those donating to a relative. The reasons for this are not clear. One possibility is that ESRD is due to the nephrectomy-related reduction in GFR, followed by an age-related decline that may be more rapid in related donors. Between 1/1/1990 and 12/31/2014, we did 2002 living donor nephrectomies. We compared long-term postdonation eGFR trajectory for donors with (n = 1245) vs. without (n = 757) a first-degree relative with ESRD. Linear mixed-effects models were used to model the longitudinal trajectory of eGFR. With all other variables held constant, we noted a steady average increase in eGFR until donors reached age 70: 1.12 (95% CI: 0.92-1.32) mL/min/1.73m² /yr between 6 weeks and 5 years postdonation; 0.24 (0.00-0.49) mL/min/1.73m² /yr between 5 and 10 years; and 0.07 (-0.10 to +0.25) mL/min/1.73m² /yr between 10 and 20 years for donors with attained age less than 70. After age 70, eGFR declined. After we adjusted for predonation factors, the difference in eGFR slopes between related and unrelated donors was 0.20 mL/min/1.753 m2 /year (0.07-0.33). Our data suggests that postdonation, kidney donor eGFR increases each year for a number of years and that eGFR trajectory does not explain any increase in ESRD after donation.


Diabetes mellitus-related hospital admissions and prescriptions of antidiabetic agents in England and Wales: an ecological study.
Around 6.5% of the population in the United Kingdom has been diagnosed with diabetes. It is associated with several long-term consequences and higher hospitalization rates. To examine the profile of hospital admissions related to diabetes mellitus and the prescription rates of antidiabetic medications in England and Wales. This is an ecological study that was conducted for the period between April 1999 and April 2020 using publicly available hospitalisation data in England and Wales. Hospital admission data for patients of all ages was extracted from Hospital Episode Statistics in England and the Patient Episode Database for Wales. The difference between admission rates in 1999 and 2020, as well as the difference between diabetes mellitus medication prescription rates in 2004 and 2020, were assessed using the Pearson Chi-squared test. A Poisson regression model with robust variance estimation was used to examine the trend in hospital admissions. A total of 1,757,892 diabetes mellitus hospital admissions were recorded in England and Wales during the duration of the study. The hospital admission rate for diabetes mellitus increased by 15.2%. This increase was concomitant with an increase in the antidiabetic medication prescribing rate of 105.9% between 2004 and 2020. Males and those in the age group of 15-59 years had a higher rate of hospital admission. The most common causes of admissions were type 1 diabetes mellitus related complications, which accounted for 47.1% of all admissions. This research gives an in-depth overview of the hospitalization profile in England and Wales during the previous two decades. In England and Wales, people with all types of diabetes and related problems have been hospitalized at a high rate over the past 20 years. Male gender and middle age were significant determinants in influencing admission rates. Diabetes mellitus type 1 complications were the leading cause of hospitalizations. We advocate establishing preventative and educational campaigns to promote the best standards of care for individuals with diabetes in order to lower the risk of diabetes-related complications.


Solid-state NMR of inorganic semiconductors.
Studies of inorganic semiconductors by solid-state NMR vary widely in terms of the nature of the samples investigated, the techniques employed to observe the NMR signal, and the types of information obtained. Compared with the NMR of diamagnetic non-semiconducting substances, important differences often result from the presence of electron or hole carriers that are the hallmark of semiconductors, and whose theoretical interpretation can be involved. This review aims to provide a broad perspective on the topic for the non-expert by providing: (1) a basic introduction to semiconductor physical concepts relevant to NMR, including common crystal structures and the various methods of making samples; (2) discussions of the NMR spin Hamiltonian, details of some of the NMR techniques and strategies used to make measurements and theoretically predict NMR parameters, and examples of how each of the terms in the Hamiltonian has provided useful information in bulk semiconductors; (3) a discussion of the additional considerations needed to interpret the NMR of nanoscale semiconductors, with selected examples. The area of semiconductor NMR is being revitalized by this interest in nanoscale semiconductors, the great improvements in NMR detection sensitivity and resolution that have occurred, and the current interest in optical pumping and spintronics-related studies. Promising directions for future research will be noted throughout.


Phase field modelling of hopper crystal growth in alloys.
Here we use phase field to model and simulate "hopper" crystals, so named because of their underlying cubic structure but with a hopper-like depression on each of the six faces. Over the past three decades simulations of single phase solidification have successfully explored dendritic structures, in two and three dimensions, formed under high undercooling from a slight perturbation in anisotropy. More recently we see the modelling of faceted structures at near equilibrium, and also, under high undercooling, the formation of dendritic-like structures in two dimensions which retain some faceting in the dendrite arms. A cubic hopper crystal appears to be a hybrid structure, somewhere between a perfect cube and a dendrite, and, to date, has not appeared in the modelling literature. In this paper we describe a model for faceted cubic growth and explore results, necessarily in three dimensions, that include perfect cube, hopper and dendritic. We also touch briefly on one other morphology-octahedral.


LRRC15 expression indicates high level of stemness regulated by TWIST1 in mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are used as a major source for cell therapy, and its application is expanding in various diseases. On the other hand, reliable method to evaluate quality and therapeutic properties of MSC is limited. In this study, we focused on TWIST1 that is a transcription factor regulating stemness of MSCs and found that the transmembrane protein LRRC15 tightly correlated with the expression of TWIST1 and useful to expect TWIST1-regulated stemness of MSCs. The LRRC15-positive MSC populations in human and mouse bone marrow tissues highly expressed stemness-associated transcription factors and therapeutic cytokines, and showed better therapeutic effect in bleomycin-induced pulmonary fibrosis model mice. This study provides evidence for the important role of TWIST1 in the MSC stemness, and for the utility of the LRRC15 protein as a marker to estimate stem cell quality in MSCs before cell transplantation.


A review of the long term results of electric bar fire burns of the hand in children.
This paper reports on the long term problems of a group of patients who had sustained burns to the palmar aspect of one or both hands between eleven and eighteen years previously. Two of the eight patients who were re-examined had abnormalities of bony development in the hand. It is thought that the contracted scars resulting from the injury affect the growth of the bones of the hand. As development of contracted scars can develop at any time until growth of the hand is complete it is necessary to follow up these children until they reach maturity.


The Safety and Efficacy of the Anterior Approach Total Hip Arthroplasty as per Body Mass Index.
Obesity is associated with component malpositioning and increased revision risk after total hip arthroplasty (THA). With anterior approaches (AAs) becoming increasingly popular, the goal of this study was to assess whether clinical outcome post-AA-THA is affected by body mass index (BMI). This multicenter, multisurgeon, consecutive case series used a prospective database of 1,784 AA-THAs (1,597 patients) through bikini (n = 1,172) or standard (n = 612) incisions. Mean age was 63 years (range, 20-94 years) and there were 57.5% women, who had a mean follow-up of 2.7 years (range, 2.0-4.1 years). Patients were classified into the following BMI groups: normal (BMI < 25.0; n = 572); overweight (BMI: 25.0-29.9; n = 739); obese (BMI: 30.0-34.9; n = 330); and severely obese (BMI ≥ 35.0; n = 143). Outcomes evaluated included hip reconstruction (inclination/anteversion and leg-length, complications, and revision rates) and patient-reported outcomes including Oxford Hip Scores (OHS). Mean postoperative leg-length difference was 2.0 mm (range: -17.5 to 39.0) with a mean cup inclination of 34.8° (range, 14.0-58.0°) and anteversion of 20.3° (range, 8.0-38.6°). Radiographic measurements were similar between BMI groups (P = .1-.7). Complication and revision rates were 2.5% and 1.7%, respectively. The most common complications were fracture (0.7%), periprosthetic joint infection (PJI) (0.5%), and dislocation (0.5%). There was no difference in dislocation (P = .885) or fracture rates (P = .588) between BMI groups. There was a higher rate of wound complications (1.8%; P = .053) and PJIs (2.1%; P = .029) among obese and severely obese patients. Wound complications were less common among obese patients with the 'bikini' incision (odds ratio 2.7). Preoperative OHS was worse among the severely obese (P < .001), which showed similar improvements (Change in OHS; P = .144). AA-THA is a credible option for obese patients, with low dislocation or fracture risk and excellent ability to reconstruct the hip, leading to comparable functional improvements among BMI groups. Obese patients have a higher risk of PJIs. Bikini incision for AA-THA can help minimize the risk of wound complications.


Role of ACTH on the cytomorphology of testes of the immature rat.
The male gametogenic development of the immature rat shows inhibitory effect by the exogenous infusion of ACTH (0.25 IU and 0.50 IU; i.p.). Seminiferous tubular degeneration, Leydig cell atrophy and Sertoli cell regression are very conspicuous in the dosage of 0.50 IU ACTH (i.p.). Cytometrical and histological evidence confirms that ACTH could be inhibited by FSH during male gametogenic development which leads to cellular degeneration of testes in the immature rat.


Rapid detection of elevated prostate-specific antigen levels in blood: performance of various membrane strip tests compared.
To compare the ability of four commercially available membrane strip tests to detect increased (4 microg/L or more) concentrations of prostate-specific antigen (PSA) in blood. Serum samples with PSA concentrations less than 4 microg/L (n = 67) and from greater than 4 microg/L to 20 microg/L (n = 32) were independently examined by two observers using the PSA membrane strip tests from Chembio, Medpro, Seratec, and Syntron. The positive and negative results of each membrane strip test were classified as either true positive or negative and false negative or positive by comparing them with the quantitative PSA assay of Immulite DPC using the conventional threshold value of 4 microg/L. The interobserver variations of the tests were between 93% and 97%. The color stability of the Seratec and Chembio tests did not show significant differences between test results read within 10 to 20 minutes of the reaction time; however, the results of the other two tests were especially affected by variations in the reading time. The sensitivity and specificity of the tests in relation to the threshold of 4 microg/L were 67% to 93% and 87% to 97%, respectively. The Syntron test and, within certain limitations, the Seratec test fulfill the concept of a rapid and convenient PSA determination to detect PSA concentrations greater than 4 microg/L. Methodologic optimization of the tests by a grading of the PSA measuring ranges (eg, between 0 and 2, 3 and 4, 4 and 6, and 7 and 10 microg/L) should be taken into account for future development.


Immunohistochemical study of bone GLA protein in primary bone tumors.
The immunoreactivity of bone GLA protein (BGP) in primary bone tumors, including osteosarcoma, chondrosarcoma, malignant fibrous histiocytoma of bone (MFH), and giant cell tumor of bone (GCT), was investigated with anti-BGP rabbit serum and peroxidase-antiperoxidase complex. As to intracellular localization, BGP antigenicity was detected in 33 of 35 cases of osteosarcoma and 12 of 25 cases of chondrosarcoma. However, there were no positive findings in all 15 cases of MFH or 20 cases of GCT. In chondrosarcoma, the frequency of positively stained cases increased according to pathologic grading (i.e., 3 of 14 cases of Grade 1, 7 of 9 cases of Grade 2, and 2 of 2 cases of Grade 3). Although the multinucleated cells in MFH or GCT were not immunostained, BGP antigenicity was observed in the multinucleated cells of osteosarcoma (12 of 15 cases). In the matrix of osteosarcoma, BGP immunoreactivity of the tumorous osteoid was observed in 28 of 32 cases. However, in the matrices of chondrosarcoma, MFH, and GCT, BGP immunoreactivity was not observed. These results suggest that the immunohistochemical study of BGP is useful for the differential diagnosis of bone tumors.


Vitiligo at the sites of irradiation in a patient with Hodgkin's disease.
Vitiligo is one of the most common skin disorders. However, the etiology of vitiligo is still unknown. Current hypotheses discuss autoimmune, autotoxic and neuronal mechanisms. Here we report the case of radiation-induced depigmentation of the skin of a patient with Hodgkin's disease and 25-year history of vitiligo. We compared possible differences in skin color, skin moisture, microcirculation and skin elasticity between normal skin and skin exhibiting persistent depigmentation in a 37-year-old patient 40 months after completion of external beam radiotherapy. Colormetrically we found a dose-dependent decrease of the red/green and yellow/blue saturation combined with an overall increase in brightness in depigmented skin when compared with normal skin. This was in agreement with a loss of melanocytes in vitiligo. Depigmentation was complete in areas receiving 40 Gy. Areas which received 30 Gy showed depigmentation only if the skin dose was increased by the loss of depth of the build-up dose region in areas with direct contact with the irradiation table. We could not show any change in skin moisture, microcirculation or skin elasticity. Complete radiation-induced depigmentation of skin from patients suffering from vitiligo is a side effect of radiation therapy. Patients should be informed about this side effect by the radiooncologist. Preventing the loss of depth of the build-up dose region might improve the cosmetic results of radiation therapy in patients with history of vitiligo.


Simulating dose reduction for myocardial perfusion SPECT using a Poisson resampling method.
The purpose of this study was to determine the lowest Tl-201 dose that does not reduce the image quality of myocardial perfusion SPECT (MPS) by Poisson resampling simulation. One hundred and twelve consecutive MPS data from patients with suspected or known coronary artery disease were collected retrospectively. Stress and rest MPS data were resampled using the Poisson method with 33%, 50%, 67%, and 100% count settings. Two nuclear medicine physicians assessed the image quality of reconstructed data visually by giving grades from - 2 to + 2. The summed stress score (SSS), summed rest score (SRS), and summed difference score (SDS) were obtained on the workstation. Image quality grades and semi-quantitative scores were then compared among these resampled images. The proportions of "adequate" image quality were 0.48, 0.75, 0.92, and 0.96 for the groups of images with 33%, 50%, 67%, and 100% data, respectively. The quality of the resampled images was significantly degraded at 50% and 33% count settings, while the image quality was not different between 67 and 100% count settings. We also found that high body mass index further decreased image quality at 33% count setting. Among the semi-quantitative parameters, SSS and SRS showed a tendency to increase with a decline in count. Based on the simulation results, Tl-201 dose for MPS can be reduced to 74 MBq without significant loss of image quality. However, the SSS and SRS can be changed significantly, and it needs to be further verified under the different conditions.


The variability of inter-spike intervals of human spindle afferents in relaxed muscles.
The impulse discharge in single afferent units was recorded in waking human subjects. Tungsten needle electrodes were percutaneously inserted in the left radial nerve, and activity in muscle spindle afferents from the extensor muscles of the forearm were studied while the subjects remained relaxed. Thirty-six spontaneously discharging single units were studied, 16 primaries, 10 secondaries and 10 non-classified. The regularity of afferent discharge and the shape of the inter-spike interval histograms was assessed by off-line statistical analysis of stationary segments of afferent discharge. The mean discharge rate of both primary and secondary afferents was generally low. Secondaries predominantly fired with low variability, whereas primaries showed high as well as low variability, but the median values for the two groups differed significantly. However, the individual unit values of coefficient of variation showed a considerable overlap between the two groups. The size of the coefficient of variation in the human spindle afferents was between that of de-efferented and of intact afferents in decerebrated cats. Determination of the coefficient of variation may therefore help, as a complementary criterion, to differentiate between primary and secondary afferents in man.


Mechanism of the reductive activation of succinate dehydrogenase.
When succinate dehydrogenase contains oxalacetate in firmly bound form, activity cannof the enzyme results in dissociation of oxalacetate and activation of the enzyme. The course of reductive titrations appears the same whether or not the enzyme contains oxalacetate, and complete reduction as monitored by bleaching of chromophoric groups requires the incorporation of 6 to 7 reducing equivalents in either case. The stoichiometry is that expected from the non-heme iron and flavin content of the enzyme. Activation of the enzyme during reductive titrations occurs predominantly with the incorporation of the second pair of electrons, while determination of activation levels at various poised potentials shows that the group involved is reduced with the uptake of 2 H+ and 2 e-. These characteristics are consistent with titration of the flavin moiety rather than non-heme iron groups. Thus it appears that activation is concurrent with the reduction of flavin to the hydroquinone form. From the measured half-reduction potential for activation, that of the flavin in an oxalacetate-free enzyme has been estimated at -90 to -60 mv at pH 7.


A systematic review of autologous transplantation methods in vitiligo.
A systematic review of the effectiveness, safety, and applicability of autologous transplantation methods in vitiligo. Computerized searches of bibliographical databases, a complementary manual literature search, and contacts with researchers and pharmaceutical firms. Predefined selection criteria were applied to all studies found. Two investigators independently assessed the articles for inclusion. When there was a disagreement, a third investigator was consulted. Sixty-three studies were found, of which 16 reported on minigrafting, 13 on split-thickness grafting, 15 on grafting of epidermal blisters, 17 on grafting of cultured melanocytes, and 2 on grafting of noncultured epidermal suspension. Of these, 39 patient series were included. The highest mean success rates (87%) were achieved with split-skin grafting (95% confidence interval, 82%-91%), and epidermal blister grafting (87%) (95% confidence interval, 83%-90%). The mean success rate of 5 culturing techniques varied from 13% to 53%. However, in 4 of the 5 culturing methods, fewer than 20 patients were studied. Minigrafting had the highest rates of adverse effects but was the easiest, fastest, and least expensive method. Because no controlled trials were included, treatment recommendations should be formulated with caution. Split-thickness and epidermal blister grafting can be recommended as the most effective and safest techniques. No definite conclusions can be drawn about the effectiveness of culturing techniques because only a small number of patients have been studied. The choice of method also depends on certain disease characteristics and the availability of specialized personnel and equipment.


Symptomatic duplication of the vertebral artery.
A case is presented of extracranial duplication of the vertebral artery in a patient who had spinal cord symptoms for 26 years. Vertebral angiograms and computed tomography with metrizamide enhancement demonstrated a bypass artery of the duplication compresing the upper cervical spinal cord intradurally at the level of the atlas; this finding was verified at operation. The symptomatology and clinical significance of this rare case are discussed.


Merging framework for estimating daily surface air temperature by integrating observations from multiple polar-orbiting satellites.
Reconstructing spatially continuous surface air temperature (SAT) is of great significance to climate and environmental studies. Substantial efforts have been made to estimate daily SAT based on land surface temperature (LST) derived from polar-orbiting satellites. However, previous studies are nearly all limited to estimating daily SAT based on MODIS LST from NASA's Terra or Aqua by applying different statistical learning methods. Various satellites from earth observation missions, particularly the missions for meteorological satellites, are capable of acquiring thermal infrared observations, but its implications for SAT estimation are significantly ignored. In this study, for the first time, we proposed a merging framework for estimating daily mean SAT by integrating LST datasets from multiple polar-orbiting satellites, including Metop-B from EUMETSAT's Polar System (EPS), SNPP and JPSS-1 from NOAA's Joint Polar Satellites System (JPSS), and Terra and Aqua from NASA's EOS. This study is also the first to explore the estimating of daily SAT based on LST derived from the meteorological satellites in EPS and JPSS. The framework integrates 10 estimation models based on different LST from the five satellites and generates daily merged SAT by averaging the daily SAT estimates from the models. Here we show that the framework significantly improves the spatial coverage of daily SAT estimates for cloud-free areas by an overall increase of 39% with respect to the mean coverage of the LST datasets from the five satellites. Daily coverage of the merged SAT from the framework is nearly all above 75% with an average of 91%. Compared to the SAT estimated from MODIS LST, overall increases in the coverage of daily SAT are 37%-51%. Estimation models in the framework all achieved comparable and satisfactory predicative performances with an average RMSE of 1.7-1.9 K for sample-based cross-validation, and 1.9-2.2 K for site-based cross-validation.


(Z)-5-(4-Bromo-phen-yl)-3-{[(3,5-di-chloro-phen-yl)amino]-methyl-idene}furan-2(3H)-one.
The title compound, C17H10BrCl2NO2, crystallizes in the monoclinic space group C2/c with a large cell volume of 6207 (3) Å3. The asymmetric unit of the title compound investigated at 120 K contains two crystallographically independent mol-ecules (Z' = 2). Each mol-ecule demonstrates slight non-planarity in the solid state and a Z-configuration for the exocyclic C=C bond. The crystal packing reveals the presence of π-π stacking inter-actions between the substituted benzene rings [centroid-centroid distances of 3.836 (5) Å, shift distances in the range 1.272-1.843 Å].


Stabilization of c-myc protein in human glioma cells.
The regulation of c-myc protein, product of c-myc/genes, was studied in four glioma cell lines by Northern blot, pulse-chase dot blot, immunoblot and immunoprecipitation analyses. Northern blot analysis revealed no overexpression of c-myc transcript, and pulse-chase dot blot analysis showed normal turnover rate of c-myc transcript, suggestive of no evidence of aberrant regulation of c-myc at post-transcriptional level. The synthesis levels of c-myc protein were shown by immunoprecipitation and closely associated with the c-myc transcript levels demonstrated by Northern blot, suggestive of no evidence of aberrant translational control of c-myc, whereas they were dissociated from the accumulation levels of c-myc protein shown by immunoblot, suggestive of an evidence of aberrant regulation of c-myc at post-translational level. The mean (+/- standard deviation) half-lives of c-myc protein in four glioma cell lines were calculated from the pulse-chase immunoprecipitation analysis, and being 98 +/- 8 to 143 +/- 11 min, were about four- to sixfold longer than normal. In surgical specimens, the immunostain of c-myc protein was not found in normal astrocytes but localized heterogenously in nuclei of reactive astrocytes and glioma cells, and increased in stained cell number in proportion to malignancy. Although this study was limited to four glioma cell lines, it suggests that the c-myc protein in glioma cells may be accumulated due to its prolonged half-life contributing to an uncontrolled proliferation.


Ethanolamine kinase activity and compositions of diacylglycerols, phosphatidylcholines and phosphatidylethanolamines in livers of choline-deficient rats.
These experiments were performed to find the reasons for the increased concentrations of docosahexaenoyl phosphatidylethanolamines (PE) in livers of choline-deficient rats. We measured the activity of ethanolamine kinase, which catalyzes the first step in PE formation. We also measured the compositions of PE and phosphatidylcholines (PC) and concentrations and fatty acid compositions of diacylglycerols (DG), which are precursors of PE. Young male rats were fed for one week a low-methionine, choline-deficient diet, or the same diet supplemented with choline. Ethanolamine kinase activity was measured in liver cytosol (100,000 g supernatant). Fatty acids were measured in total liver diacylglycerols and in microsomal PE and PC. Ethanolamine kinase activities were equal in choline-deficient and choline-supplemented rats. Concentrations of DG were elevated 6-fold by choline deficiency. The percentage of docosahexaenoic acid (22:6n-3) in microsomal PE was nearly doubled by choline deficiency. Although the increased concentrations of PE in choline-deficient livers cannot be attributed to increased activity of ethanolamine kinase, the rate of PE formation probably was increased by increases in concentrations of its precursors, including DG. The disproportionate increase in 22:6n-3 PE probably was caused by a selective formation of PE from DG that contain 22:6n-3.


Tolerability and Pharmacokinetics of SYN-004, an Orally Administered β-Lactamase for the Prevention of Clostridium difficile-Associated Disease and Antibiotic-Associated Diarrhea, in Two Phase 1 Studies.
SYN-004 is an orally administered β-lactamase enzyme, designed to be given concurrently with certain intravenous β-lactam antibiotics like cephalosporins. SYN-004 is intended to degrade residual antibiotics excreted into the intestine as a result of hepatobiliary excretion and to prevent the disruption of the gut microbiome by these excess antibiotics. Preserving the gut microbiome is expected to prevent secondary infections by pathogens like Clostridium difficile and protect against other antibiotic-associated diarrheas. Two, randomized, double blind, placebo-controlled Phase 1 clinical studies were conducted in normal healthy adult volunteers to assess the tolerability and systemic absorption of single and multiple doses of SYN-004. A single-ascending dose study investigated single oral doses of 75-750 mg SYN-004 and was conducted in 40 subjects (five cohorts of six active and two placebo subjects). A multiple-ascending dose study investigated doses of 75-300 mg SYN-004, administered every 6 h for 7 days and was conducted in 24 subjects (three cohorts of six active and two placebo subjects). The safety and tolerability of SYN-004 was assessed and serial plasma and serum samples were collected to assess the pharmacokinetics and potential immunogenicity of SYN-004. Minimal and mild adverse events were reported in ~30 % of the subjects who received active drug and placebo and no antidrug antibodies were detected in any subject. Analysis of serial plasma samples demonstrated negligible systemic bioavailability of SYN-004 with most plasma concentrations being below the lower limit of quantitation (0.8 ng/mL) for the assay. SYN-004 was well tolerated in the 48 subjects who received active drug, and adverse events in those subjects were comparable to the 16 subjects who received placebo, up to the maximum doses administered in each study. SYN-004 was well tolerated up to a single oral dose of 750 mg and multiple doses of 300 mg every 6 h for 7 days. The pharmacokinetic results support that SYN-004 remained localized in the intestine.


Differential growth factor control of bone formation through osteoprogenitor differentiation.
The osteogenic factors bone morphogenetic protein (BMP-7), platelet-derived growth factor (PDGF)-BB, and fibroblast growth factor (FGF-2) regulate the recruitment of osteoprogenitor cells and their proliferation and differentiation into mature osteoblasts. However, their mechanisms of action on osteoprogenitor cell growth, differentiation, and bone mineralization remain unclear. Here, we tested the hypothesis that these osteogenic agents were capable of regulating osteoblast differentiation and bone formation in vitro. Normal human bone marrow stromal (HBMS) cells were treated with BMP-7 (40 ng ml(-1)), PDGF-BB (20 ng ml(-1)), FGF-2 (20 ng ml(-1)), or FGF-2 plus BMP-7 for 28 days in a serum-containing medium with 10 mM beta-glycerophosphate and 50 microg ml(-1) ascorbic acid. BMP-7 stimulated a morphological change to cuboidal-shaped cells, increased alkaline phosphatase (ALKP) activity, bone sialoprotein (BSP) gene expression, and alizarin red S positive nodule formation. Hydroxyapatite (HA) crystal deposition in the nodules was demonstrated by Fourier transform infrared (FTIR) spectroscopy only in BMP-7- and dexamethasone (DEX)-treated cells. DEX-treated cells appeared elongated and fibroblast-like compared to BMP-7-treated cells. FGF-2 did not stimulate ALKP, and cell morphology was dystrophic. PDGF-BB had little or no effect on ALKP activity and biomineralization. Alizarin Red S staining of cells and calcium assay indicated that BMP-7, DEX, and FGF-2 enhanced calcium mineral deposition, but FTIR spectroscopic analysis demonstrated no formation of HA similar to human bone in control, PDGF-BB-, and FGF-2-treated samples. Thus, FGF-2 stimulated amorphous octacalcium phosphate mineral deposition that failed to mature into HA. Interestingly, FGF-2 abrogated BMP-7-induced ALKP activity and HA formation. Results demonstrate that BMP-7 was competent as a sole factor in the differentiation of human bone marrow stromal cells to bone-forming osteoblasts confirmed by FTIR examination of mineralized matrix. Other growth factors, PDGF, and FGF-2 were incompetent as sole factors, and FGF-2 inhibited BMP-7-stimulated osteoblast differentiation.


Distinguishing outcomes of neonatal intestinal volvulus: Review of our experience over the last 20 years.
There are two types of intestinal volvulus: midgut (MGV) and segmental (SV). Patients with different types of intestinal volvulus are often included in the same case series, which may affect the perception of how severe "intestinal volvuli" are. We aimed to compare both types of intestinal volvulus. This is a retrospective observational study including all patients with MGV and SV up to 28 days of life admitted to a tertiary hospital in Spain over a 20-year-period (1999-2019). A comparison between groups and a logistic regression model for mortality were done. We identified 32 patients: 23 MGV and 9 SV. Malrotation was exclusive of MGV. Prenatal diagnosis, cystic fibrosis, and intestinal resection were significantly more frequent in SV. Surgery was performed at a significantly lower age in SV. The mortality observed in acute MGV with intestinal compromise (41.7%) is four times higher than the mortality of SV (11.1%). The overall mortality of all MGV patients (21.7%) is almost twice that of SV. Mortality was best predicted by the presence of hemodynamic instability (OR 27.5 95% CI 2.50-302.17; p = 0.007). SV and MGV have a different clinical presentation. Hemodynamic instability is the major risk factor for death.


Induction of micronuclei by bleomycin in G0 human lymphocytes: II. Potentiation by radioprotectors.
Dimethylsulfoxide (DMSO) and WR-1065 are radioprotectors, in that they reduce the effectiveness with which ionizing radiation causes genetic damage. Unlike their protective effects with radiation, these agents potentiate the induction of micronuclei by bleomycin in the cytokinesis-block assay in G0 human lymphocytes. High concentrations of DMSO (1 M) are required to cause potentiation. In contrast, WR-1065 causes dose-dependent potentiation at relatively low concentrations (1.25 to 10 mM). Cytogenetic analysis supports the results from the micronucleus assay, showing higher levels of genetic damage induced by the combination of bleomycin with DMSO or WR-1065 than by bleomycin alone. Possible mechanisms of potentiation are proposed.


BLIMP1 guides the fate of effector B and T cells.
B-lymphocyte-induced maturation protein 1 (BLIMP1) is a transcriptional repressor, and its importance in controlling the terminal differentiation of antibody-secreting cells (ASCs) is well established. However, as we discuss in this Progress article, it has now become evident that the ASC programme consists of a discrete BLIMP1-independent initiation phase, followed by a second step in which BLIMP1 is absolutely required for the differentiation of fully mature ASCs. In addition, an important role for BLIMP1 in maintaining the homeostasis of effector T cells is emerging, suggesting intriguing parallels between the control of effector-cell fates in both B and T cells.


Anxiety, depression, and sleep quality among breast cancer patients in North China: Mediating roles of hope and medical social support.
Sleep disorders are highly prevalent among breast cancer patients and have a detrimental impact on their quality of life. This study aims to investigate the serial multiple mediating roles of social support and hope in the relationship between anxiety, depression, and sleep quality in breast cancer patients. A cross-sectional study was conducted in China from October 2021 to February 2022. A total of 315 breast cancer patients were assessed using self-reported questionnaires, including the Pittsburgh Sleep Quality Index (PSQI), Medical Outcomes Study Social Support Survey (MOS-SSS), Herth Hope Index (HHI), and Hospital Anxiety and Depression Scale (HADS). Mediation analysis was performed using the R Statistical Software. Sleep quality exhibited a negative correlation with hope and medical social support (P < 0.01), and a positive correlation with anxiety and depression (P < 0.01). Anxiety and depression accounted for 18.8% and 12.8% of the variance in sleep quality, respectively. Bootstrap analyses of the anxiety-medical social support-hope-sleep quality pathway indicated the presence of direct effects [B = 0.331, 95%CI (0.215, 0.493)] and indirect effects of anxiety on sleep quality mediated solely by medical social support [B = 0.054, 95%CI (0.015, 0.108)] and hope [B = 0.041, 95%CI (0.018, 0.073)], as well as combined effects [B = 0.012, 95%CI (0.004, 0.025)]. Similarly, the depression-medical social support-hope-sleep quality pathway revealed direct effects [B = 0.235, 95%CI (0.104, 0.372)] and indirect effects of depression on sleep quality mediated solely by medical social support [B = 0.078, 95%CI (0.016, 0.150)] and hope [B = 0.049, 95%CI (0.018, 0.086)], as well as combined effects [B = 0.017, 95%CI (0.004, 0.034)]. This research validates the hypothesis that medical social support and hope serve as mediators between anxiety, depression, and sleep quality in breast cancer patients. Interventions targeting anxiety, depression, medical social support, and hope have the potential to effectively enhance sleep quality.


[Pediatric brucellosis : A case report and literature review].
Brucellosis is an overlooked infection of widespread geographic distribution. This disease is rarely evoked when assessing unexplained pediatric fever, and only 20-30 cases (children and adults) are confirmed per year. Risk factors for contracting brucellosis are exposure to bodily fluids and consumption of unpasteurized dairy products from infected animals. Most cases of brucellosis are associated with traveling to or importing contaminated goods from endemic areas. Here, we report a case of brucellosis in a 16-month-old patient hospitalized for an acute febrile illness in a French general pediatric ward. An antibiotic regimen of rifampicin and co-trimoxazole given over 6 weeks led to successful cure without relapse. The child had eaten a cake made from unpasteurized goat's milk and imported from Oran, a region in Algeria. His mother had consumed the same cake and was hospitalized for brucellosis 15 days later. Clinicians should suspect brucellosis when encountering febrile patients who have traveled to endemic areas, been exposed to body fluids or products of abortion of farm animals, or consumed unpasteurized products.