Indoor and outdoor air concentrations of BTEX and NO2: correlation of repeated measurements.
Studies on health effects of air pollutants ideally define exposure through the collection of air samples in the participants' homes. Concentrations derived from these samples are then considered as an estimate for the average concentration of air pollutants in the homes. Conclusions drawn from such studies therefore depend very much on the validity of the measured air pollution concentrations. In this paper we analysed repeated BTEX and NO(2) measurements with a time period of several months lying between the two conducted home visits. We investigated the variability of their concentrations over time by determining correlation coefficients and calculating within- and between-home variances. Our population consisted of 631 homes of participants from two cohort studies within the framework of the German study on Indoor Factors and Genetics in Asthma. Air pollutants were measured using passive samplers both indoors and outdoors. The measured BTEX concentrations were poorly correlated, with Pearson's correlation coefficient r ranging from -0.19 to 0.27. Additionally, a considerable seasonal effect could be observed. A higher correlation was found for the NO(2) concentrations with r ranging between 0.24 and 0.55. For the BTEX, the between-home variance was bigger than the within-home variance, for NO(2) both variances were of about the same order. Our results indicate that in a setting of moderate climate like in Germany, the variability of BTEX and NO(2) concentrations over time is high and a single measurement is a poor surrogate for the long-term concentrations of these air pollutants.


Cryopreservation of human embryonic stem cells without the use of a programmable freezer.
An effective freezing-thawing technique is crucial for the clinical application of human embryonic stem (ES) cells. The aim of this study was to find an optimal cryopreservation protocol for human ES cells using slow freezing-rapid thawing without a programmable freezer. The human ES cell line, SNUhES-3, was cultured on an STO feeder layer in gelatin-coated tissue culture dishes. All cryopreservation steps were performed using a simple commercial freezing container. The survival rate of cryopreserved-thawed human ES cells was estimated by counting colony numbers under a stereomicroscope. Initially, we compared the survival rates of cryopreserved human ES cells using three cryoprotectants: dimethylsulphoxide (DMSO), ethylene glycol (EG) and glycerol. In this experiment, 5% DMSO/95% fetal bovine serum (FBS) (vol/vol) showed the highest survival rate. We next tested the impact of various concentrations of FBS (95, 50 and 5%) with 5% DMSO, and then examined the effects of adding EG or glycerol to 5% DMSO + optimal FBS. No significant difference in survival rate was observed between 95 and 50% FBS in the presence of 5% DMSO. A significant improvement in survival rate was obtained by adding 10% EG to 5% DMSO+50% FBS. After thawing, surviving cells were found to maintain the inherent characteristics of human ES cells. 5% DMSO+50% FBS+10% EG may be an optimal cryoprotectant for the slow freezing-rapid thawing of human ES cells.


Toward an ethics of global health (de)funding: Thoughts from a maternity hospital project in Kabul, Afghanistan.
Funding and defunding decisions in global health are often not subject to ethical scrutiny although they carry the potential for iatrogenic violence. The funding and defunding of a maternal health project in Kabul, Afghanistan during the 2000s reveals the post 9/11 science-politics dynamics that resulted in the emergence of maternal mortality in Afghanistan as a humanitarian object. Despite concerns raised by the Afghan Ministry of Public Health, U.S. Department of Health and Human Services subcontractors renovated one of four public maternity hospitals in Kabul, doubling the number of births per year and increasing the rate of caesarean sections. Project defunding in 2011 was due to a confluence of primarily political factors. Project actors - Afghan and internationals - expressed ethical concerns about the abrupt defunding and the particular risks to women undergoing emergency caesarean sections at the hospital. The analysis presented here has wider relevance for the global surgery movement and concerns about fluctuations in donor funding in global health. There is a need for an ethics of global health funding and defunding decisions that encompasses policies, relationships, stronger local public health systems and civic participation. Global health (de)funding must be made more of an object of ethical deliberation and negotiation.


[Teacher development and post-graduate studies in health: an experience at the Federal University of São Paulo].
The aim of this study was to analyze the views and conceptions shared by the graduate students who attended the Pedagogy and Didactics in Health Sciences Course, offered by the Graduate Programs at the UNIFESP. The methodological approach consisted of bibliographic research on the higher education teaching; documental analysis involving the national legislation for higher education, teaching and graduate studies and documents related to this Course. Graduate students from 1998 and 2003 were mapped in order to build the samples of those (112 egresses) that were involved in teaching activities. The data were collected through a semi-structured questionnaire. The data analysis, oriented by the Content Analysis Technique, reveals that this experience has an influence on the way these professors understand and practice their teaching skills, showing the importance for the faculty development at the higher education level in Health Sciences.


Characterization of human inducible costimulator ligand expression and function.
The inducible costimulator (ICOS) is the newest member of the CD28/CD152 receptor family involved in regulating T cell activation. We constructed a soluble-Ig fusion protein of the extracellular domain of human ICOS and used it as a probe to characterize expression patterns of the ICOS ligand (ICOSL). ICOSIg did not bind to CD80- or CD86-transfected Chinese hamster ovary cell lines, demonstrating that ICOSL is distinct from those ligands identified for CD28/CD152. ICOSIg showed selective binding to monocytic and B cell lines, whereas binding was undetectable on unstimulated monocytes and peripheral blood T and B cells. Expression of ICOSL was induced on monocytes after integrin-dependent plastic adhesion. Pretreatment of monocytes with mAb to the beta2-integrin subunit CD18 decreased adhesion and abolished ICOSL up-regulation but had no effect on CD80/86 (CD152 ligand (CD152L)) expression. Both ICOSL and CD152L were up-regulated on monocytes by IFN-gamma but by distinct signaling pathways. Unlike CD152L expression, ICOSL expression did not change when monocytes were differentiated into dendritic cells (DCs) or after DCs were induced to mature by LPS, TNF-alpha, or CD40 ligation. Addition of ICOSIg to allogeneic MLRs between DCs and T cells reduced T cell proliferative responses but did so less efficiently than CTLA4Ig (CD152Ig) did. Similarly, ICOSIg also blocked Ag-specific T cell proliferation to tetanus toxoid. Thus, ICOSL, like CD80/86, is expressed on activated monocytes and dendritic cells but is regulated differently and delivers distinct signals to T cells that can be specifically inhibited by ICOSIg.


Donor-Acceptor Conjugated Acetylenic Polymers for High-Performance Bifunctional Photoelectrodes.
Due to the drastic required thermodynamical requirements, a photoelectrode material that can function as both a photocathode and a photoanode remains elusive. In this work, we demonstrate for the first time that, under simulated solar light and without co-catalysts, donor-acceptor conjugated acetylenic polymers (CAPs) exhibit both impressive oxygen evolution (OER) and hydrogen evolution (HER) photocurrents in alkaline and neutral medium, respectively. In particular, poly(2,4,6-tris(4-ethynylphenyl)-1,3,5-triazine) (pTET) provides a benchmark OER photocurrent density of ~200 μA cm-2 at 1.23 V vs. reversible hydrogen electrode (RHE) at pH 13 and a remarkable HER photocurrent density of ~190 μA cm-2 at 0.3 V vs. RHE at pH 6.8. By combining theoretical investigations and electrochemical-operando Resonance Raman spectroscopy, we show that the OER proceeds with two different mechanisms, with the electron-depleted triple bonds acting as single-site OER in combination with the C4-C5 atoms of the phenyl rings as dual sites. The HER, instead, occurs via an electron transfer from the tri-acetylenic linkages to the triazine rings, which act as the HER active sites. This work represents a novel application of organic-based materials and contributes to the development of high-performance photoelectrochemical catalysts for the solar fuels' generation.


Sec6-dependent sorting of fungal extracellular exosomes and laccase of Cryptococcus neoformans.
The cell wall of pathogenic fungi such as Cryptococcus neoformans, provides a formidable barrier to secrete virulence factors that produce host cell damage. To study secretion of virulence factors to the cell periphery, sec6 RNAi mutant strains of C. neoformans were tested for virulence factor expression. The studies reported here show that SEC6 RNAi mutant strains were defective in a number of virulence factors including laccase, urease as well as soluble polysaccharide and demonstrated attenuated virulence in mice. Further analysis by transmission electron microscopy detected the production of abundant extracellular exosomes in wild-type strains containing empty plasmid, but a complete absence in the iSEC6 strain. In addition, a green fluorescent protein-laccase fusion protein demonstrated aberrant localization within cytoplasmic vesicles in iSEC6 strains. In contrast, iSEC6 strains retained normal growth at 37 degrees C, as well as substantially normal capsule formation, phospholipase activity and total secreted protein. These results provide the first molecular evidence for the existence of fungal exosomes and associate these vesicles with the virulence of C. neoformans.


State variation in opioid and benzodiazepine prescriptions between independent and nonindependent advanced practice registered nurse prescribing states.
Many people lack access to primary care services in the United States. One possible solution is to increase utilization of advanced practice registered nurses (APRNs). A common patient safety concern about independent prescribing by APRNs is that prescribers will increase prescriptions for medications with abuse/dependence potential, such as opioids or benzodiazepines. The purpose was to investigate the relationship in opioid- and benzodiazepine-prescribing rates between independent vs. nonindependent APRN prescribing states. Tertiary analysis of a Centers for Disease Control and Prevention study reporting state variation in prescribing rates of opioids and benzodiazepines using 2012 Intercontinental Marketing Services Health retail prescription data representing 259,000,000 prescriptions. Analyses were performed using different definitions for independent states: (a) states allowing at least one APRN type independent prescribing and (b) states allowing all APRN types independent prescribing. ANOVA tests were used to test for differences in mean number of opioid- and benzodiazepine-prescribing rates per 100 residents. Analysis of Covariance tests were employed controlling for state characteristics previously determined to affect controlled substance-prescribing rates (e.g., Medicare rates, race, socioeconomic status, number of physicians/capita). There were significantly higher opioid and benzodiazepine prescriptions in states with nonindependent APRN prescribing laws than those in states with independent APRN prescribing laws and no significant differences in long-acting opioids or high-dose opioids. This study found no evidence to support the argument that independent prescribing increases prescriptions with abuse potential. Independent prescriptive authority, only one piece of APRN practice, has been one of the most controversial issues but one with great potential to help ease access to U.S. health care problems. Empirical evidence demonstrating the safety of this practice can help promote this potential.


Vitamin D pathway-related gene polymorphisms and their association with metabolic diseases: A literature review.
Given that the relationship between vitamin D status and metabolic diseases such as obesity and type 2 diabetes (T2D) remains unclear, this review will focus on the genetic associations, which are less prone to confounding, between vitamin D-related single nucleotide polymorphisms (SNPs) and metabolic diseases. A literature search of relevant articles was performed on PubMed up to December 2019. Those articles that had examined the association of vitamin D-related SNPs with obesity and/or T2D were included. Two reviewers independently evaluated the eligibility for the inclusion criteria and extracted the data. In total, 73 articles were included in this review. There is a lack of research focusing on the association of vitamin D synthesis-related genes with obesity and T2D; however, the limited available research, although inconsistent, is suggestive of a protective effect on T2D risk. While there are several studies that investigated the vitamin D metabolism-related SNPs, the research focusing on vitamin D activation, catabolism and transport genes is limited. Studies on CYP27B1, CYP24A1 and GC genes demonstrated a lack of association with obesity and T2D in Europeans; however, significant associations with T2D were found in South Asians. VDR gene SNPs have been extensively researched; in particular, the focus has been mainly on BsmI (rs1544410), TaqI (rs731236), ApaI (rs7975232) and FokI (rs2228570) SNPs. Even though the association between VDR SNPs and metabolic diseases remain inconsistent, some positive associations showing potential effects on obesity and T2D in specific ethnic groups were identified. Overall, this literature review suggests that ethnic-specific genetic associations are involved. Further research utilizing large studies is necessary to better understand these ethnic-specific genetic associations between vitamin D deficiency and metabolic diseases.


Exon duplications in the ATP7A gene: frequency and transcriptional behaviour.
Menkes disease (MD) is an X-linked, fatal neurodegenerative disorder of copper metabolism, caused by mutations in the ATP7A gene. Thirty-three Menkes patients in whom no mutation had been detected with standard diagnostic tools were screened for exon duplications in the ATP7A gene. The ATP7A gene was screened for exon duplications using multiplex ligation-dependent probe amplification (MLPA). The expression level of ATP7A was investigated by real-time PCR and detailed analysis of the ATP7A mRNA was performed by RT-PCR followed by sequencing. In order to investigate whether the identified duplicated fragments originated from a single or from two different X-chromosomes, polymorphic markers located in the duplicated fragments were analyzed. Partial ATP7A gene duplication was identified in 20 unrelated patients including one patient with Occipital Horn Syndrome (OHS). Duplications in the ATP7A gene are estimated from our material to be the disease causing mutation in 4% of the Menkes disease patients. The duplicated regions consist of between 2 and 15 exons. In at least one of the cases, the duplication was due to an intra-chromosomal event. Characterization of the ATP7A mRNA transcripts in 11 patients revealed that the duplications were organized in tandem, in a head to tail direction. The reading frame was disrupted in all 11 cases. Small amounts of wild-type transcript were found in all patients as a result of exon-skipping events occurring in the duplicated regions. In the OHS patient with a duplication of exon 3 and 4, the duplicated out-of-frame transcript coexists with an almost equally represented wild-type transcript, presumably leading to the milder phenotype. In general, patients with duplication of only 2 exons exhibit a milder phenotype as compared to patients with duplication of more than 2 exons. This study provides insight into exon duplications in the ATP7A gene.


Multi-species, multi-transcription factor binding highlights conserved control of tissue-specific biological pathways.
As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.


Ultra-short-bowel syndrome is not an absolute indication to small-bowel transplantation in childhood.
Short-bowel syndrome (SBS) either in adults or in children is considered as an indication to small-bowel transplantation (SBTx), particularly in its most severe form with a residual bowel length below 20 cm. Among factors likely to worsen the prognosis, more recent reports also indicate the number of surgical interventions, early onset sepsis and early development of liver disease. We report six cases of ultra-short-bowel syndrome followed from birth to verify the importance of various prognostic factors. In our case series, the male sex is predominating (5:1). Intestinal resection was indicated in 3 patients for multiple intestinal atresias, in 2 for volvulus and in 1 for necrotizing enterocolitis. The length of intestine remaining was invariably less than 20 cm and 2 patients had a preserved ileocecal valve. In most cases, more than 50% of the colon remained. The number of abdominal operations ranged from 1 to 4. In almost all cases (5 of 6), sepsis and hepatopathy developed early. Our experience suggests that rather than depending on the length of intestine remaining or the presence of the ileocecal valve, the prognosis of patients with the extreme-short-bowel syndrome depends on recurrent neonatal onset sepsis and early onset liver impairment. In addition, our case review shows that the extreme-short-bowel syndrome is not necessarily an indication for bowel transplantation.


Dynamics and evolution of β-catenin-dependent Wnt signaling revealed through massively parallel clonogenic screening.
Wnt/β-catenin signaling is of significant interest due to the roles it plays in regulating development, tissue regeneration and disease. Transcriptional reporters have been widely employed to study Wnt/β-catenin signal transduction in live cells and whole organisms and have been applied to understanding embryonic development, exploring oncogenesis and developing therapeutics. Polyclonal heterogeneity in reporter cell lines has historically been seen as a challenge to be overcome in the development of novel cell lines and reporter-based assays, and monoclonal reporter cell lines are commonly employed to reduce this variability. A375 cell lines infected with a reporter for Wnt/β-catenin signaling were screened over short (<6) and long (>25) generational timescales. To characterize phenotypic divergence over these time-scales, a microfabricated cell array-based screen was developed enabling characterization of 1119 clonal colonies in parallel. This screen revealed phenotypic divergence after <6 generations at a similar scale to that observed in monoclonal cell lines cultured for >25 generations. Not only were reporter dynamics observed to diverge widely, but monoclonal cell lines were observed with seemingly opposite signaling phenotypes. Additionally, these observations revealed a generational-dependent trend in Wnt signaling in A375 cells that provides insight into the pathway's mechanisms of positive feedback and self-inhibition.


Syntrophic co-culture amplification of production phenotype for high-throughput screening of microbial strain libraries.
Microbes can be engineered to synthesize a wide array of bioproducts, yet production phenotype evaluation remains a frequent bottleneck in the design-build-test cycle where strain development requires iterative rounds of library construction and testing. Here, we present Syntrophic Co-culture Amplification of Production phenotype (SnoCAP). Through a metabolic cross-feeding circuit, the production level of a target molecule is translated into highly distinguishable co-culture growth characteristics, which amplifies differences in production into highly distinguishable growth phenotypes. We demonstrate SnoCAP with the screening of Escherichia coli strains for production of two target molecules: 2-ketoisovalerate, a precursor of the drop-in biofuel isobutanol, and L-tryptophan. The dynamic range of the screening can be tuned by employing an inhibitory analog of the target molecule. Screening based on this framework requires compartmentalization of individual producers with the sensor strain. We explore three formats of implementation with increasing throughput capability: confinement in microtiter plates (102-104 assays/experiment), spatial separation on agar plates (104-105 assays/experiment), and encapsulation in microdroplets (105-107 assays/experiment). Using SnoCAP, we identified an efficient isobutanol production strain from a random mutagenesis library, reaching a final titer that is 5-fold higher than that of the parent strain. The framework can also be extended to screening for secondary metabolite production using a push-pull strategy. We expect that SnoCAP can be readily adapted to the screening of various microbial species, to improve production of a wide range of target molecules.


Development of a Vascularized Heterotopic Neonatal Rat Heart Transplantation Model.
Rodent adult-to-adult heterotopic heart transplantation is a well-established animal model, and the detailed surgical technique with several modifications has been previously described. In immature donor organ transplantation, however, the surgical technique needs to be revised given the smaller size and fragility of the donor graft. Here, we report our surgical technique for heterotopic abdominal (AHTx) and femoral (FHTx) neonatal rat heart transplantation based on an experience of over 300 cases. Heterotopic heart transplantation was conducted in syngeneic Lewis rats. Neonatal rats (postnatal day 2-4) served as donors. AHTx was performed by utilizing the conventional adult-to-adult transplant method with specific modifications for optimal aortotomy and venous anastomosis. In the FHTx, the donor heart was vascularized by connecting the donor's aorta and pulmonary artery to the recipient's right femoral artery and vein, respectively, in an end-to-end manner. A specifically fashioned butterfly-shaped rubber sheet was used to align the target vessels properly. The transplanted graft was visually assessed for its viability and was accepted as a technical success when the viability met specific criteria. Successfully transplanted grafts were subject to further postoperative evaluation. Forty cases (AHTx and FHTx; n = 20 each) were compared regarding perioperative parameters and outcomes. Both models were technically feasible (success rate: AHTx 75% vs. FHTx 70%) by refining the conventional heterotopic transplant technique. Injury to the fragile donor aorta and congestion of the graft due to suboptimal venous connection were predominant causes of failure, leading to refractory bleeding and poor graft viability. Although the FHTx required significantly longer operation time and graft ischemic time, the in situ graft viabilities were comparable. The FHTx provided better postoperative monitoring as it enabled daily graft palpation and better echocardiographic visualization. We describe detailed surgical techniques for AHTx and FHTx while addressing neonatal donor-specific issues. Following our recommendations potentially reduces the learning curve to achieve reliable and reproducible results with these challenging animal models.


Modelling transport and mean age of dense core vesicles in large axonal arbours.
A model simulating the transport of dense core vesicles (DCVs) in type II axonal terminals of Drosophila motoneurons has been developed. The morphology of type II terminals is characterized by the large number of en passant boutons. The lack of both scaled-up DCV transport and scaled-down DCV capture in boutons results in a less efficient supply of DCVs to distal boutons. Furthermore, the large number of boutons that DCVs pass as they move anterogradely until they reach the most distal bouton may lead to the capture of a majority of DCVs before they turn around in the most distal bouton to move in the retrograde direction. This may lead to a reduced retrograde flux of DCVs and a lack of DCV circulation in type II terminals. The developed model simulates DCV concentrations in boutons, DCV fluxes between the boutons, age density distributions of DCVs and the mean age of DCVs in various boutons. Unlike published experimental observations, our model predicts DCV circulation in type II terminals after these terminals are filled to saturation. This disagreement is likely because experimentally observed terminals were not at steady state, but rather were accumulating DCVs for later release. Our estimates show that the number of DCVs in the transiting state is much smaller than that in the resident state. DCVs travelling in the axon, rather than DCVs transiting in the terminal, may provide a reserve of DCVs for replenishing boutons after a release. The techniques for modelling transport of DCVs developed in our paper can be used to model the transport of other organelles in axons.


Using Inpatient Portals to Engage Family Caregivers in Acute Care Setting: A Literature Review.
This study aims to review the literature evaluating the design, acceptance, use and usability of inpatient portals for family caregivers. Fourteen articles were included. Information about patient medication, lab results and healthcare team was most important. Most caregivers were satisified and perceived the ease of use and usefulnesss of portals. Further research is needed to collect sufficient evidence with regard to the impact of inpatient portals on patient engagement and quality of care.


Metabolic responses of the kidney in fetal sheep: effect of acute and spontaneous hypoxemia.
To examine the effects of hypoxemia on carbohydrate and O2 consumption by the fetal kidney, we inserted catheters into the descending aorta, inferior vena cava, and left renal vein of 14 fetal sheep at 120-130 days gestation. Three to nine days after surgery, nine fetuses had an arterial PO2 of 22 +/- 2 mmHg and O2 content of 2.68 +/- 0.65 mM. In these fetuses, the kidneys consumed O2 (107 +/- 21 mumol X min-1 X 100 g-1, mean +/- SD) and lactate (14 +/- 9.6 mumol X min-1 X 100 g-1) but produced glucose (5.6 +/- 6.5 mumol X min-1 X 100 g-1; 95% confidence limits, 0.62 and 10.5). When acute hypoxemia was induced by decreasing maternal fractional inspired O2 (FIO2) to 0.09, renal O2 consumption fell slightly (to 82 +/- 21 mumol X min-1 X 100 g-1), and there was net glucose uptake and net lactate release. A group of five fetuses was spontaneously hypoxemic 3-5 days after surgery and had an arterial PO2 of 14 +/- 2 mmHg and O2 content of 1.99 +/- 0.51 mM. Renal blood flow and O2 consumption were greater in these fetuses than in the normoxemic fetuses. There was net lactate uptake and no net flux of glucose across the renal circulation. These results demonstrate that renal metabolism of carbohydrate is altered by changes in fetal oxygenation.


Absence of ductal hyper-keratinization in mouse age-related meibomian gland dysfunction (ARMGD).
Meibomian gland dysfunction (MGD) is frequent with aging and is the primary cause of dry eye disease, the most prevalent ocular complaint. We used a novel 3-D reconstruction technique, immunofluorescent computed tomography (ICT), to characterize meibomian gland keratinization and cell proliferation in a mouse model of age-related meibomian gland dysfunction (ARMGD). To visualize the changes associated with ARMGD, 5-month and 2-year old mouse eyelids were 3-D reconstructed by ICT using antibodies to cytokeratin (CK) 1, 5 and 6 and the proliferation marker Ki67. We quantified total gland, ductal and lipid volume from the reconstructions, observing a dramatic decrease in old glands. In young glands, proliferative ductules suggest a potential site of acinar progenitors that were found to be largely absent in aged, atrophic glands. In the aged mouse, we observed an anterior migration of the mucocutaneous junction (MCJ) and an absence of hyper-keratinization with meibomian gland atrophy. Thus, we propose that changes in the MCJ and glandular atrophy through a loss of meibocyte progenitors are most likely responsible for ARMGD and not ductal hyper-keratinization and gland obstruction.


Modified diagnostic criteria, grading classification and newly elucidated pathophysiology of hepatic SOS/VOD after haematopoietic cell transplantation.
Sinusoidal obstruction syndrome (SOS), previously known as hepatic veno-occlusive disease (VOD), remains a multi-organ system complication following haematopoietic cell transplantation (HCT). When SOS/VOD is accompanied by multi-organ dysfunction, overall mortality rates remain >80%. However, the definitions related to the diagnosis and grading of SOS/VOD after HCT are almost 25 years old and require new and contemporary modifications. Importantly, the pathophysiology of SOS/VOD, including the contribution of dysregulated inflammatory and coagulation cascades as well as the critical importance of liver and vascular derived endothelial dysfunction, have been elucidated. Here we summarise new information on pathogenesis of SOS/VOD; identify modifiable and unmodifiable risk factors for disease development; propose novel, contemporary and panel opinion-based diagnostic criteria and an innovative organ-based method of SOS/VOD grading classification; and review current approaches for prophylaxis and treatment of SOS/VOD. This review will hopefully illuminate pathways responsible for drug-induced liver injury and manifestations of disease, sharpen awareness of risk for disease development and enhance the timely and correct diagnosis of SOS/VOD post-HCT.


Large-scale sea ice-Surface temperature variability linked to Atlantic meridional overturning circulation.
Due to its involvement in numerous feedbacks, sea ice plays a crucial role not only for polar climate but also at global scale. We analyse state-of-the-art observed, reconstructed, and modelled sea-ice concentration (SIC) together with sea surface temperature (SST) to disentangle the influence of different forcing factors on the variability of these coupled fields. Canonical Correlation Analysis provides distinct pairs of coupled Arctic SIC-Atlantic SST variability which are linked to prominent oceanic and atmospheric modes of variability over the period 1854-2017. The first pair captures the behaviour of the Atlantic meridional overturning circulation (AMOC) while the third and can be associated with the North Atlantic Oscillation (NAO) in a physically consistent manner. The dominant global SIC-Atlantic SST coupled mode highlights the contrast between the responses of Arctic and Antarctic sea ice to changes in AMOC over the 1959-2021 period. Model results indicate that coupled SST-SIC patterns can be associated with changes in ocean circulation. We conclude that a correct representation of AMOC-induced coupled SST-SIC variability in climate models is essential to understand the past, present and future sea-ice evolution.


Cardiovascular safety pharmacology studies in dogs enabled for a poorly soluble molecule using spray-dried dispersion: Impact on lead selection.
The aim of this study was to identify an adequate formulation for a poorly soluble lead molecule (BI-A) that would achieve sufficiently high plasma concentrations after oral administration in dogs to enable a robust cardiovascular safety pharmacology assessment in telemetry-instrumented conscious dogs during lead optimization in drug discovery. A spray-dried dispersion of BI-A (BI-A-SDD) containing a 1:2 ratio of BI-A and hydroxypropyl methylcellulose acetate succinate-LF was prepared using a Büchi spray dryer B-90 (B-90). Physical form characterization, an in vitro dissolution test and a preliminary pharmacokinetic (PK) study following oral administration of BI-A-SDD were performed. Thereafter, effects on cardiovascular parameters in conscious, chronically-instrumented dogs were investigated for 24h after a single oral dose (5, 10, and 50mg/kg) using a modified Latin square cross-over study design. The BI-A-SDD powder was confirmed to be amorphous and was stable as an aqueous suspension for at least 4h. The BI-A-SDD suspension provided a greater rate and extent of dissolution than the crystalline BI-A suspension and the supersaturation was maintained for at least 4h. In PK studies the Cmax of the BI-A-SDD formulation (25.4μM; 77-fold the projected efficacious Cmax of 0.33μM) was 7.5-fold higher than the Cmax observed using oral administration of a 10% hydroxypropyl-β-cyclodextrin formulation at 100mg/kg in dogs (3.4μM). In conscious, chronically-instrumented dogs, the doses tested and plasma concentrations achieved were sufficient to enable a robust safety pharmacology evaluation. Multiple off-target hemodynamic effects were detected including acute elevations in aortic blood pressure (up to 22% elevation in systolic and diastolic blood pressure) and tachycardia (68% elevation in heart rate), results that were confirmed in other in vivo models. These results led to a deprioritization of BI-A. The study demonstrated that a spray-dried dispersion, prepared using the B-90 in drug discovery, enhanced the oral exposure of a poorly water-soluble molecule, BI-A, and thereby enabled its evaluation in safety pharmacology studies that ultimately resulted in deprioritization of BI-A from a pool of lead compounds.


[Expression and enzymatic activity of glutathione s-transferase in tissues of Boophilus microplus females].
Cellular detoxification and excretion enzymes are important to the maintenance of cellular homeostasis. In this work mRNA transcription, protein expression and enzymatic activity of Glutathione S-transferases (GSTs), enzymes involved in the excretion of endo and xenobiotic compounds were analyzed. These parameters are elements believed to protect cells against chemical toxicity and oxidative stress in different tissues (salivary gland, ovary and synganglion) from partially engorged females and engorged females of Boophilus microplus. The results presented showed elevated GST activity in partially engorged females. The enzymatic activity decreased during the preoviposition period in engorged females. GST mRNA transcription was detected in salivary glands and synganglion from partially engorged and engorged females, but not in ovary. The results of this work help to elucidate the role of GST in tick development and assist in the understanding of the importance of GST in tick females during the preparation for oviposition.


Morphometric analysis of the distal femur in total knee arthroplasty and native knees.
Analysis of the morphology of the distal femur, and by extension of the femoral components in total knee arthroplasty (TKA), has largely been related to the aspect ratio, which represents the width of the femur. Little is known about variations in trapezoidicity (i.e. whether the femur is more rectangular or more trapezoidal). This study aimed to quantify additional morphological characteristics of the distal femur and identify anatomical features associated with higher risks of over- or under-sizing of components in TKA. We analysed the shape of 114 arthritic knees at the time of primary TKA using the pre-operative CT scans. The aspect ratio and trapezoidicity ratio were quantified, and the post-operative prosthetic overhang was calculated. We compared the morphological characteristics with those of 12 TKA models. There was significant variation in both the aspect ratio and trapezoidicity ratio between individuals. Femoral trapezoidicity was mostly due to an inward curve of the medial cortex. Overhang was correlated with the aspect ratio (with a greater chance of overhang in narrow femurs), trapezoidicity ratio (with a greater chance in trapezoidal femurs), and the tibio-femoral angle (with a greater chance in valgus knees). This study shows that rectangular/trapezoidal variability of the distal femur cannot be ignored. Most of the femoral components which were tested appeared to be excessively rectangular when compared with the bony contours of the distal femur. These findings suggest that the design of TKA should be more concerned with matching the trapezoidal/rectangular shape of the native femur. The distal femur is considerably more trapezoidal than most femoral components, and therefore, care must be taken to avoid anterior prosthetic overhang in TKA


Impact of a statewide ST-segment-elevation myocardial infarction regionalization program on treatment times for women, minorities, and the elderly.
Prior studies have demonstrated differences in time to reperfusion for ST-segment-elevation myocardial infarction (STEMI) in women, minorities, and the elderly, relative to their counterparts. Regionalization has been shown to improve overall STEMI treatment times, but its impact on care differences among these important patient subgroups is unknown. The objective of this analysis was to assess the impact of a statewide system of STEMI care (The Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments) on treatment times according to patient sex, race, and age. STEMI treatment times were determined before (July 2005 to September 2005) and after (January 2007 to March 2007) a year-long implementation of coordinated regional treatment protocols. Times in the pre- and postintervention periods were compared by mixed-effects models. A total of 2063 STEMI patients were analyzed: 1140 at percutaneous coronary intervention hospitals and 923 at non-percutaneous coronary intervention hospitals. The Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments was associated with significant improvements in treatment times in women and the elderly, including door-to-ECG, door-to-device, door-in-door-out, and door-to-needle times (all P<0.05). Temporal improvements in treatment times at percutaneous coronary intervention hospitals were not significantly different in blacks than in whites. There was a reduction in baseline treatment disparities in door-to-ECG times in women versus men (4.4-minute reduction in difference; 95% CI, -8.1 to -0.4; P=0.03). After Reperfusion of Acute Myocardial Infarction in North Carolina Emergency Departments, an age-treatment time gap persisted in the elderly, relative to younger patients. A statewide STEMI regionalization program was associated with comparable improvement in treatment times for female, black, and elderly patients compared with middle-aged, white male patients. Nevertheless, there remain opportunities to further narrow treatment differences, particularly among the elderly.


[Adverse reaction surveillance system for vaccination in the Republic of Cuba].
We briefly sets forth the design of a surveillance system of adverse events as a part of the Vaccination Program in Cuba since it has had a world impact and thus, the real scope of such events can be known in the country. On the other hand, this system may be useful for Cuban vaccine-producing industries to prove innocousness of their products after these being licensed. Family physician and nurse program which covers 98% of the Cuban population will make the active-passive surveillance of all those persons who had been vaccinated in a territory possible. This surveillance system will be able to measure risks of adverse events by vaccine, age, number of doses, province and municipalities and by batch and manufacturer so that the causes leading to those events can be known. For this reason, it will contribute to improve the quality of services, protect the vaccination quality and upgrade the Cuban surveillance system.


SEPSIS. Educational and Best Practice Frontiers. Beyond the Boundaries of Fatality, Enhancing Clinical Skills and Precision Medicine.
Dissemination and exploitation of knowledge regarding affordable clinical skills and innovative precision medicine, two current topics in active development in medicine, may contribute to improve also sepsis management. Sepsis is a life-threatening organ dysfunction due to a dysregulated host response to infection. Sepsis is strongly related to all body organs or to systemic diseases and to the quality of the best-practice in use, which is particularly critical in surgical or intervention techniques. Trauma, surgical and mini-invasive procedures, vascular or endoscopic interventions, otolaryngology, obstetrics-gynecological and urological procedures, malnutrition, dental, skin, chronic liver, kidney and respiratory disease are frequently involved. Accordingly, apart from the clinical risk analysis and management of the process of care, the actual factors that may be easily neglected are the techniques used, the personal skills of the health professionals and the quality of the equipment. The quest for biomarkers consistent with the unmet needs of medical doctors and of their patient and the efforts for overcoming bacterial antibiotic resistances are currently the main foci of medical research. In addition, in this regard, research and innovation would benefit from greater knowledge, skills and use of bioinformatics and omics. The caveats related to in-silico approaches must be flagged: algorithms may equally warrant scientific innovations or hide the lack of them; a patient is more than a set of covariates. Epidemiology and prevention includes all the actions suitable for achieving an adequate hygiene and immunization of populations and for safer hospital policies and procedures during Patients' stays. In any subset, the most unresolved critical point in sepsis is a timely diagnosis. This is impaired by low degrees of suspicion for the possibility of emerging sepsis, by the shortage of use of the simplest microbiological testing but, equally or more, by the insufficient diffusion of non-invasive imaging skills suitable to detect and monitor the emerging sites and sources of infection. In primary care, in emergency facilities, in hospital wards and in intensive care units, inclusion of appropriate knowledge, skills, expertise and imaging equipment must be extended as much as possible. The low cost of UltraSound machines and of increasing bioinformatics literacy by e-learning, makes such investments affordable even in limited-resources contexts. Frontier educational and best practice intervention enhancing affordable clinical skills and innovative precision medicine may lead beyond the boundaries of fatal outcomes in sepsis.


Nonbonded Force Field Parameters from Minimal Basis Iterative Stockholder Partitioning of the Molecular Electron Density Improve CB7 Host-Guest Affinity Predictions.
Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host-guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with an aromatic or adamantane core and the CB7 host using molecular electron density derived nonbonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the Minimal Basis Iterative Stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound states. The resulting nonbonded force field parameters improve binding affinity prediction, especially for guests with an adamantane core in which repulsive exchange and dispersion interactions to the host dominate.


Chronic kidney disease, cardiovascular risk, and response to angiotensin-converting enzyme inhibition after myocardial infarction: the Survival And Ventricular Enlargement (SAVE) study.
Persons with end-stage renal disease and those with lesser degrees of chronic kidney disease (CKD) have an increased risk of death after myocardial infarction (MI) that is not fully explained by associated comorbidities. Future cardiovascular event rates and the relative response to therapy in persons with mild to moderate CKD are not well characterized. We calculated the estimated glomerular filtration rate (eGFR) using the 4-variable Modification of Diet in Renal Disease method in 2183 Survival And Ventricular Enlargement (SAVE) trial subjects. SAVE randomized post-MI subjects (3 to 16 days after MI) with left ventricular ejection fraction < or =40% and serum creatinine <2.5 mg/dL to captopril or placebo. Cox proportional hazards models were used to evaluate the relative hazard rates for death and cardiovascular events associated with reduced eGFR. Subjects with reduced eGFR were older and had more extensive comorbidities. The multivariable adjusted risk ratio for total mortality associated with reduced eGFR from 60 to 74, 45 to 59, and <45 mL x min(-1) x 1.73 m(-2) (compared with eGFR > or =75 mL x min(-1) x 1.73 m(-2)) was 1.11 (0.86 to 1.42), 1.24 (0.96 to 1.60) and 1.81 (1.32 to 2.48), respectively (P for trend =0.001). Similar adjusted trends were present for CV mortality (P=0.001), recurrent MI (P=0.017), and the combined CV mortality and morbidity outcome (P=0.002). The absolute benefit of captopril tended to be greater in subjects with CKD: 12.4 versus 5.5 CV events prevented per 100 subjects with (n=719) and without (n=1464) CKD, respectively. CKD was associated with a heightened risk for all major CV events after MI, particularly among subjects with an estimated glomerular filtration rate <45 mL x min(-1) x 1.73 m(-2). Randomization to captopril resulted in a reduction of CV events irrespective of baseline kidney function.


Infection with chronic hepatitis C virus and liver transplantation: a role for interferon therapy before transplantation.
An analysis of the National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplant Registry data shows that the greater the viral load at the time of transplantation, the more rapidly clinically evident posttransplantation hepatitis C virus (HCV) disease recurs. These data suggest that aggressive pretransplantation treatment of HCV might delay recurrent posttransplantation HCV disease and enhance posttransplantation survival. We have taken an aggressive approach to treating HCV infection pretransplantation with the use of high-dose (5 MU) daily interferon alpha(2b) in an effort to clear the virus before transplantation. A total of 27 patients with HCV-induced cirrhosis were seen and underwent transplantation at Loyola University Medical Center (Maywood, IL) between February 1997 and December 2001. There were 22 men and five women, with a mean age of 56 +/- 2 years. The majority had genotype 1 disease (67%). Of the 27 patients, 7 had a baseline platelet count <50,000/mm(3) and were excluded from interferon therapy. The remaining 20 were treated for a mean of 14 +/- 2.5 (range, 0.5 to 33.5) months before orthotopic liver transplantation (OLT). Twelve (60%) responded to the therapy with serologic clearance of HCV before OLT. The mean time from initiation of therapy to the first negative qualitative polymerase chain reaction was 4.5 +/- 1.5 (range, 0.5 to 12) months. Four of the 12 patients in whom the virus cleared did not have evidence of HCV recurrence after OLT, representing 20% of those treated and 33% of those who had HCV clearance before OLT. The duration of post-OLT freedom from HCV infection in these individuals has been 33.6 +/- 11.3 (range, 0 to 47.4) months. These data suggest that with careful supervision, cirrhotic patients can tolerate high-dose interferon. In addition, a viral clearance can be achieved in a significant number of cirrhotic patients with high-dose interferon. One third of patients, in whom the HCV cleared before OLT, did not have evidence of disease recurrence after OLT. It is thus anticipated that with early and aggressive pre-OLT HCV therapy, possibly with the use of pegylated interferon, even better results may be obtained.


Dissolved Uranium and Arsenic in Unregulated Groundwater Sources - Western Navajo Nation.
Concentrations of dissolved uranium (U) and arsenic (As) above drinking water standards in unregulated water sources pose various human health risks. Although high natural background concentrations may occur in some environments (Runnells et al. 1992), anthropogenic contamination concerns are especially troublesome on the Navajo Nation (NN), where past U mining activity may have contaminated water supplies. This research investigated U and As groundwater contamination issues in unregulated wells in the western portion of the NN. Objectives of this research were to provide insights to human health risks by assessing the spatial extent and seasonal variability of U and As concentrations while effectively communicating the potential contamination risks to the local Navajo people. Eighty-two unregulated wells were sampled in 2018; nine of these sources exceeded the maximum contaminant level (MCL) for drinking water standards for U (30 μg/L), and 14 exceeded the MCL for drinking water standards for As (10 μg/L). U and As levels were highest in the southwest portion of the study area and seasonal variability was observed in a subset of wells, especially shallower hand dug wells and hand pumps. The results were compiled into a report that was presented to NN chapters included in the study as well as the Navajo Department of Water Resources and the NN Environmental Protection Agency. Implications for regional water quality patterns can help to direct policy recommendations for well monitoring, water use, and remediation targets.


[Immunity status of children under the conditions of heavy metal-polluted city].
This study assessed immunological changes in apparently healthy children under a slight (less than the sanitary standards) urban pollution with heavy metals (Co, Pb, Cr, Cd, Mn, Ni, Zn, and Cu). Their pollution of the urban environment was determined with the contamination of snow cover and ambient air in Kazan. With low levels of ambient air pollution with heavy metals, monitoring the level of environmental pollution is an adequate method for evaluating the urban area, which allows the latter to be ranged by the degree of pollution. Apparently healthy children who live under relatively good environmental conditions are at risk for allergic and autoimmune diseases or secondary immunological somatic pathology.


The impact of symbolic and non-symbolic quantity on spatial learning.
An implicit mapping of number to space via a "mental number line" occurs automatically in adulthood. Here, we systematically explore the influence of differing representations of quantity (no quantity, non-symbolic magnitudes, and symbolic numbers) and directional flow of stimuli (random flow, left-to-right, or right-to-left) on learning and attention via a match-to-sample working memory task. When recalling a cognitively demanding string of spatial locations, subjects performed best when information was presented right-to-left. When non-symbolic or symbolic numerical arrays were embedded in these spatial locations, and mental number line congruency prompted, this effect was attenuated and in some cases reversed. In particular, low-performing female participants who viewed increasing non-symbolic number arrays paired with the spatial locations exhibited better recall for left-to-right directional flow information relative to right-to-left, and better processing for the left side of space relative to the right side of space. The presence of symbolic number during spatial learning enhanced recall to a greater degree than non-symbolic number--especially for female participants, and especially when cognitive load is high--and this difference was independent of directional flow of information. We conclude that quantity representations have the potential to scaffold spatial memory, but this potential is subtle, and mediated by the nature of the quantity and the gender and performance level of the learner.


Progesterone inhibits the induction of aromatase activity in rat granulosa cells in vitro.
The development of ovulatory follicles is suppressed during reproductive states with high circulating levels of progesterone. We have investigated the effects of progesterone on estradiol secretion by rat granulosa cells in vitro to determine if progesterone has direct effects on follicular aromatization. Relatively undifferentiated granulosa cells were obtained from hypophysectomized (HPX), diethylstilbestrol-treated immature rats and differentiated granulosa cells were obtained from preovulatory follicles on the morning of proestrus. Progesterone suppressed, in a dose-dependent fashion, the accumulation of estradiol when HPX or proestrous cells were cultured with follicle-stimulating hormone (FSH) (300 ng/ml) and testosterone (0.5 microM), but granulosa cells from proestrous rats were less sensitive to the inhibitory effects of progesterone. When aromatase was first induced in cells from HPX rats by culturing them for 1, 2, or 3 days with FSH, the cells were less susceptible to the inhibitory effects of progesterone during the subsequent 3 days of culture. The inhibitory effects of progesterone on estradiol secretion appeared irreversible when cells were exposed to progesterone for longer than 1 day. The effects of progesterone on HPX granulosa cells were specific since the progesterone precursor, pregnenolone, was as inhibitory as progesterone, while the progesterone metabolite, 17 alpha-hydroxyprogesterone, had no effect. When granulosa cells from proestrous follicles were cultured with testosterone and graded doses of progesterone, a slight inhibition of estradiol production occurred. This inhibition was much less than that observed when FSH was present. Therefore, the inhibitory effects of progesterone are exerted primarily on the induction of aromatase by FSH, rather than on the functioning of existing aromatase. Whole proestrous follicles were also cultured with graded doses of progesterone in the presence or absence of FSH and/or testosterone. In those experiments progesterone increased estradiol on the first day of culture, but inhibited the effects of FSH in maintaining estradiol secretion later in culture. These experiments have shown that progesterone exerts a specific and irreversible inhibitory effect on estradiol production by granulosa cells. Less differentiated granulosa cells appear to be more sensitive to the inhibitory effects of progesterone. These results suggest that in vivo progesterone may directly suppress development of ovulatory follicles by inhibiting aromatase in granulosa cells of developing follicles.


Vasa praevia: a case report and literature review.
Background. The aim of this article is to present a rare clinical case of vasa praevia as well as to assess the relevance of the problem by reviewing the latest literature sources. Materials and methods. In this report we present a case of a 33-year-old woman diagnosed with vasa praevia at 33 weeks of pregnancy, after hospitalisation with preterm rupture of membranes following the delivery of a live healthy baby through a lower segment Caesarean section during 33rd week of gestation at Vilnius University Hospital Santariškių Clinics. We investigated all the documentation of the patient before and after delivery. Results and conclusions. Vasa praevia is a rather rare pathology which is likely to occur during pregnancy, may result in heavy bleeding and be particularly threatening to the fetus life. A timely diagnosis for these women is essential. The gold standard for vasa praevia diagnosis is the fetal ultrasound scan. Vasa praevia pathology is found during the routine second trimester ultrasound check-up. The selection of proper tactics applied during pregnancy care is essential. At the gestational age of 28-32, it is advisable to mature fetal lungs as well as the fetus condition should be investigated by a perinatologist. The mode of delivery is the C-section which tends to reduce the frequency of possible complications.


Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties.
Comparative studies of the benzisoxazole derivative risperidone (R 64 766) were made with ritanserin, a selective centrally acting serotonin-S2 antagonist and with haloperidol, a selective centrally acting dopamine-D2 antagonist. Risperidone like ritanserin shows activity in all tests related to serotonin-S2 antagonism, but at even lower doses (peripheral S2-antagonism at 0.0011 mg/kg, central S2-antagonism at 0.014 mg/kg). Like haloperidol, risperidone shows activity in all tests related to dopamine-D2 antagonism; activity in rats for both compounds starts at 0.016 mg/kg, but some central nervous system controlled functions, including the induction of catalepsy, are relatively much less affected by risperidone. Qualitatively, risperidone is a mixed serotonin-dopamine antagonist. Quantitatively, its study in dogs reveals potent dopamine-D2 antagonistic activity with excellent p.o. bioavailability and a relatively long duration of action. From the obtained pharmacological data, risperidone could be expected to possess the complementary clinical effects of a ritanserin-like serotonin-S2 and an haloperidol-like dopamine-D2 antagonist. Serotonin-S2 antagonism may improve the quality of sleep, reduce negative and affective symptoms in schizophrenic patients and decrease extrapyramidal symptoms induced by classical neuroleptics. Because risperidone is a dopamine-D2 antagonist, antidelusional, antihallucinatory and antimanic actions are expected. The first clinical studies indicate that two additional therapeutic targets, which are not reached with classical neuroleptics, may be obtained with risperidone in the monotherapy of schizophrenia and related disorders: very important contact and mood-elevating properties and extrapyramidal symptoms-free maintenance therapy.


[Changes in the state of monooxygenase system and lipid peroxidation under the effects of carcinogenic dust].
The work was aimed to study relationship of monooxygenase system and lipid peroxidation in experiments and in clinical group. The examinees were workers engaged into graphite ware production and exposed to low fibrogenic dust of coke and graphite with carcinogens (including 3,4-benzpyrene). The experimental data and examination materials prove the carcinogens to alter seriously those systems. Long stimulation of monooxygenase system and activation of lipid peroxidation could result in more intensive carcinogenic effects of polycyclic aromatic hydrocarbons being a component of coal pitch.


Fibroblasts remodeling of type IV collagen at a biomaterials interface.
This paper describes the fate of adsorbed type IV collagen (Col IV) in contact with fibroblasts on model biomaterial surfaces, varying in wettability, chemistry and charge. We found that fibroblasts not only interact but also tend to remodel differently adsorbed Col IV employing two distinct mechanisms: mechanical reorganization and proteolytic degradation. Apart from the trend of adsorption -NH2 > CH3 > COOH > OH- the cells interact better with NH2 and OH surfaces -i.e. independently of the amount of adsorbed Col IV - evident from the quantitative measurements of cell adhesion and spreading and the improved recruitment of alpha 1 and alpha 2 integrins as well as p-FAK in focal adhesions. The linearly arranged Col IV co-localize with FN fibrils formed from either secreted, or exogenously added protein, which confirms their interdependence during a reorganization process. We further found that this reorganization is better pronounced on hydrophilic OH and positively charged NH2 surfaces correlating with the improved cellular interaction. Conversely, the fibroblasts tend to round on COOH and CH3 surfaces in compliance with the altered integrin signaling and also the increased pericellular proteolysis activity quantified by the increased de-quenching of adsorbed FITC-Col IV and zymography. Taken together, these results show that remodeling of Col IV at a cell-biomaterial interface depends strongly on the surface properties of a material and affects significantly its biological performance.


Cardiopulmonary bypass in pregnancy.
Cardiac surgery carried out on cardiopulmonary bypass (CPB) in a pregnant woman is associated with poor neonatal outcomes although maternal outcomes are similar to cardiac surgery in non-pregnant women. Most adverse maternal and fetal outcomes from cardiac surgery during pregnancy are attributed to effects of CPB. The CPB is associated with utero-placental hypoperfusion due to a number of factors, which may translate into low fetal cardiac output, hypoxia and even death. Better maternal and fetal outcomes may be achieved by early pre-operative optimization of maternal cardiovascular status, use of perioperative fetal monitoring, optimization of CPB, delivery of a viable fetus before the operation and scheduling cardiac surgery on an elective basis during the second trimester.


Traditional Oriental Medicines and Alzheimer's Disease.
Alzheimer's disease (AD), which is the most major cause of dementia, is a progressive neurodegenerative disease that affects cognitive functions. Even though the prevalence of AD is continuously increasing, few drugs including cholinesterase inhibitors and N-methyl D-aspartate-receptor antagonists were approved to treat AD. Because the clinical trials of AD drugs with single targets, such as β-amyloid and tau, have failed, the development of multi-target drugs that ameliorate many of the symptoms of AD is needed. Thus, recent studies have investigated the effects and underlying mechanisms of herbal formulae consisting of various herb combinations used to treat AD. This review discusses the results of clinical and nonclinical studies of the therapeutic efficacy in AD and underlying mechanisms of the herbal formulae of traditional Oriental medicines and bioactive compounds of medicinal plants.


[Surgical pulmonary biopsies in patients with HIV infection: results apropos of a series of 21 cases].
This retrospective study reports the results of surgical lung biopsies in 21 patients infected by HIV. Diagnostic was assessed by surgical lung biopsies in 66% of cases with a 5% immediate post-operative mortality and a 80% survival rate after one month. Therapeutic management was modified in 38% of cases. These results are in concordance with previously published literature and emphasize that such a procedure should only be performed after other diagnostic procedures, including at least a bronchial endoscopy associated to a BAL and/or transbronchial biopsies.


Opioid growth factor arrests the progression of clinical disease and spinal cord pathology in established experimental autoimmune encephalomyelitis.
An endogenous neuropeptide, opioid growth factor (OGF), chemically termed [Met(5)]-enkephalin, arrested the progression of established disease in a mouse model of multiple sclerosis (MS) called experimental autoimmune encephalomyelitis (EAE). This study treated mice who demonstrated 2 consecutive days of behavioral decline following injections of myelin oligodendrocyte glycoprotein (MOG) with daily injections of OGF (10mg/kg) or saline (0.1ml) for 40 days. Within 6 days of OGF treatment, mice initially demonstrating clinical signs of EAE had significant reductions (45% reduction) in their behavioral scores relative to EAE mice receiving saline. Behavior was attenuated for the entire 40-day period with mice receiving OGF showing only limp tails and wobbly gait in comparison to saline-treated EAE mice who displayed paralysis of one or more limbs. Neuropathological studies revealed that OGF treatment initiated after the appearance of disease reduced the number of activated astrocytes and damaged neurons, decreased demyelination, and inhibited T cell proliferation. These results demonstrate that OGF can halt the progression of established EAE, return aberrant pain sensitivity to normal levels, inhibit proliferation of T cells and astrocytes, and prevent further spinal cord pathology. The data extend our observations that OGF given at the time of disease induction prevented disease onset, reduced the severity of clinical signs of disease, and reversed neurological deficits in a non-toxic manner. Our data substantiate the role of the OGF-OGFr axis in EAE and support the use of OGF as a biotherapy for MS.


Yeast and the AIDS virus: the odd couple.
Despite being simple eukaryotic organisms, the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe have been widely used as a model to study human pathologies and the replication of human, animal, and plant viruses, as well as the function of individual viral proteins. The complete genome of S. cerevisiae was the first of eukaryotic origin to be sequenced and contains about 6,000 genes. More than 75% of the genes have an assigned function, while more than 40% share conserved sequences with known or predicted human genes. This strong homology has allowed the function of human orthologs to be unveiled starting from the data obtained in yeast. RNA plant viruses were the first to be studied in yeast. In this paper, we focus on the use of the yeast model to study the function of the proteins of human immunodeficiency virus type 1 (HIV-1) and the search for its cellular partners. This human retrovirus is the cause of AIDS. The WHO estimates that there are 33.4 million people worldwide living with HIV/AIDS, with 2.7 million new HIV infections per year and 2.0 million annual deaths due to AIDS. Current therapy is able to control the disease but there is no permanent cure or a vaccine. By using yeast, it is possible to dissect the function of some HIV-1 proteins and discover new cellular factors common to this simple cell and humans that may become potential therapeutic targets, leading to a long-lasting treatment for AIDS.


A Comprehensive Review of Myocardial Bridging: Exploring Diagnostic and Treatment Modalities.
Myocardial bridging (MB) is a congenital coronary artery anomaly involving an overlying myocardium's partial or complete encasement of a coronary artery segment. The obstruction can lead to significant cardiac symptoms, resulting in myocardial ischemia, arrhythmia, and sudden cardiac death. Several approaches, including invasive and non-invasive methods, have been proposed to diagnose and manage MB. Invasive modalities, such as intravascular ultrasound (IVUS) and coronary angiography, offer high specificity and sensitivity. In contrast, non-invasive methods like Doppler ultrasound, multislice computed tomography (MSCT), and magnetic resonance imaging (MRI) are advantageous due to their non-invasive nature, high sensitivity and specificity, and cost-effectiveness. Treatment options for MB mainly focus on relieving symptoms and preventing adverse outcomes. The use of pharmacological agents and surgical and percutaneous interventions has been documented in numerous studies. Studies conclude that MB is a treatable cardiac anomaly, and a combined approach of diagnosis, treatment, and follow-up is necessary to reduce the morbidity and mortality associated with this condition.


Dietary choline augments associative memory function in Limax maximus.
Previous clinical and experimental work has shown that increased dietary intake of choline elevates blood choline and brain acetylcholine levels. This change in neuronal acetylcholine concentration may augment learning and memory functions. We tested this prediction using the mollusc Limax maximus, an animal which can be readily conditioned to avoid food odors. In our experiments, initial learning of a food avoidance task was not augmented by the high choline diet. However, the duration of memory retention was prolonged. In previous studies, we have shown that intake of the choline enriched diet significantly increases blood choline and amplifies transmission at an identified cholinergic synapse in Limax. Together, these results support the involvement of cholinergic synapses in the memory retention mechanism.


The Xenopus laevis centrosome aurora/Ipl1-related kinase.
The cDNA encoding the protein kinase pEg2 was originally cloned through a differential screening performed during the early development of Xenopus laevis. pEg2 orthologues were found in various organisms and were classified in a new family of oncogenic mitotic protein kinases named 'aurora/Ipl1-related kinases' after the Drosophila melanogaster gene aurora and the Saccharomyces cerevisiae gene Ipl1. The catalytic activity of pEg2 is necessary for the mitotic microtubule spindle formation in Xenopus laevis egg extracts. The addition of a dominant negative form of pEg2 to in vitro spindle assembly assays leads to monopolar spindles generated by a defect of centrosome separation. In Xenopus cultured cells, pEg2 was confined around the pericentriolar material once centrosomes were duplicated. The centrosome localization does not depend on the presence of microtubules. However, in vitro, the protein binds to taxol-stabilized microtubules independently of its kinase activity. During mitosis the location of the protein changes, in metaphase the kinase localizes on the microtubules at the poles of the mitotic spindle whereas it is not present on astral microtubules. This localization persists until the segregation of the chromosomes is completed. The presence of the kinase on the spindle may reveal another yet unknown function.


Homologous Ad26.COV2.S vaccination results in reduced boosting of humoral responses in hybrid immunity, but elicits antibodies of similar magnitude regardless of prior infection.
The impact of previous SARS-CoV-2 infection on the durability of Ad26.COV2.S vaccine-elicited responses, and the effect of homologous boosting has not been well explored. We followed a cohort of healthcare workers for 6 months after receiving the Ad26.COV2.S vaccine and a further one month after they received an Ad26.COV2.S booster dose. We assessed longitudinal spike-specific antibody and T cell responses in individuals who had never had SARS-CoV-2 infection, compared to those who were infected with either the D614G or Beta variants prior to vaccination. Antibody and T cell responses elicited by the primary dose were durable against several variants of concern over the 6 month follow-up period, regardless of infection history. However, at 6 months after first vaccination, antibody binding, neutralization and ADCC were as much as 59-fold higher in individuals with hybrid immunity compared to those with no prior infection. Antibody cross-reactivity profiles of the previously infected groups were similar at 6 months, unlike at earlier time points, suggesting that the effect of immune imprinting diminishes by 6 months. Importantly, an Ad26.COV2.S booster dose increased the magnitude of the antibody response in individuals with no prior infection to similar levels as those with previous infection. The magnitude of spike T cell responses and proportion of T cell responders remained stable after homologous boosting, concomitant with a significant increase in long-lived early differentiated CD4 memory T cells. Thus, these data highlight that multiple antigen exposures, whether through infection and vaccination or vaccination alone, result in similar boosts after Ad26.COV2.S vaccination.


[Non-invasive monitoring based on bioreactance reveals significant hemodynamic instability during elective cesarean delivery under spinal anesthesia].
Blood pressure monitoring offers a limited understanding of the hemodynamic consequences of spinal anesthesia for cesarean delivery. The purpose of this study was to assess, with the aid of a non-invasive cardiac output monitor based on bioreactance, the hemodynamic changes during elective cesarean delivery under spinal anesthesia in which intermittent boluses of phenylephrine were used to prevent and treat hypotension. This observational study was conducted with the Research Ethics Board approval, and all participants provided written informed consent. Healthy patients undergoing elective cesarean delivery under spinal anesthesia were enrolled. Intermittent boluses of phenylephrine were administered in an attempt to maintain systolic blood pressure at baseline levels, and patients were assessed with a non-invasive cardiac output monitor based on bioreactance. Hemodynamic data was collected continuously at baseline, and during the postspinal and postdelivery periods. Data was analyzed using a mixed model ANOVA, and a p < 0.05 was considered significant. Systolic blood pressure was maintained within 79.2 ± 14.2 and 105.8 ± 10.0 percent of baseline during the postspinal period, and 78.4 ± 11.3 and 100.9 ± 10.7 percent of baseline in the postdelivery period (mean ± SD) There were significant fluctuations in systolic blood pressure, heart rate, and cardiac output during the postspinal period, and significant fluctuations in systolic blood pressure and cardiac output in the postdelivery period. A new non-invasive monitor based on bioreactance reveals significant hemodynamic fluctuations during cesarean delivery under spinal anesthesia, despite attempts to maintain blood pressure at baseline levels with intermittent boluses of phenylephrine.


Cardiac fibroblasts are major production and target cells of adrenomedullin in the heart in vitro.
Adrenomedullin (AM) is a potent vasodilator peptide. Plasma AM concentration is increased in patients with various heart diseases, and both myocytes (MCs) and non-myocytes (NMCs) secrete AM and express its receptors. These facts suggest that cardiac cells possess an autocrine/paracrine capability mediated by AM. MCs and NMCs were prepared from cardiac ventricles of neonatal rats. AM and endothelin-1 concentrations were measured by radioimmunoassays, and interleukin-6 level by a specific bioassay. Total nitrite/nitrate contents were measured with a fluorescence assay kit. A basal secretion rate of AM from NMCs was 2.8-fold higher than that from MCs. Interleukin-1beta, tumor necrosis factor-alpha and lipopolysaccharide stimulated AM secretion from NMCs but not from MCs. AM stimulated interleukin-6 production in the presence of these cytokines or lipopolysaccharide, which was more prominent in NMCs. In the presence of interleukin-1beta, AM augmented nitric oxide synthesis 2.7-fold in NMCs, but slightly in MCs. NMCs secreted endothelin-1 at a rate nine times higher than MCs, and AM inhibited endothelin-1 secretion from NMCs. This in vitro study suggests that AM in the heart is mainly produced in NMCs and exerts its effects through NMCs, especially under inflammatory conditions.


Development of blobs in the visual cortex of macaques.
We have examined the area of the primary visual cortex and the number and size of blobs within it in 10 neonatal and 11 adult rhesus monkeys. The average area of the primary visual cortex (V1) increases from 919 mm2 in newborns to 1,069 mm2 in adult animals (16%). The number of blobs decreases per unit area from an average of 5.2/mm2 at birth to 4.3/mm2 in maturity (18%). As a consequence, the number of blobs remains approximately the same during maturation, at about 4,800/hemisphere. These observations correct a preliminary report on a subset of the animals studied here (Purves and LaMantia: Proc Natl Acad Sci 87:5765, '90), in which it appeared that blob number might increase between birth and maturity. As in other regions of the developing postnatal brain, we found no net loss of modular circuitry.


Movement of IS26-associated antibiotic resistance genes occurs via a translocatable unit that includes a single IS26 and preferentially inserts adjacent to another IS26.
The insertion sequence IS26 plays a key role in disseminating antibiotic resistance genes in Gram-negative bacteria, forming regions containing more than one antibiotic resistance gene that are flanked by and interspersed with copies of IS26. A model presented for a second mode of IS26 movement that explains the structure of these regions involves a translocatable unit consisting of a unique DNA segment carrying an antibiotic resistance (or other) gene and a single IS copy. Structures resembling class I transposons are generated via RecA-independent incorporation of a translocatable unit next to a second IS26 such that the ISs are in direct orientation. Repeating this process would lead to arrays of resistance genes with directly oriented copies of IS26 at each end and between each unique segment. This model requires that IS26 recognizes another IS26 as a target, and in transposition experiments, the frequency of cointegrate formation was 60-fold higher when the target plasmid contained IS26. This reaction was conservative, with no additional IS26 or target site duplication generated, and orientation specific as the IS26s in the cointegrates were always in the same orientation. Consequently, the cointegrates were identical to those formed via the known mode of IS26 movement when a target IS26 was not present. Intact transposase genes in both IS26s were required for high-frequency cointegrate formation as inactivation of either one reduced the frequency 30-fold. However, the IS26 target specificity was retained. Conversion of each residue in the DDE motif of the Tnp26 transposase also reduced the cointegration frequency. Importance: Resistance to antibiotics belonging to several of the different classes used to treat infections is a critical problem. Multiply antibiotic-resistant bacteria usually carry large regions containing several antibiotic resistance genes, and in Gram-negative bacteria, IS26 is often seen in these clusters. A model to explain the unusual structure of regions containing multiple IS26 copies, each associated with a resistance gene, was not available, and the mechanism of their formation was unexplored. IS26-flanked structures deceptively resemble class I transposons, but this work reveals that the features of IS26 movement do not resemble those of the IS and class I transposons studied to date. IS26 uses a novel movement mechanism that defines a new family of mobile genetic elements that we have called "translocatable units." The IS26 mechanism also explains the properties of IS257 (IS431) and IS1216, which belong to the same IS family and mobilize resistance genes in Gram-positive staphylococci and enterococci.


The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.
Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.


[Evaluation of the humoral immune response by Western Blot test in mice immunized with expression genomic library of Trypanosoma cruzi].
An expression genomic library of Trypanosoma cruzi was built by using plasmid pc DNA3 as a vector. This library served to immunize by intramuscular administration BALB/c inbred mice. A positive control group to which T. cruzi soluble antigens were administered and other group which was given the same plasmid used for the building of the genomic library were included in this study; another group was not immunized. Blood was extracted from the retrorbital plexus of all the mice two weeks after the third vaccination so as to study the specific antibody response to soluble parasite anigens through the Western Blot technique. The antibody response was shown in animals immunized with the expression genomic library and with soluble parasite antigens.


Fulfillment of the premenstrual dysphoric disorder criteria confirmed using a self-rating questionnaire among Japanese women with depressive disorders.
Some women with depressive disorders experience severe premenstrual symptoms. However, there have been few studies in which premenstrual symptoms in women suffering from depressive disorders were assessed. In this study, we aimed to investigate premenstrual symptoms in women with depressive disorders using the premenstrual dysphoric disorder (PMDD) scale. We administered questionnaires to 65 Japanese female outpatients who had been diagnosed with a major depressive disorder or dysthymic disorder and to 303 healthy women as control subjects. The questionnaire consisted of items on demographics and the PMDD scale, which was modified from the premenstrual symptoms screening tool (PSST) developed by Steiner et al. (Arch Womens Ment Health 2003, 6:203-209). Twenty-eight women (43.1%) with depressive disorder fulfilled certain items of the PMDD scale. These women are considered to have coexisting PMDD and a depressive disorder, or to have premenstrual exacerbation (PME) of a depressive disorder. On the other hand, 18 women (5.9%) in the control group were diagnosed as having PMDD. The depressive disorder group who fulfilled the PMDD criteria had more knowledge of the term premenstrual syndrome (PMS) and took more actions to attenuate premenstrual symptoms than the control group with PMDD. Our findings demonstrated that the occurrence of severe premenstrual symptoms is much higher in women with depressive disorders than in healthy subjects. This is partially due to this group containing women with PME, but mainly due to it containing women with PMDD. The higher percentage of PMDD suggests similarity between PMDD and other depressive disorders. Furthermore, educating healthy Japanese women and women with depressive disorders about premenstrual symptoms and evidence-based treatment for them is necessary.


Ion implantation and protein coating of detachable coils for endovascular treatment of cerebral aneurysms: concepts and preliminary results in swine models.
Complete anatomic obliteration remains difficult to achieve with endovascular treatment of wide-necked aneurysms using Guglielmi detachable platinum coils (GDCs). Ion implantation is a physicochemical surface modification process resulting from the impingement of a high-energy ion beam. Ion implantation and protein coating were used to alter the surface properties (thrombogenicity, endothelial cellular migration, and adhesion) of GDCs. These modified coils were compared with standard GDCs in the treatment of experimental swine aneurysms. In an initial study, straight platinum coils were used to compare the acute thrombogenicity of standard and modified coils. Modified coils were coated with albumin, fibronectin, or collagen and underwent Ne+ ion implantation at a dose of 1 x 10(15) ions/cm2 and an energy of 150 keV. Coils were placed in common iliac arteries of 17 swine for 1 hour, to evaluate their acute interactions with circulating blood. In a second study, GDCs were used to treat 34 aneurysms in an additional 17 swine. GDCs were coated with fibronectin, albumin, collagen, laminin, fibrinogen, or vitronectin and then implanted with ions as described above. Bilateral experimental swine aneurysms were embolized with standard GDCs on one side and with ion-implanted, protein-coated GDCs on the other side. The necks of aneurysms were evaluated macroscopically at autopsy, by using post-treatment Day 14 specimens. The dimensions of the orifice and the white fibrous membrane that covered the orifice were measured as the fibrous membrane to orifice proportion. Histopathological evaluation of the neck region was performed by light microscopy and scanning electron microscopy. Fibronectin-coated, ion-implanted coils showed the greatest acute thrombogenicity (average thrombus weight for standard coils, 1.9 +/- 1.5 mg; weight for fibronectin-coated coils, 8.6 +/- 6.2 mg; P < 0.0001). By using scanning electron microscopy, an intensive blood cellular response was observed on ion-implanted coil surfaces, whereas this was rare with standard coils. At Day 14, greater fibrous coverage of the necks of aneurysms was observed in the ion-implanted coil group (mean fibrous membrane to orifice proportion of 69.8 +/- 6.2% for the ion-implanted coil group, compared with 46.8 +/- 15.9% for the standard coil group; P = 0.0143). The results of this preliminary experimental study indicate that ion implantation combined with protein coating of GDCs improved cellular adhesion and proliferation. Future application of this technology may provide early wound healing at the necks of embolized, wide-necked, cerebral aneurysms.


Transforming growth factor-beta1 reduces expansion of open wounds in the fetal rabbit.
Open wounds in the fetal rabbit do not heal by contraction and actually expand between 60% and 90% over a period of 5 days. Experiments were carried out to determine whether transforming growth factor-beta1 can reduce expansion of open wounds in the fetal rabbit. This study was based on the concept that transforming growth factor-beta1 causes differentiation of fibroblasts into contractile fibroblasts or "myofibroblasts." To test this hypothesis, pregnant New Zealand White rabbits underwent laparotomy and hysterotomy on day 24 of gestation. A circular full-thickness cutaneous wound was made on the back of each fetus. After wounding, either vehicle alone or vehicle with transforming growth factor-beta1 was applied topically to the wound site, and each fetus was then returned to the uterus. The hysterotomy and laparotomy were closed in standard fashion. On postoperative day 5, fetuses were harvested by repeat Cesarean section. Wound areas were determined from photographs, calculated as percentage of original wound size, and expressed in square millimeters. In addition, a portion of each wound was fixed and processed for histologic and immunohistochemical analysis. At harvest, the control wounds had expanded by an average of 87% of the original area. In marked contrast, the transforming growth factor-beta1-treated wounds had only expanded an average of 16%. Thus, transforming growth factor-beta1 significantly decreased the area of the open fetal wounds compared with control (p < 0.001). By histologic examination, no significant difference was found between the test group and the control group with regards to inflammation, neovascularization, collagen deposition, elastin content, glycosaminoglycan content, or hyaluronic acid content. Most notably, however, there was an increased density of fibroblasts in the transforming growth factor-beta1-treated group. In addition, immunohistochemical staining with an anti-alpha-smooth muscle actin antibody showed the presence of contractile fibroblasts in the wound margins in the transforming growth factor-beta1-treated group but failed to show any positive-staining fibroblasts in the matrices of the control group. These results indicate that open wounds in the fetal rabbit treated in vivo with transforming growth factor-beta1 were significantly smaller than control wounds. This process appears to result from the recruitment and differentiation of normal dermal fibroblasts into contractile fibroblasts containing alpha-smooth muscle actin.


Safety of BNT162b2 mRNA COVID-19 vaccine in children with chronic kidney disease: a national population study from South Korea.
In South Korea, COVID-19 vaccination has been recommended to adolescents aged 12 - 17 since October, 2021. We aimed to assess the rate of adverse events following COVID-19 vaccination in adolescents with chronic kidney disease (CKD) in South Korea, using national cohort data. We retrieved the clinical information of adolescents 12 - 17 years old from the Korea Disease Control and Prevention Agency-COVID19-National Health Insurance Service (K-COV-N) database, to calculate incidence rates of purpura and other hemorrhagic conditions, Guillain-Barré syndrome (GBS), Kawasaki disease/multisystem inflammatory syndrome in children (MIS-C), myocarditis and/or pericarditis, and anaphylaxis in adolescents with CKD, after BNT162b2 vaccination. Among the 2306 adolescents with CKD, 62.7% (n = 1446) had received the BNT-162b2 vaccine. GBS, Kawasaki disease/MIS-C, and anaphylaxis or anaphylactic shock did not occur during the observation period. Purpura and hemorrhagic conditions were more frequent in the unvaccinated group (7/860 vs. 1/1446), while myocarditis/pericarditis was observed only in the vaccinated group (0/860 vs. 1/1446). Adjusted odds ratio for any of the two adverse events was lower in vaccinated adolescents than in the unvaccinated group which did not reach statistical significance (adjusted odds ratio = 0.14, 95% confidence interval: 0.02, 1.16, P = 0.068). In this national cohort study of adolescents with CKD in South Korea, we observed no evidence of increased risk of adverse events following BNT162b2 vaccination. Our finding offers insights into the safety of COVID-19 vaccines, empowering adolescent patients with CKD and their caregivers to make informed decisions.


Right hepatectomy with preservation of the entire caudate lobe in patients with metastatic liver tumors: a case of a new hepatectomy technique and treatment strategy for patients with marginal liver function.
Performing major hepatectomy for patients with marginal hepatic function is challenging. In some cases, the procedure is contraindicated owing to the threat of postoperative liver failure. In this case report, we present the first case of marginal liver function (indocyanine green clearance retention rate at 15 min [ICGR15]: 28%) successfully treated with right hepatectomy, resulting in total caudate lobe preservation. A 71-year-old man was diagnosed with sigmoid colon cancer with three liver metastases (S5, S7, and S8). All of metastatic lesions shrunk after chemotherapy, but his ICGR15 and indocyanine green clearance rate (ICGK) were 21% and 0.12, respectively. Moreover, the remnant liver volume was only 39%. Therefore, portal venous embolism (PVE) of the right portal vein was suggested. Portography showed divergence of the considerably preserved right caudate lobe branch (PV1R) from the root of the right portal vein. The liver function was reevaluated 18 days after PVE was suggested. During this time, the ICGR15 (21-28%) and ICGK rate (0.12-0.10) deteriorated. The right caudate lobe was significantly enlarged; thus, a total caudate lobe-preserving hepatectomy (TCPRx) was performed. Patients eligible for TCPRx included those with (1) hepatocellular carcinoma or metastatic liver cancer, (2) no tumor in the caudate lobe, (3) marginal liver function (ICG Krem greater than 0.05 if TCPRx was adapted; otherwise, less than 0.05) and Child-Pugh classification category A, and (4) preserved PV1R and right caudate bile duct branch. The procedure was performed through (A) precise estimation of the remnant liver volume preoperatively, (B) repeated intraoperative cholangiography to confirm the biliary branch of the right caudate lobe (B1R) conservation, and (C) stapler division of posterior and anterior Glisson's pedicles laterally to avoid injuries to the PV1R and B1R. Right hepatectomy with total caudate lobe preservation, following PVE, was a safe and viable surgical technique for patients with marginal liver function.


[Clinicopathologic evaluation on colorectal laterally spreading tumor (LST)].
Clinicopathologic characteristics of 92 colorectal laterally spreading tumors (LST) endoscopically or surgically resected were examined. Lesions were macroscopically classified into two categories according to their surface structure :(1) granular type (G type, 47 lesions), (2) flat type (F type, 45 lesions). The size (maximum diameter) of G type lesions was 24.7 +/- 11.3 mm (Mean +/- SD) and that of F type lesions was 14.2 +/- 7.4 mm. The size of G type lesions was significantly larger than that of F type lesions (p < 0.01). Among G type lesions, cancerous lesion was present in 2 (25.0%) of 8 lesions 10-14 mm in diameter, 2 (22.2%) of 9 lesions 15-19 mm in diameter and 19 (63.3%) of 30 lesions more than 20mm in diameter. Regarding F type lesions, cancerous lesion was present in 15 (46.9%) of 32 lesions 10-14 mm in diameter, 4 (80.0%) of 5 lesions 15-19 mm in diameter and 8 (100%) of 8 lesions more than 20mm in diameter. The incidence of carcinoma in F type lesions was higher than that in G type lesions irrespective of size. F type lesions with carcinoma showed a trend toward a higher frequency of submucosal invasion and F type lesions with adenoma revealed tendency of showing severe atypia in comparison with G type lesions. The adenomatous component of LST showed a tubulo-villous architecture in 13 (28.3%) of 46 G type lesions, however none of F type lesions had a tubulo-villous component. These results indicated that clinicopathologic characteristics of F type are obviously different from G type. Furthermore, F type had a higher malignant potential than G type and is thought to have a more important role as a precursor of colorectal carcinoma than G type.


Demographic determinants of acute gastrointestinal illness in Canada: a population study.
Gastrointestinal illness is an important global public health issue, even in developed countries, where the morbidity and economic impact are significant. Our objective was to evaluate the demographic determinants of acute gastrointestinal illness in Canadians. We used data from two population-based studies conducted in select communities between 2001 and 2003. Together, the studies comprised 8,108 randomly selected respondents; proxies were used for all respondents under 12 years and for respondents under 19 years at the discretion of the parent or guardian. Using univariate and multivariate logistic regression, we evaluated the following demographic determinants: age, gender, cultural group, and urban/rural status of the respondent, highest education level of the respondent or proxy, number of people in the household, and total annual household income. Two-way interaction terms were included in the multivariate analyses. The final multivariate model included income, age, gender, and the interaction between income and gender. After adjusting for income, gender, and their interaction, children under 10 years had the highest risk of acute gastrointestinal illness, followed by young adults aged 20 to 24 years. For males, the risk of acute gastrointestinal illness was similar across all income levels, but for females the risk was much higher in the lowest income category. Specifically, in those with total annual household incomes of less than $20,000, the odds of acute gastrointestinal illness were 2.46 times higher in females than in males. Understanding the demographic determinants of acute gastrointestinal illness is essential in order to identify vulnerable groups to which intervention and prevention efforts can be targeted.