Victims of human trafficking and exploitation in the healthcare system: a retrospective study using a large multi-state dataset and ICD-10 codes.
Trafficking and exploitation for sex or labor affects millions of persons worldwide. To improve healthcare for these patients, in late 2018 new ICD-10 medical diagnosis codes were implemented in the US. These 13 codes include diagnosis of adult and child sexual exploitation, adult and child labor exploitation, and history of exploitation. Here we report on a database search of a large US health insurer that contained approximately 47.1 million patients and 0.9 million provider organizations, not limited to large medical systems. We reported on any diagnosis with the new codes between 2018-09-01 and 2022-09-01. The dataset was found to contain 5,262 instances of the ICD-10 codes. Regression analysis of the codes found a 5.8% increase in the uptake of these codes per year, representing a decline relative to 6.7% annual increase in the data. The codes were used by 1,810 different providers (0.19% of total) for 2,793 patients. Of the patients, 1,248 were recently trafficked, while the remainder had a personal history of exploitation. Of the recent cases, 86% experienced sexual exploitation, 14% labor exploitation and 0.8% both types. These patients were predominantly female (83%) with a median age of 20 (interquartile range: 15-35). The patients were characterized by persistently high prevalence of mental health conditions (including anxiety: 21%, post-traumatic stress disorder: 20%, major depression: 18%), sexually-transmitted infections, and high utilization of the emergency department (ED). The patients' first report of trafficking occurred most often outside of a hospital or emergency setting (55%), primarily during office and psychiatric visits.


Hematopoietic stem cell transplantation for non-malignant gastrointestinal diseases.
Both, autologous and allogeneic hematopoietic stem cell transplantation (HSCT) can be used to cure or ameliorate a variety of malignant and non-malignant diseases. The rationale behind this strategy is based on the concept of immunoablation using high-dose chemotherapy, with subsequent regeneration of naive T-lymphocytes derived from reinfused hematopoietic progenitor cells. In addition, the use of HSCT allows for the administration of high-dose chemotherapy (whether or not combined with immunomodulating agents such as antithymocyte globulin) resulting in a prompt remission in therapy-refractory patients. This review gives an update of the major areas of successful uses of HSCT in non-malignant gastrointestinal disorders. A Medline search has been conducted and all relevant published data were analyzed. HSCT has been proved successful in treating refractory Crohn's disease (CD). Patients with refractory celiac disease type II and a high risk of developing enteropathy associated T-cell lymphoma have shown promising improvement. Data concerning HSCT and mesenchymal SCT in end-stage chronic liver diseases are encouraging. In refractory autoimmune gastrointestinal diseases high-dose chemotherapy followed by HSCT seems feasible and safe and might result in long-term improvement of disease activity. Mesenchymal SCT for a selected group of CD is promising and may represent a significant therapeutic alternative in treating fistulas in CD.


Characteristics of Gut Microbiome After Traumatic Brain Injury.
Preclinical studies have reported significant changes in the gut microbiome after traumatic brain injury (TBI). We hypothesized that TBI induces the growth of Proteobacteria in the human gut. Our primary outcome was to study the profile of the human fecal microbiome after TBI and the secondary outcome was to identify colonization with colistin-resistant and multidrug-resistant pathogens. Consecutive patients with moderate-severe TBI admitted to the neurotrauma-intensive care unit within 48 hours of injury were enrolled into this observational study. Samples from rectal swabs obtained on days 0, 3, and 7 after admission were assessed for microbial growth and antibiotic resistance. Demographic data and variables such as hypotension, blood transfusion, surgery, start of nasogastric feeding, use of antibiotics, length of hospital stay and mortality were noted. One hundred one patients were enrolled into this study; 57 (56.4%) underwent surgery, 80 (79.2%) required blood transfusion, 15 (14.9%) had an episode of hypotension, 37 (36.6%) received enteral feed within the first 3 days, and 79 (78.2%) received antibiotics. Rectal microbiological samples were collected from 101, 95, and 85 patients on days 0, 3, and 7, respectively. All organisms isolated at the 3 time-points belonged to the Proteobacteria phylum, with Enterobacteriaceae forming the largest group. Colistin-resistant organisms were found in 17 (16.8%) of 101 patients and multidrug-resistant organisms in 25 (64.1%) of the 39 patients in whom isolates were tested against the entire panel of antimicrobials. TBI is associated with widespread colonization with Proteobacteria as early as 48 hours after injury. Colonization with colistin and multidrug-resistant organisms highlights the importance of the judicious use of antibiotics.


Dual roles of hydrogen peroxide in promoting zebrafish renal repair and regeneration.
Acute renal injury (AKI) is a serious disorder of renal failure or renal damage that occurs within hours or days. At present, there is no approved pharmaceutical treatment for AKI. Zebrafish is an excellent model for studying the repair of AKI because of its remarkable ability to repair kidney injury. Using zebrafish AKI model inducing by gentamicin, we found that hydrogen peroxide (H2O2) plays dual roles during the period of AKI recovery including renal repair and kidney regeneration. In the repair stage of AKI, H2O2 was produced in proximal and distal segments of renal tubules. By inhibiting H2O2 generation using Duox Vivo-Morpholino or chemical inhibitor, it was observed of severe damage of renal tubules, and extensive cell apoptosis. In the stage of regeneration, we found that H2O2 was highly generated in renal interstitium. Inhibiting production of H2O2 could significantly down-regulate the ability of kidney regeneration, which was associated with the failure of proliferation of renal progenitor cells. Therefore, H2O2 acts as a protective factor in renal repair and an initial signal of kidney regeneration, indicating the key roles of H2O2 in promoting recovery of AKI in zebrafish.


Functional Outcomes and Delayed Cerebral Ischemia Following Nonperimesencephalic Angiogram-Negative Subarachnoid Hemorrhage Similar to Aneurysmal Subarachnoid Hemorrhage.
The angiogram-negative subarachnoid hemorrhage (SAH) literature includes patients with perimesencephalic hemorrhage, which is recognized to have a much better outcome than aneurysmal SAH. To evaluate the clinical outcomes of Nonperimesencephalic Angiogram-Negative SAH (NPAN-SAH). A prospective, spontaneous SAH database of 1311 patients that accrued between April 2006 and December 2014 was screened. All patients with NPAN-SAH and 2 consecutive negative cerebral angiograms were included. We identified 191 (11%) from a total of 1311 patients with spontaneous SAH. Amongst angiogram-negative patients, 83 (4.9%) were adjudicated to have NPAN-SAH. Patient characteristics were similar across the groups, except NPAN-SAH patients were more likely to be men and had higher rates of diabetes. In a multivariable logistic regression model, NPAN-SAH patients were less likely to develop vasospasm, after adjusting for Fisher grade, sex, and diabetes (odds ratio [OR]: 0.197, 95% confidence interval [CI; 0.07-0.55], P = .002). In another adjusted model accounting for Hunt and Hess clinical grade, NPAN-SAH patients were also less likely to develop vasospasm (OR: 0.2, 95% CI [0.07-0.57], P = .002). We found no statistical significance between 2 groups for rebleed, developing hydrocephalus, seizures, or delayed cerebral ischemia. NPAN-SAH patients were equally associated with poor functional outcome (modified Rankin scale ≥3; OR: 1.16, 95% CI [0.615-2.20], P = .6420), and death (OR: 1.22, 95% CI [0.362-4.132], P = .7455) compared to aneurysmal SAH. Although the risk of vasospasm may be lower, patients with NPAN-SAH are equally associated with delayed cerebral ischemia, poor outcome, and death as compared to patients with aneurysmal SAH. Furthers studies may be necessary to further clarify these findings.


Successful Outcome of Post Liposuction Extensive Necrotizing Soft Tissue Infection of Abdomen and Concomitant Jejunal Perforation-A Case Report.
Introduction Liposuction is one of the common cosmetic surgery procedures performed. Although rare, the complications associated with it are necrotizing soft tissue infection and bowel perforation. We would like to share our experience of such a complication that was managed successfully. Case Report We were referred a 65-year-old male patient with signs and symptoms of intestinal obstruction who had undergone liposuction of abdomen 1 week before and now had discoloration of the abdominal skin. The discoloration was present from just below the costal margin and was extending up to bilateral inguinal regions. Laterally the discoloration extended up to the mid axillary line on both sides. Imaging studies showed dilated small bowel. During laparotomy, he underwent debridement of all discolored skin and repair of the single jejunal perforation. Postoperatively patient was first managed on intravenous fluids, nasogastric aspiration and total parenteral nutrition for 10 days. The wound was managed with silver dressings that led to healthy granulations. The patient was at high risk for anesthesia for skin grafting; hence, he was managed with allograft for 10 days. The patient then underwent skin grafting once he was fit. The graft took up well and he resumed regular activities. Conclusion This is unique as the patient had extensive necrotizing soft tissue infection of the abdominal skin after liposuction along with intestinal perforation and obstruction that was managed successfully due to aggressive surgical intervention, allograft, and good supportive care both in the intensive care unit and in ward.


Molecular Pathways Leading to Induction of Cell Death and Anti-Proliferative Properties by Tacrolimus and mTOR Inhibitors in Liver Cancer Cells.
Orthotopic liver transplantation (OLT) is the recommended treatment for patients at early stages of hepatocarcinoma (HCC) with portal hypertension and/or increased bilirubinemia, but without vascular-associated diseases. Tumor recurrence, which is the main drawback for the survival of patients submitted to OLT for HCC, has been related to tumor-related variables and the immunosuppressive therapies. We have previously shown that Tacrolimus (FK506) exerts a more potent pro-apoptotic and anti-proliferative effects than the mammalian target of rapamycin (mTOR) inhibitors (Sirolimus and Everolimus) in liver cancer cells. This study identified the role of the immunosuppressant partners such as FK506-binding proteins (FKBPs) in the induction of cell death and arrest of cell proliferation by immunosuppressants in two representative liver cancer cells. The regulation of endoplasmic reticulum (ER) stress, apoptosis/autophagy, cell proliferation, and FKBPs expression was determined in Tacrolimus-, Sirolimus- and Everolimus-treated primary human hepatocytes, and hepatoma HepG2 and Huh7 cell lines. The functional repercussion of FKBPs on cell death and proliferation was also addressed using the siRNA technology. The assessed antitumoral properties of the immunosuppressants were associated to microRNAs (miRNAs) pattern. The enhanced pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with increased protein kinase RNA-like endoplasmic reticulum kinase (PERK)-related ER stress, Ser15P-p53/p53 ratio and p21 protein expression that may counterbalance the risk of proliferative upregulation caused by enhanced Thr172P-Cdk4/Cdk4 activation in liver cancer cells. The inhibition of the mTOR pathway by Sirolimus and Everolimus was related to an induction of autophagy; and at a high dose, these drugs impaired translation likely at a very early step of the elongation phase. Tacrolimus and mTOR inhibitors increased the protein expression of FKBP12 and FKBP51 that appeared to play pro-survival role. Interestingly, the administration of immunosuppressants yields a specific pattern of miRNAs. Tacrolimus and mTOR inhibitors decreased miR-92a-1-5p, miR-197-3p, miR-483-3p and miR-720, and increased miR-22-3p, miR-376a-3p, miR-663b, miR-886-5p, miR-1300 and miR-1303 expressions in HepG2 cells. The more potent pro-apoptotic and anti-proliferative properties of Tacrolimus versus mTOR inhibitors were associated with an increased activation of PERK and p53 signaling, and p21 protein expression. FKBP12 and FKBP51 appeared to be the most relevant partners of Tacrolimus and mTOR inhibitors exerting a pro-survival effect in HepG2 cells. The observed effects of immunosuppressants were related to a specific miRNA signature in liver cancer cells.


Sensing Performance Analysis on Quartz Tuning Fork-Probe at the High Order Vibration Mode for Multi-Frequency Scanning Probe Microscopy.
Multi-frequency scanning near-field optical microscopy, based on a quartz tuning fork-probe (QTF-p) sensor using the first two orders of in-plane bending symmetrical vibration modes, has recently been developed. This method can simultaneously achieve positional feedback (based on the 1st in-plane mode called the low mode) and detect near-field optically induced forces (based on the 2nd in-plane mode called the high mode). Particularly, the high mode sensing performance of the QTF-p is an important issue for characterizing the tip-sample interactions and achieving higher resolution microscopic imaging but the related researches are insufficient. Here, we investigate the vibration performance of QTF-p at high mode based on the experiment and finite element method. The frequency spectrum characteristics are obtained by our homemade laser Doppler vibrometer system. The effects of the properties of the connecting glue layer and the probe features on the dynamic response of the QTF-p sensor at the high mode are investigated for optimization design. Finally, compared with the low mode, an obvious improvement of quality factor, of almost 50%, is obtained at the high mode. Meanwhile, the QTF-p sensor has a high force sensing sensitivity and a large sensing range at the high mode, indicating a broad application prospect for force sensing.


Oxidatively modified low density lipoprotein is a chemoattractant for human T lymphocytes.
Oxidatively modified low density lipoprotein (Ox-LDL) is a known chemoattractant for monocytes. Here we demonstrate, using a modified Boyden chamber assay, that human peripheral blood T lymphocytes, but not B lymphocytes, also respond chemotactically to Ox-LDL, showing a threefold increase over control and an optimum response at 10 micrograms/ml. Copper and endothelial cell-oxidized LDL and beta-VLDL were used and gave similar results. The activity was not chemokinetic and native LDL possessed no chemoattractant activity. The chemoattractant activity was found to reside in the lipid fraction of Ox-LDL. Lysophosphatidylcholine is a major phospholipid component of Ox-LDL and is known to be chemotactic for monocytes. We show that lysophosphatidylcholine is also chemotactic for T lymphocytes with a maximal fourfold increase at 10 microM. Nonmetabolizable analogues of lysophosphatidylcholine had no such chemotactic effect. Thus, Ox-LDL, by virtue of its lysophosphatidylcholine content, may contribute to the recruitment of both T lymphocytes and monocytes into developing atherosclerotic lesions.


Psychosocial histories, social environment, and HIV risk behaviors of injection and noninjection drug using homeless youths.
Injection drug use is a common risk behavior for HIV infection among homeless, runaway and street youths. However, the psychosocial histories and current social environment of these youths are not well understood. The authors recruited 186 homeless, runaway and street youths using systematic street-based sampling methods, and assessed psychosocial histories, current daily activities, and sexual and drug-related risk behaviors using qualitative and quantitative techniques. Youths reported high lifetime rates of injection drug use (45%), recent drug and alcohol use (100%), and current homelessness (84%). Injection drug using youths were more likely than noninjection drug using youths to report traumatic psychosocial histories, including parental substance use and forced institutionalization, use of alcohol and other noninjection drugs, a history of survival sex, and the use of squats or abandoned buildings as shelter. These findings underscore the need for multifaceted service and prevention programs to address the varied needs of these high-risk youths.


Phylogenetic Signal, Root Morphology, Mycorrhizal Type, and Macroinvertebrate Exclusion: Exploring Wood Decomposition in Soils Conditioned by 13 Temperate Tree Species.
Woodlands are pivotal to carbon stocks, but the process of cycling C is slow and may be most effective in the biodiverse root zone. How the root zone impacts plants has been widely examined over the past few decades, but the role of the root zone in decomposition is understudied. Here, we examined how mycorrhizal association and macroinvertebrate activity influences wood decomposition across diverse tree species. Within the root zone of six predominantly arbuscular mycorrhizal (AM) (Acer negundo, Acer saccharum, Prunus serotina, Juglans nigra, Sassafras albidum, and Liriodendron tulipfera) and seven predominantly ectomycorrhizal (EM) tree species (Carya glabra, Quercus alba, Quercus rubra, Betula alleghaniensis, Picea rubens, Pinus virginiana, and Pinus strobus), woody litter was buried for 13 months. Macroinvertebrate access to woody substrate was either prevented or not using 0.22 mm mesh in a common garden site in central Pennsylvania. Decomposition was assessed as proportionate mass loss, as explained by root diameter, phylogenetic signal, mycorrhizal type, canopy tree trait, or macroinvertebrate exclusion. Macroinvertebrate exclusion significantly increased wood decomposition by 5.9%, while mycorrhizal type did not affect wood decomposition, nor did canopy traits (i.e., broad leaves versus pine needles). Interestingly, there was a phylogenetic signal for wood decomposition. Local indicators for phylogenetic associations (LIPA) determined high values of sensitivity value in Pinus and Picea genera, while Carya, Juglans, Betula, and Prunus yielded low values of sensitivity. Phylogenetic signals went undetected for tree root morphology. Despite this, roots greater than 0.35 mm significantly increased woody litter decomposition by 8%. In conclusion, the findings of this study suggest trees with larger root diameters can accelerate C cycling, as can trees associated with certain phylogenetic clades. In addition, root zone macroinvertebrates can potentially limit woody C cycling, while mycorrhizal type does not play a significant role.


Alpha-tACS alters attentional control but not cognitive functions as video games do: A psychophysical investigation based on the theory of visual attention.
Video game players' faster speed of information processing has been shown to coincide with altered posterior alpha power modulation, that is, brain oscillatory activity around 10 Hz. Thus, it was proposed that improved cognitive processing in video game players may be related to differential alpha activity. However, a causal relationship thereof has not yet been established. We addressed this by conducting a non-invasive brain stimulation study to demonstrate that modulating alpha power using transcranial alternating current stimulation (tACS) may impact on speed of information processing. Furthermore, we aimed to show that this effect correlated with altered attentional control, for example, visuospatial attention and/or top-down control processing, given that this has been suggested to contribute to video gaming effects. Therefore, we recruited 19 non-video game players to undergo one of five brain stimulation conditions while performing a visual short-term memory task at five different days, respectively. Thus, we applied tACS either at 10 Hz (alpha frequency) or at 16.18 Hz (control frequency) either over their left or right posterior parietal cortex (PPC) or a sham stimulation. Individuals' speed of information processing, visuospatial attention and top-down control processing were operationalised using a computational modelling approach based on the theory of visual attention. We found that alpha-tACS applied over individuals' left PPC altered their visuospatial attention orientation but not their speed of information processing. Thus, we were not able to establish a causal relationship between speed of information processing and altered visuospatial attention processing through alpha power modulation using non-invasive brain stimulation.


Exploring biomedical ontology mappings with graph theory methods.
In the era of semantic web, life science ontologies play an important role in tasks such as annotating biological objects, linking relevant data pieces, and verifying data consistency. Understanding ontology structures and overlapping ontologies is essential for tasks such as ontology reuse and development. We present an exploratory study where we examine structure and look for patterns in BioPortal, a comprehensive publicly available repository of live science ontologies. We report an analysis of biomedical ontology mapping data over time. We apply graph theory methods such as Modularity Analysis and Betweenness Centrality to analyse data gathered at five different time points. We identify communities, i.e., sets of overlapping ontologies, and define similar and closest communities. We demonstrate evolution of identified communities over time and identify core ontologies of the closest communities. We use BioPortal project and category data to measure community coherence. We also validate identified communities with their mutual mentions in scientific literature. With comparing mapping data gathered at five different time points, we identified similar and closest communities of overlapping ontologies, and demonstrated evolution of communities over time. Results showed that anatomy and health ontologies tend to form more isolated communities compared to other categories. We also showed that communities contain all or the majority of ontologies being used in narrower projects. In addition, we identified major changes in mapping data after migration to BioPortal Version 4.


Two novel variants in CYP1B1 gene: a major contributor of autosomal recessive primary congenital glaucoma with allelic heterogeneity in Pakistani patients.
To find the CYP1B1 mutations associated with primary congenital glaucoma (PCG) in Pakistani consanguineous pedigrees. After getting informed consent, 11 consanguineous pedigrees belonging to different ethnic groups were enrolled. Detailed medical history was recorded and pedigrees were drawn. The standard ophthalmological examination was done to characterize the phenotype. Genomic DNA was extracted from 10 mL whole blood and coding exons and exon intron boundaries of CYP1B1 gene were directly sequenced. Bioinformatics tools were used to model the mutant protein and predict the effect of novel variants on protein structure and function. Sequencing analysis revealed 5 different CYP1B1 variants in 7 families (7/11; 64%), including two novel variants. A common mutation, p.R390H was found in four families, whereas p.P437L was found once in a family. Two novel variants, a homozygous non sense variant p.L13* and a compound heterozygous variant, p.P350T along with p.V364M were segregating with PCG in two families. All the patients had the variable onset and severity of the disease. The success rate of early clinical interventions was observed dependent on mutation types and position. Two different haplotypes were associated with frequently found mutation, p.R390H. Identification of novel CYP1B1 variants reassert the genetic heterogeneity of Pakistani PCG patients. The patients with missense mutations show severe phenotypic presentations and poor vision after surgical interventions as compare to patients with null variants. This may help to better understand the role of CYP1B1 mutations in the development of PCG and its course of pathogenicity.


PCL/gelatin scaffolds and beta-boswellic acid synergistically increase the efficiency of CGR8 stem cells differentiation into dopaminergic neuron: A new paradigm of Parkinson's disease cell therapy.
Parkinson's disease is a progressive degenerative disorder in the central nervous system, which is distinguished by the death of dopamine-producing nerve cells. Levodopa, a dopamine precursor drug, is the current standard of care of symptomatic treatment for Parkinson's disease. However, the long-term use of the drug is associated with the development of motor fluctuations and dyskinesias. Cellular therapies aim to deploy fetal dopaminergic neurons as a means to replace the missing dopamine-producing cells. The present study aims to study the impact of beta-boswellic acid (BBA) coupled with poly ε-caprolactone (PCL)/gelatin scaffolds on the dopaminergic differentiation course of CGR8 embryonic stem cells (ESCs). For this purpose, CGR8 ESCs were cultured on PCL/gelatin scaffolds and a five-step protocol was employed to be promoted the neural differentiation of CGR8 ESCs. Gene expression analysis by real-time qPCR demonstrated that PCL/gelatin scaffolds along with BBA treatment impose synergistic effects on the derivation of dopaminergic-like cells from CGR8 ESCs. Reverse-phase high-performance liquid chromatography confirmed the functionality of the derived neurons by demonstrating the efficient secretion of dopamine in response to stimuli. Our results suggested that the generation of functional dopaminergic-like cells from CGR8 ESCs was increased and supported by PCL/gelatin scaffolds and BBA treatment can heighten the efficiency. The result of this study may open insight into Parkinson's disease cell therapy and provide future directions for tissue engineering aimed at the treatment of Parkinson's disease.


Transcriptome analysis of temporal regulation of carbon metabolism by CcpA in Bacillus subtilis reveals additional target genes.
The pleiotropic regulator of carbon metabolism in Gram-positive bacteria, CcpA, regulates gene expression by binding to so-called cre elements, which are located either upstream or in promoter regions, or in open-reading frames. In this study we compared the transcriptomes of Bacillus subtilis 168 and its ccpA deletion mutant during growth in glucose-containing rich medium. Although growth was similar, glucose was completely consumed by the wild-type strain in the stationary phase, while it was still present in the culture of the mutant. At that stage, direct and indirect effects on gene expression were observed. During exponential growth, CcpA mainly influences the carbohydrate and energy metabolism, whereas from transition phase onwards its function expands on a broader range of physiological processes including nucleotide metabolism, cell motility and protein synthesis. A genome wide search revealednew putative cre sites, which could function in vivo according to our transcriptome data. Comparison of our data with published transcriptome data of ccpA mutant analysis in the exponential growth phase confirmed earlier identified CcpA regulon members. It also allowed identification of potential new CcpA-repressed genes, amongst others ycgN and the ydh operon. Novel activated members include opuE andthe opuAABC, yhb and man operons, which all have a putative cre site that appears to be dependent on helical topology. A comparative analysis of these genes with the known activated genes i.e.ackA and pta revealed the presence of a possible upstream activating region (UAR) as has been shown to be functional for the activation of ackA. The data suggest that at later growth phases CcpA may regulate gene expression by itself or complexed with other, yet unknown cofactors.


The obese person as an adolescent.
Obesity constitutes a major health problem in the United States. Hypertension, atherosclerosis, coronary artery disease, diabetes and gout are often associated with obesity and may be a direct result of persistent obesity in adult life. Obesity frequently has its beginnings in childhood and adolescence. Unfortunately, obesity which develops in early life is a progressive problem. Eighty per cent of overweight children and adolescents will continue to be overweight as adults.(12) Furthermore, adults with a history of obesity in childhood are the most resistant to treatment. Recent studies have shown there is more than one body constitutional type among obese adolescents. Obese adolescents tend to eat less than non-obese controls. While obesity may be found to have many different causative factors, efforts to control this disease may be most successful in the area of primary prevention.


The first discovery of the genus Haploglossa Kraatz species (Coleoptera: Staphylinidae: Aleocharinae) in Korea, with a description of new species.
The genus Haploglossa Kraatz is recorded for the first time in Korea with a description of Haploglossa koreana Song Ahn, sp. nov. and a redescription of H. villosula (Stephens). A key, habitus photographs and illustrations of the diagnostic characters of the known Korean species are provided.


Phosphodiester oligonucleotides inhibit mitosis and trigger apoptosis by a non-antisense, p53-mediated mechanism.
Oligodeoxyribonucleotides (ODNs) are currently employed to switch-off genes selectively routinely in the laboratory practice. The drawback of ODN application is that they have been often reported to elicit non-antisense effects by different mechanisms. Recently, it has been shown that double-stranded DNA oligonucleotides (30-mers) with protruding ends activate p53 in a cell-free system. In a previous work, we described that simple addition to the culture medium of heterogeneous DNA combined with cationic lipids culminated in inhibition of mitosis and induction of apoptosis. Here, we report that the same effects are achieved by lipotransfecting cultured cells with phosphorodiester ODNs (30-mers). Such effects of ODN were mediated by a non-antisense mechanism that required the wild-type form of the p53 oncosuppressor protein and was dependent on ODN concentration. Mitosis inhibition and apoptosis induction appeared to be determined by the 3' and 5' free ends of ODNs, which activated p53 independently from their sequence. Most probably, this mechanism is analogous to that evoked by genotoxic agent-induced DNA damage or by lipotransfecting cells with heterogeneous DNA.


Pain after percutaneous liver biopsy for diffuse hepatic disease: a randomized trial comparing subcostal and intercostal approaches.
To compare pain levels as measured by visual analog scale (VAS) and analgesic requirement between intercostal and anterior subcostal ultrasound (US)-guided biopsy. Seventy consecutive patients were randomized to undergo biopsy via an intercostal (n = 33) or subcostal (n = 37) approach. The groups were matched with regard to baseline characteristics: mean age, 44 years; age range, 20-70 years; sex, 43 male and 27 female; and indications of hepatitis C in 69%, hepatitis B in 16%, and others in 15%. The VAS score was obtained immediately after biopsy and hourly for 4 hours until the patients were discharged. Analgesic requirements and postprocedural complications were documented. No significant difference in VAS scores was seen between the groups. At hours 0, 1, 2, 3, and 4, the VAS scores (on a scale of 100) in the intercostal and subcostal groups were 10.3 +/- 16.7 versus 11.8 +/- 16.0 (P = .70), 19.1 +/- 24.0 versus 13.9 +/- 16.2 (P = .30), 11.5 +/- 14.8 versus 11.8 +/- 15.1 (P = .93), 6.2 +/- 8.9 versus 7.5 +/- 11.5 (P = .63), and 5.4 +/- 8.2 versus 4.7 +/- 8.5 (P = .72), respectively. The average VAS was less than 10. In the intercostal biopsy group, 36.4% of patients required additional analgesia after biopsy, compared with 27.0% in the subcostal biopsy group (P = .64). One patient in the intercostal group refused to have future follow-up biopsy even if it was clinically indicated, compared with no such patients in the subcostal biopsy group. No differences in diagnostic samples or major complications were seen in either group. US-guided percutaneous liver biopsy performed with fentanyl and midazolam premedication is a well-tolerated procedure with minimal patient discomfort. The location of the biopsy does not influence the outcome of the procedure.


High quality of screening colonoscopy in Austria is not dependent on endoscopist specialty or setting.
International studies have shown differences in the outcome of screening colonoscopies related to the endoscopist's specialty and setting of colonoscopy. The aim of this study was to investigate the impact of these two factors on quality parameters for screening colonoscopy in a quality-assured screening program. Adenoma detection rate (ADR), cecal intubation rate (CIR), polypectomy rate, flat polyp detection rate, carcinoma detection rate, sedation rate, complication rates, and other parameters of 59 901 screening colonoscopies performed by 178 endoscopists were analyzed in relation to specialty (35 gastroenterologists: 10 066 colonoscopies [16.8 %]; 84 nongastroenterologists: 26 271 colonoscopies [43.9 %]; 59 surgeons: 23 564 [39.3 %]), and setting (hospital: 12 580 [21.6 %] colonoscopies; office: 45 781 [78.4 %] colonoscopies). The overall ADR was 20.5 % and the CIR was 95.6 %. The ADR did not show any statistical significance, either in relation to specialty or to setting. A significant difference in the CIR was found between hospital-based and office-based internists (98.5 % vs. 96.8 %, respectively; P = 0.0005; odds ratio [OR] 2.2, 95 % confidence interval [CI] 1.4 - 3.4). Hospital-based internists had a significantly higher flat polyp detection rate (7.5 % vs. 4.1 %; P = 0.02; OR 1.9, 95 %CI 1.1 - 3.2) and a significantly lower carcinoma detection rate (0.4 % vs. 0.6 %; P = 0.03; OR 0.7, 95 %CI 0.5 - 1.0) compared with office-based internists. Complication rates were significantly lower among surgeons than among internists (0.1 % vs. 0.2 %; P = 0.03; OR 0.5, 95 %CI 0.3 - 1.0). Endoscopists participating in the Austrian quality assurance program offered high quality screening colonoscopy regardless of their specialty and setting. The implementation of a standardized quality program is therefore a decisive factor in quality improvement of screening colonoscopy.


Mechanism of cell-intrinsic adaptation to Adams-Oliver Syndrome gene DOCK6 disruption highlights ubiquitin-like modifier ISG15 as a regulator of RHO GTPases.
DOCK6 is a RAC1/CDC42 guanine nucleotide exchange factor, however, little is known about its function and sub-cellular localization. DOCK6 regulates the balance between RAC1 and RHOA activity during cell adhesion and is important for CDC42-dependent mitotic chromosome alignment. Surprisingly, a cell intrinsic adaptation mechanism compensates for errors in these DOCK6 functions that arise as a consequence of prolonged DOCK6 depletion or complete removal in DOCK6 knockout cells. Down-regulation of the ubiquitin-like modifier ISG15 accounts for this adaptation. Strikingly, although most other DOCK family proteins are deployed on the plasma membrane, here we show that DOCK6 localizes to the endoplasmic reticulum (ER) in dependence of its DHR-1 domain. ER localization of DOCK6 opens up new insights into its functions.


The Advanced Hybrid Closed Loop Improves Glycemia Risk Index, Continuous Glucose Monitoring Index, and Time in Range in Children with Type 1 Diabetes: Real-World Data from a Single Center Study.
Introduction: The Glycemia Risk Index (GRI) and Continuous Glucose Monitoring Index (COGI) are newly defined composite metric parameters derived from continuous glucose monitoring (CGM) data. GRI is divided into five separate risk zones (from lowest to highest: A-E). In this study, the effect of the advanced hybrid closed loop (AHCL) system on GRI and COGI in children with type 1 diabetes was evaluated. Materials and Methods: Forty-five children who had started using the AHCL and whose baseline and sixth-month CGM data were available were analyzed in terms of achievement of CGM consensus goals and changes in GRI scores and zones. The paired t-test was used for the analyses. Results: The mean age and duration of diabetes of the participants were 10.95 ± 3.41 and 3.85 ± 2.67 years, respectively. The mean GRI score significantly decreased from 35.66 ± 17.46 at baseline to 22.83 ± 9.08 at 6 months (P < 0.001). Although the proportion of those in the A zone was 20% at baseline, it increased to 42% at 6 months. AHCL also improved COGI from 72.59 ± 12.44 to 82.90 ± 7.72 (P < 0.001). Time in range (TIR) increased significantly from 70.54% to 80.51% (P < 0.001) at 6 months. Conclusion: AHCL provides not only an improvement in TIR but also a significant improvement in both GRI and COGI at 6 months. The incorporation of GRI and COGI alongside TIR may enhance the assessment of the glycemic profile by providing a more comprehensive and in-depth analysis.


Routine use of concurrent fluoroscopic imaging during superficial endovenous interventions: A position statement of the International Union of Phlebology, the Australasian College of Phlebology, the Australia and New Zealand Society for Vascular Surgery, the American Venous Forum, the American Vein and Lymphatic Society, the European College of Phlebology and the Interventional Radiology Society of Australasia.
International evidence-based guidelines recommend preoperative duplex ultrasound mapping in the assessment of chronic venous disease, and concurrent ultrasound imaging to guide superficial endovenous interventions such as endovenous laser ablation, radiofrequency ablation, cyanoacrylate adhesive closure, and sclerotherapy (ultrasound-guided sclerotherapy). Other imaging modalities such as venography, alone or in combination with computed tomography scan or magnetic resonance imaging, may be included in the preoperative assessment of a small and select group of patients to exclude central venous obstruction, certain deep venous pathologies, pelvic origin extrapelvic varices, and complex vascular malformations. The signatory scientific and medical societies recommend against the routine use of fluoroscopy and other radiation-based imaging in the investigation and treatment of superficial venous disease.


Memory performance is related to the cortisol awakening response in older people, but not to the diurnal cortisol slope.
There are large individual differences in age-related cognitive decline. Hypothalamic-pituitary-adrenal axis (HPA-axis) functioning has been suggested as one of the mechanisms underlying these differences. This study aimed to investigate the relationships between the diurnal cortisol cycle, measured as the cortisol awakening response (CAR), and the diurnal cortisol slope (DCS) and the memory performance of healthy older people. To do so, we assessed the verbal, visual, and working memory performance of 64 participants (32 men) from 57 to 76 years old who also provided 14 saliva samples on two consecutive weekdays to determine their diurnal cortisol cycle. The CAR was linearly and negatively associated with verbal (significantly) and visual (marginally) memory domains, but not with working memory. Sex did not moderate these relationships. Furthermore, no associations were found between the DCS and any of the three memory domains assessed. Our results indicate that the two components of the diurnal cortisol cycle have different relationships with memory performance, with the CAR being more relevant than DCS in understanding the link from HPA-axis activity and regulation to different types of memory. These results suggest that the CAR is related to memory domains dependent on hippocampal functioning (i.e., declarative memory), but not to those that are more dependent on prefrontal cortex functioning (i.e., working memory).


Tracing the sources and microbial degradation of PCBs in field sediments by a multiple-line-of-evidence approach including compound-specific stable isotope analysis.
Comprehensive monitoring is crucial for tracing micropollutants in the natural environment. To better evaluate the sources and natural attenuation of polychlorinated biphenyls (PCBs), three composite sediment cores were sampled from a closed pond near e-waste recycling plants, and a multiple-line-of-evidence approach (MLEA) including quantification, enantiomer analysis, microbial community profiling, and compound-specific isotope analysis (CSIA) was used to investigate the fate of PCBs in sediment cores. The difference in the maximum PCB concentrations and associated depths between sites 1/2 and 3 and the corresponding significant (p < 0.01) difference in δ13C values strongly indicated two different PCB inputs at sites 1/2 and 3. A significant (p < 0.01) negative correlation between the variation in chlorine per biphenyl (CPB) and Log the abundance of Dehalococcoides/total molar concentration of PCBs (Log Dhc/TPCB) along the cores suggested that different degrees of PCB degradation occurred and that Dehalococcoides likely participated in PCB degradation in these sediments. Nonracemic compositions and pronounced stable carbon isotope fractionation (Δδ13C > 1‰) of PCB congeners were observed, confirming that in situ degradation occurred in the sediment cores. The progressive enrichment in 13C with increasing core depth suggested strengthened microbial degradation of the residual congener pools. The results of this study suggested that MLEA analysis of PCBs can provide reliable information to better monitor the sources and fate of these compounds in the environment.


Structure-function analysis of the ribozymes of chrysanthemum chlorotic mottle viroid: a loop-loop interaction motif conserved in most natural hammerheads.
Loop-loop tertiary interactions play a key role in the folding and catalytic activity of natural hammerhead ribozymes. Using a combination of NMR spectroscopy, site-directed mutagenesis and kinetic and infectivity analyses, we have examined the structure and function of loops 1 and 2 of the (+) and (-) hammerheads of chrysanthemum chlorotic mottle viroid RNA. In both hammerheads, loop 1 is a heptanucleotide hairpin loop containing an exposed U at its 5' side and an extrahelical U at its 3'-side critical for the catalytic activity of the ribozyme in vitro and for viroid infectivity in vivo, whereas loop 2 has a key opened A at its 3'-side. These structural features promote a specific loop-loop interaction motif across the major groove. The essential features of this tertiary structure element, base pairing between the 5' U of loop 1 and the 3' A of loop 2, and interaction of the extrahelical pyrimidine of loop 1 with loop 2, are likely shared by a significant fraction of natural hammerheads.


[Biomechanical evaluation of biointegrable suture anchors composed of bovine compact bone in a pull-to-failure test in porcine tibial head specimens].
Suture anchors of various designs have gained wide acceptance for securing soft tissues to bone. The biointegrable Tutofix CB anchors derived from bovine compact bone are available with diameters of 3 mm (CB3 anchor), 4 mm (CB4 anchor) and 5 mm (CB5 anchor). The CB anchors are push-in anchors and, from the biomechanical standpoint, they are a combination of press-fit and angulation anchors. The purpose of this study was to evaluate the CB anchors for singular pull load-to-failure strength using porcine tibial head specimens as a test model. In all specimens, the joint surface was removed by performing a subchondral osteotomy. Axial PQ-CT scans of 12 specimens were obtained to determine the trabecular BMD. The anchors were implanted posteromedially and centrolaterally in the porcine tibial head specimens. After threading the anchors with a steel suture and predrilling of the anchor holes perpendicular to the osteotomy surface they were inserted 4 mm below the osteotomy surface. A universal testing machine applied tensile loads parallel to the axis of insertion at rates of 10 mm/min and 500 mm/min until pull-out failure or anchor breakage and mean anchor fixation strengths were calculated. The fixation strength of the CB anchors was found to be much higher at the dorsomedial implantation site than at the centrolateral implantation site. The CB4 anchors and CB5 anchors provided nearly the same fixation strength at a level much higher than that of the CB3 anchors. Bone mineral density had a strong influence on axial pull-out force of the anchors, especially the CB4 anchors and CB5 anchors. The overall correlation coefficient for bone mineral density with ultimate load-to-failure was 0.869 for the CB4 anchors and 0.716 for the CB5 anchors. Differences in failure strengths were also seen between the low and high extraction rates. With the high extraction rate much higher failure strengths were obtained than with the low extraction rate. The sudden pull eccentrically on the anchors caused a better fixation due to angulation of the anchor within the drill holes. In spite of the double worst-case scenario in the testing conditions, the CB anchors provided a high fixation strength in the trabecular bone of porcine tibial head specimens with the CB4 anchors and CB5 anchors being nearly equal and both being superior to the CB3 anchors. Bone mineral density had a strong influence on the axial pull-out force. Our results show that the CB anchors seem to be a reasonable alternative to metal and bioabsorbable suture anchors.


Voluntary stopping of eating and drinking at the end of life - a 'systematic search and review' giving insight into an option of hastening death in capacitated adults at the end of life.
The terminally ill person's autonomy and control are important in preserving the quality of life in situations of unbearable suffering. Voluntary stopping of eating and drinking (VSED) at the end of life has been discussed over the past 20 years as one possibility of hastening death. This article presents a 'systematic search and review' of published literature concerned with VSED as an option of hastening death at the end of life by adults with decision-making capacity. Electronic databases PubMed, EBSCOhost CINAHL and Ovid PsycINFO were systematically searched. Additionally, Google Scholar was searched and reference lists of included articles were checked. Data of the included studies were extracted, evaluated and summarized in narrative form. Overall, out of 29 eligible articles 16 were included in this review. VSED can be defined as an action by a competent, capacitated person, who voluntarily and deliberately chooses to stop eating and drinking with the primary intention of hastening death because of the persistence of unacceptable suffering. An estimated number of deaths by VSED was only provided by one study from the Netherlands, which revealed a prevalence of 2.1% of deaths/year (on average 2800 deaths/year). Main reasons for patients hastening death by VSED are: readiness to die, life perceived as being pointless, poor quality of life, a desire to die at home, and the wish to control the circumstances of death. The physiological processes occurring during VSED and the supportive care interventions could not be identified through our search. The included articles provide marginal insight into VSED for hastening death. Research is needed in the field of theory-building and should be based on qualitative studies from different perspectives (patient, family members, and healthcare workers) about physiological processes during VSED, and about the prevalence and magnitude of VSED. Based on these findings supportive care interventions for patients and family members and recommendations for healthcare staff should be developed and tested.


Cadmium accumulation by a Citrobacter sp. immobilized on gel and solid supports: Applicability to the treatment of liquid wastes containing heavy metal cations.
Polyacrylamide gel-immobilized cells of a Citrobacter sp. removed cadmium from flows supplemented with glycerol 2-phosphate, the metal uptake mechanism being mediated by the activity of a cell-bound phosphatase that precipitates liberated inorganic phosphate with heavy metals at the cell surface. The constraints of elevated flow rate and temperature were investigated and the results discussed in terms of the kinetics of immobilized enzymes. Loss in activity with respect to cadmium accumulation but not inorganic phosphate liberation was observed at acid pH and was attributed to the pH-dependent solubility of cadmium photsphate. Similarly high concentrations of chloride ions, and traces of cyanide inhibited cadmium uptake and this was attributed to the ability of these anions to complex heavy metals, especially the ability of CN(-) to form complex anions with Cd(2+). The data are discussed in terms of the known chemistry of chloride and cyanide-cadmium complexes and the relevance of these factors in the treatment of metal-containing liquid wastes is discussed. The cells immobilized in polyacrylamide provided a convenient small-scale laboratory model system. It was found that the Citrobacter sp. could be immobilized on glass supports with no chemical treatment or modification necessary. Such cells were also effective in metal accumulation and a prototype system more applicable to the treatment of metal-containing streams on a larger scale is described.


Identification of an N-domain histidine essential for chaperone function in calreticulin.
Calreticulin is an endoplasmic reticulum (ER) luminal Ca(2+)-binding chaperone involved in folding of newly synthesized glycoproteins via the "calreticulin-calnexin cycle." We reconstituted ER of calreticulin-deficient cells with N-terminal histidine (His25, His82, His128, and His153) calreticulin mutants and carried out a functional analysis. In crt(-/-) cells bradykinin-dependent Ca2+ release is altered, and the reestablishment of bradykinin-dependent Ca2+ release was used as a marker for calreticulin function. Bradykinin-dependent Ca2+ release from the ER was rescued by wild type calreticulin and by the His25, His82, or His128 mutant but not by the His153 mutant. Wild type calreticulin and the His25, His82, and His128 mutants all prevented in vitro thermal aggregation of malate dehydrogenase and IgY, whereas the His153 mutant did not, indicating that His153 chaperone function was impaired. Biophysical analysis of His153 mutant revealed that conformation changes in calreticulin mutant may be responsible for the loss of its chaperone activity. We conclude that mutation of a single amino acid residue in calreticulin has devastating consequences for its chaperone function, indicating that mutations in chaperones may play a significant role in protein folding disorders.


Towards Adaptive Grids for Atmospheric Boundary-Layer Simulations.
We present a proof-of-concept for the adaptive mesh refinement method applied to atmospheric boundary-layer simulations. Such a method may form an attractive alternative to static grids for studies on atmospheric flows that have a high degree of scale separation in space and/or time. Examples include the diurnal cycle and a convective boundary layer capped by a strong inversion. For such cases, large-eddy simulations using regular grids often have to rely on a subgrid-scale closure for the most challenging regions in the spatial and/or temporal domain. Here we analyze a flow configuration that describes the growth and subsequent decay of a convective boundary layer using direct numerical simulation (DNS). We validate the obtained results and benchmark the performance of the adaptive solver against two runs using fixed regular grids. It appears that the adaptive-mesh algorithm is able to coarsen and refine the grid dynamically whilst maintaining an accurate solution. In particular, during the initial growth of the convective boundary layer a high resolution is required compared to the subsequent stage of decaying turbulence. More specifically, the number of grid cells varies by two orders of magnitude over the course of the simulation. For this specific DNS case, the adaptive solver was not yet more efficient than the more traditional solver that is dedicated to these types of flows. However, the overall analysis shows that the method has a clear potential for numerical investigations of the most challenging atmospheric cases.


Interpersonal disturbance in OCD and its place in the professional consultation.
People with obsessive-compulsive disorder (OCD) typically experience their relationships with others with a high level of trepidation and bring their anxieties into their work with professionals. We have written this paper to describe experiences of working with people with diagnoses of OCD and the impression that we have formed about the kinds of relationship that builds up in the early stages of this work. We believe that it is important to consider the quality of these professional relationships because of their impact on the patient's ability to benefit from whatever intervention we propose. Here, we place particular attention on the roles of magical thinking, disturbed relationships and the fear of rejection. The perspective presented here is designed to complement those of other approaches to OCD - including the neurological, behavioural and cognitive-behavioural. The following themes relating to the social and interpersonal experiences of people with OCD are examined here: (a) their general tentativeness and uncertainty in social interactions, (b) their fear of being damaged by others in social interactions, (c) their magical thinking relating to damaging others.


Self-control Mediates the Relationship between Psychosocial Strengths and Perceived Severity of COVID-19 among Frontline Healthcare Professionals of Pakistan: A Single Center Experience.
To examine the relationship between psychosocial strengths (resilience, self-efficacy beliefs and social support) and perceived severity of COVID-19 and also to gauge the mediating role of self-control among frontline health care professionals of Pakistan. A cross-sectional research design was utilized from March to April 2020 from one medical teaching hospital of South Punjab. As it was a single center experience so all the doctors were approached and asked to participate in this research. In total, 284 doctors (out of 300 approx.) completed online survey. The data were collected through online google forms consisting of self-report measures i.e. Brief Resilience Scale, Short General Self Efficacy Scale, Brief Scale for Social Support, Risk Behavior Diagnostic Scale and Brief Self-Control Scale. The results were analyzed by using SmartPLS (3.0), direct effect of psychosocial strengths on perceived severity of COVID-19 and indirect effect of self-control were assessed through path coefficients, t-values and r-square values. The results confirmed that there was significant negative relationship between psychosocial strengths and perceived severity of COVID-19 (β = -0.854, t =14.279) with 72% variance in perceived severity due to psychosocial strengths. Further, the results also suggest that self-control proved significant mediator between psychosocial strengths and perceived severity (β = -0.604, t = 11.004, variance in perceived severity is 74%). In the time of pandemic, medical professionals are working as frontline force and can have several uncertainties regarding the risk associated with outbreak of COVID-19. This study concludes psychosocial strengths can play a significant role in subsiding the risk associated with severity of disease. Whereas, self-control can significantly contribute to buffer the negative influence of COVID-19 among frontline medical professionals. In line with findings of this study, there is a dire need to initiate psychotherapeutic studies for medical professionals to boost up their psychosocial strengths that would make them resilient against COVID-19.


[Morphological changes in rat liver in toxic drug-induced hepatitis and stimulation of repair processes].
Despite a large choice of drugs used for the treatment of chronic liver diseases, they often give only a temporary positive effect. In this study the effect of ursodeoxycholic acid on liver regeneration was investigated using the animal model of toxic hepatitis induced by anticonvulsive drug depackin, which is employed in infant neurology. The results of the study demonstrate stimulatory effect of ursodeoxycholic acid on regeneration process in animals' damaged liver, therefore its use may be recommended for the complex treatment of patients with toxic liver lesions.


Human dendritic cells skew isotype switching of CD40-activated naive B cells towards IgA1 and IgA2.
Within T cell-rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on approximately 10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-beta, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40-50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-beta. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-beta. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell-dependent B cell growth and differentiation, by inducing the IgA isotype switch.


Principles of operation of a cerebellar learning circuit.
We provide behavioral evidence using monkey smooth pursuit eye movements for four principles of cerebellar learning. Using a circuit-level model of the cerebellum, we link behavioral data to learning's neural implementation. The four principles are: (1) early, fast, acquisition driven by climbing fiber inputs to the cerebellar cortex, with poor retention; (2) learned responses of Purkinje cells guide transfer of learning from the cerebellar cortex to the deep cerebellar nucleus, with excellent retention; (3) functionally different neural signals are subject to learning in the cerebellar cortex versus the deep cerebellar nuclei; and (4) negative feedback from the cerebellum to the inferior olive reduces the magnitude of the teaching signal in climbing fibers and limits learning. Our circuit-level model, based on these four principles, explains behavioral data obtained by strategically manipulating the signals responsible for acquisition and recall of direction learning in smooth pursuit eye movements across multiple timescales.


An ethnobotanical survey of wild edible plants of Paphos and Larnaca countryside of Cyprus.
An ethnobotanical survey of wild edible plants of Cyprus was carried out in two sites, Paphos vine zone and Larnaca mixed farming zone. These are among the areas in Cyprus whose inhabitants subsisted primarily on pastoralism and agriculture and therefore still preserve the traditional knowledge on wild edible plants. The information was collected for three-year period, in the framework of the EU-funded RUBIA Project. Four hundred and thirteen interviews have been administered to 89 informants of various ages and background categories in 29 villages of Paphos site, and 8 in Larnaca site. A total of 78 species were recorded. Ethnographic data related to vernacular names, traditional tools and recipes have also been recorded. A comparison of the data collected from the two sites is undertaken. During this ethnobotanical research it was verified that wild edibles play an important role in Cyprus in rural people, however, it was realized that the transmission of folk uses of plants decreased in the last generations. The research of ethnobotany should be extended to other areas of Cyprus in order not only to preserve the traditional knowledge related to plants but to make it available to future generations as well.


Semisynthetic supra plasma expanders: a new class of therapeutics to improve microcircualtion in sickle cell anaemia.
Compromised microcirculation and endothelial dysfunction are hallmarks of sickle cell disease (SCD). EAF PEG Haemoglobin (Hb) and EAF PEG Albumin (Alb) represent a novel class of semisynthetic colloidal supra plasma expanders that improve microcirculation. The therapeutic activity of supra plasma expanders to attenuate vaso-occlusion and restore the haemodynamic functions in patients with SCD has been investigated using NY1DD, a transgenic mouse model of mild SCD without anaemia. Vaso-occlusion and perturbation of haemodynamics are amplified in NY1DD by hypoxia-reoxygenation protocol. EAF P5K6 Alb and Alb T12 (Alb conjugated with 12 copies of antioxidant tempo) attenuate vaso-occlusion when infused at the start of reoxygenation. However, only EAF PEG Alb restores haemodynamics close to levels in control C57BL. EAF P5K6 Alb-T12, active plasma expander conjugated with antioxidant, completely clears vaso-occlusion and restores normal haemodynamics. EAF PEG Hb also completely clears vaso-occlusion and restores normal haemodynamics. Pretreating NY1DD with EAF PEG Hb protects it from hypoxia reoxygenation-induced damages. EAF P5K6 Alb T12 attenuates the endothelial dysfunction in S + S Antilles mice as reflected by the vasodilatory response of its arteries and arterioles to vaso-dilators. Active plasma expanders are novel therapeutics to restore normal haemodynamics in SCD patients to improve tissue oxygenation during episodes of painful vaso-occlusive crisis. Abbreviations: 2-IT: 2-immothiolane; Mal-T: 4-Maleimido tempo; Alb: human serum albumin (HSA); Alb-T12: human albumin conjugated with 12 copies of tempo; EAF: extension arm facilitated; EAF PEG Hb: extension arm facilitated PEGylated haemoglobin; EAF PEG Alb: extension arm facilitated PEGylated albumin; EAF P3K6 Hb: extension arm facilitated PEGylated haemoglobin conjugated with 6 copies of PEG3K; EAF P5K6 Alb T12: extension arm facilitated PEGylated albumin conjugated with 6 copies of PEG5K and 12 copies of tempo; Hb: haemoglobin; HAS: human serum albumin (Alb); PEG: polyethylene glycol; MP4: MalPEG Hb, is formulated at 4.2 g/dL in lactated Ringer's solution, a product of Sangart; SCD: sickle cell disease; NO: nitric oxide; SEC: size exclusive chromatography; Vrbc: red cell velocity; Q: volumetric flow rates, Q; SNP: sodium nitroprusside.


Normal laboratory values for differential white cell counts established by manual and automated cytochemical methods (Hemalog D-TM).
The central 95 percentile estimates of the normal white cell types (as determined by a standard differential count) were calculated from 777 normal individuals. The results were divided into groups by age and sex and expressed both as percentages and as absolute numbers of cells.A similar survey was made using the prototype of a new automated differential counting method (Hemalog-D(TM)). The two sets of laboratory values showed no statistically significant differences regarding age or sex and were strikingly similar in most cell types with the exception of band and juvenile forms of granulocytes. As expected, the normal range using the manual technique was somewhat broader than that found with the automated method. In addition to being the first comparison of machine counts with visual differentials this study provides additional insight into the age distributions of normal cells.


Insights into mechanisms of intestinal segmentation in guinea pigs: a combined computational modeling and in vitro study.
Segmentation in the guinea pig small intestine consists of a number of discrete motor patterns including rhythmic stationary contractions that occur episodically at specific locations along the intestine. The enteric nervous system regulates segmentation, but the exact circuit is unknown. Using simple computer models, we investigated possible circuits. Our computational model simulated the mean neuron firing rate in the feedforward ascending and descending reflex pathways. A stimulus-evoked pacemaker was located in the afferent pathway or in a feedforward pathway. Output of the feedforward pathways was fed into a simple model to determine the response of the muscle. Predictions were verified in vitro by using guinea pig jejunum, in which segmentation was induced with luminal fatty acid. In the computational model, local stimuli produced an oral contraction and anal dilation, similar to in vitro responses to local distension, but did not produce segmentation. When the stimulus was distributed, representing a nutrient load, the result was either a tonic response or globally synchronized oscillations. However, when we introduced local variations in synaptic coupling, stationary contractions occurred around these locations. This predicts that severing the ascending and descending pathways will induce stationary contractions. An acute lesion in our in vitro model significantly increased the number of stationary contractions immediately oral and anal to the lesion. Our results suggest that spatially localized rhythmic contractions arise from a local imbalance between ascending excitatory and descending inhibitory muscle inputs and require a distributed stimulus and a rhythm generator in the afferent pathway.


Analysis of FK506, timcodar (VX-853) and FKBP51 and FKBP52 chaperones in control of glucocorticoid receptor activity and phosphorylation.
The immunosuppressive ligand FK506 and the FK506-binding protein FKBP52 are stimulatory to glucocorticoid receptor (GR) activity. Here, we explore the underlying mechanism by comparing GR activity and phosphorylation status in response to FK506 and the novel nonimmunosuppressive ligand timcodar (VX-853) and in the presence and absence of FKBP52 and the closely related protein FKBP51. Using mouse embryonic fibroblast cells (MEFs) deficient knockout (KO) in FKBP51 or FKBP52, we show decreased GR activity at endogenous genes in 52KO cells, but increased activity in 51KO cells. In 52KO cells, elevated phosphorylation occurred at inhibitory serine 212 and decreased phosphorylation at the stimulatory S220 residue. In contrast, 51KO cells showed increased GR phosphorylation at the stimulatory residues S220 and S234. In wild-type (WT) MEF cells, timcodar, like FK506, potentiated dexamethasone-induced GR transcriptional activity at two endogenous genes. Using 52KO and 51KO MEF cells, FK506 potentiated GR activity in 51KO cells but could not do so in 52KO cells, suggesting FKBP52 as the major target of FK506 action. Like FK506, timcodar potentiated GR in 51KO cells, but it also increased GR activity in 52KO cells. Knock-down of FKBP51 in the 52KO cells showed that the latter effect of timcodar required FKBP51. Thus, timcodar appears to have a dual specificity for FKBP51 and FKBP52. This work demonstrates phosphorylation as an important mechanism in FKBP control of GR and identifies the first nonimmunosuppressive macrolide capable of targeting GR action.


Establishment of a whole-chick sternum model that recapitulates normal cartilage development.
A serum-free organ culture model for chondrocyte maturation, using the Avian sternum, was developed. Day-14 chick embryo sterna were placed in organ culture in the presence of defined medium. The optimal medium for chondrocyte terminal differentiation contained specific concentrations of dexamethasone, insulin, thyroid hormone and ascorbic acid. Three parameters, including sternal growth, cell diameter and type X collagen production, were analyzed as indicators of chondrocyte terminal differentiation. These parameters were analyzed in cephalic, middle and caudal regions of the organ-cultured chick sterna and compared to sterna grown in ovo. This study demonstrates that the organ-cultured tissue maintains normal morphological characteristics and terminal differentiation in the cephalic region only, similar to in ovo development, while maintaining normal cell-matrix relationships.


Treatment of accidental hypothermia with cardiopulmonary bypass: a case report.
This case report describes the successful treatment of severe accidental hypothermia of a 40-year-old woman. At arrival in the operating theatre her rectal temperature was 23 degrees C, her nasal temperature 21 degrees C and her periferal temperature 14 degrees C. The patient presented with a severe respiratory and metabolic acidosis which was corrected during cardiopulmonary bypass (CPB). She was rewarmed to obtain a rectal and nasal temperature of 34 degrees C. After 272 minutes, the patient was weaned successfully from CPB. The patient remained at mild hypothermia (34 degrees C) for 24 hours in the intensive care unit (ICU). The chest X-ray showed some signs of acute respiratory distress syndrome (ARDS) in spite of normal blood gas values. This improved within a few days and, after five days, she was transferred to the nursing department. On the seventh day, the patient was discharged from hospital without physical or neurological complaints.


Effectiveness of Cyantraniliprole for Managing Bemisia tabaci (Hemiptera: Aleyrodidae) and Interfering with Transmission of Tomato Yellow Leaf Curl Virus on Tomato.
Cyantraniliprole is the second xylem-systemic active ingredient in the new anthranilic diamide class. Greenhouse (2006), growth chamber (2007), and field studies (2009-2010) were conducted to determine the efficacy of cyantraniliprole for managing Bemisia tabaci (Gennadius) biotype B and in interfering with transmission of tomato yellow leaf curl virus (TYLCV) by this whitefly. Cyantraniliprole applied as soil treatments (200 SC) or foliar sprays (100 OD) provided excellent adult whitefly control, TYLCV suppression, and reduced oviposition and nymph survival, comparable to current standards. The positive results observed in these greenhouse experiments with a high level of insect pressure (10× the field threshold of one adult per plant) and disease pressure (five adults per plant, with a high level of confidence that TYLCV virulent adults were used), indicate a great potential for cyantraniliprole to be used in a whitefly management program. Field evaluations of soil drench treatments confirmed the suppression of TYLCV transmission demonstrated in the greenhouse studies. Field studies in 2009 and 2010 showed that cyantraniliprole (200 SC) provided TYLCV suppression for 2 wk after a drench application, when using a susceptible (2009) or imidacloprid-tolerant (2010) whitefly population. Cyantraniliprole was demonstrated to be a promising tool for management of TYLCV in tomato production, which is very difficult and expensive, and which has limited options. The integration of cyantraniliprole into a resistance management program will help to ensure the continued sustainability of this and current insecticides used for the management of insect vectors, including whiteflies and the TYLCV they spreads.


Purinergic signaling in oligodendrocyte development and function.
Myelin, an insulating membrane that enables rapid action potential propagation, is an essential component of an efficient, functional vertebrate nervous system. Oligodendrocytes, the myelinating glia of the central nervous system (CNS), produce myelin throughout the CNS, which requires continuous proliferation, migration, and differentiation of oligodendrocyte progenitor cells. Because myelination is essential for efficient neurotransmission, researchers hypothesize that neuronal signals may regulate the cascade of events necessary for this process. The ability of oligodendrocytes and oligodendrocyte progenitor cells to detect and respond to neuronal activity is becoming increasingly appreciated, although the specific signals involved are still a matter of debate. Recent evidence from multiple studies points to purinergic signaling as a potential regulator of oligodendrocyte development and differentiation. Adenosine triphosphate (ATP) and its derivatives are potent signaling ligands with receptors expressed on many populations of cells in the nervous system, including cells of the oligodendrocyte lineage. Release of ATP into the extracellular space can initiate a multitude of signaling events, and these downstream signals are specific to the particular purinergic receptor (or receptors) expressed, and whether enzymes are present to hydrolyze ATP to its derivatives adenosine diphosphate and adenosine, each of which can activate their own unique downstream signaling cascades. This review will introduce purinergic signaling in the CNS and discuss evidence for its effects on oligodendrocyte proliferation, differentiation, and myelination. We will review sources of extracellular purines in the nervous system and how changes in purinergic receptor expression may be coupled to oligodendrocyte differentiation. We will also briefly discuss purinergic signaling in injury and diseases of the CNS.


[CT enterography with polyethylene glycol electrolyte solution for diagnosis of Crohn's disease].
This study aimed to assess the diagnostic usefulness of CT enterography (CTE) in Crohn's disease in Japanese patients. A total of 32 cases with bowel symptoms underwent CT enterography with polyethylene glycol electrolyte solution as oral contrast medium, among which 18 were clinically diagnosed as Crohn's disease and 14 were not: ulcerative colitis 1, Beçhet disease 1, simple ulcer 1, inflammatory bowel disease without definite diagnosis 5 and bowel symptoms of unknown origin 6. The incidence of bowel wall thickening, mural hyperenhancement, "the comb sign", mesenteric lymph nodes swelling, and stenosis were significantly higher in Crohn's disease than in other disease. Moreover, uneven bowel wall thickening and unilateral mural hyperenhancement on CTE were characteristic features of Crohn's disease, which our original quantitative evaluation with imaging analysis could support. Consequently, CTE is useful in Japanese patients with Crohn's disease.


Nucleophilicities and carbon basicities of pyridines.
Rate and equilibrium constants for the reactions of pyridines with donor-substituted benzhydrylium ions have been determined spectrophotometrically. The correlation equation log k(20 degrees C)=s(N+E), in which s and N are nucleophile-specific parameters and E is an electrophile-specific parameter, has been used to determine the nucleophilicity parameters of various pyridines in CH(2)Cl(2) and aqueous solution and to compare them with N of other nucleophiles. It is found that the nucleophilic organocatalyst 4-(dimethylamino)pyridine (DMAP) and tertiary phosphanes have comparable nucleophilicities and carbon basicities despite widely differing Brønsted basicities. For that reason, these reactivity parameters are suggested as guidelines for the development of novel organocatalysts. The Marcus equation is employed for the determination of the intrinsic barriers of these reactions.


Antiphospholipid syndrome, "the best prophet of the future".
The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by the occurrence of venous and arterial thromboses, often multiple, and obstetric-related adverse events in the presence of antiphospholipid antibodies (aPL). APS, first described in 1983, as thrombosis, abortion and cerebral disease, is nowadays recognised as a systemic disease with a wide constellation of clinical manifestations related to acute and chronic vascular lesions. The presence of aPL is the serological hallmark of APS representing a heterogeneous population of autoantibodies with many antigenic specificities directed to phospholipid-binding proteins, either alone or in combination with phospholipids. Many assays have been developed for aPL detection. Particularly, anticardiolipin antibodies, anti-β2-glycoprotein I antibodies and lupus anticoagulant are essential tools for APS diagnosis. The cumulative evidence indicates that aPL are pathogenic autoantibodies binding to target cells and promoting thrombosis and pregnancy complications through a wide range of pathological mechanisms not yet fully understood. Finally, the recognition of the important role of aPL to assess the individual risk of thrombosis or pregnancy complications has expanded the concept of aPL, and currently aPL profile is regarded as a major risk factor for clinical thrombotic events.


Predictors of infection, symptoms development, and mortality in people with SARS-CoV-2 living in retirement nursing homes.
Since the start of the pandemic, millions of people have been infected, with thousands of deaths. Many foci worldwide have been identified in retirement nursing homes, with a high number of deaths. Our study aims were to evaluate the spread of SARS-CoV-2 in the retirement nursing homes, the predictors to develop symptoms, and death. We conducted a retrospective study enrolling all people living in retirement nursing homes (PLRNH), where at least one SARS-CoV-2 infected person was present. Medical and clinical data were collected. Variables were compared with Student's t-test or Pearson chi-square test as appropriate. Uni- and multivariate analyses were conducted to evaluate variables' influence on infection and symptoms development. Cox proportional-hazards model was used to evaluate 30 days mortality predictors, considering death as the dependent variable. We enrolled 382 subjects. The mean age was 81.15±10.97 years, and males were 140(36.7%). At the multivariate analysis, mental disorders, malignancies, and angiotensin II receptor blockers were predictors of SARS-CoV-2 infection while having a neurological syndrome was associated with a lower risk. Only half of the people with SARS-CoV-2 infection developed symptoms. Chronic obstructive pulmonary disease and neurological syndrome were correlated with an increased risk of developing SARS-CoV-2 related symptoms. Fifty-six (21.2%) people with SARS-CoV-2 infection died; of these, 53 died in the first 30 days after the swab's positivity. Significant factors associated with 30-days mortality were male gender, hypokinetic disease, and the presence of fever and dyspnea. Patients' autonomy and early heparin treatment were related to lower mortality risk. We evidenced factors associated with infection's risk and death in a setting with high mortality such as retirement nursing homes, that should be carefully considered in the management of PLRNH.


Transcellular metabolism of leukotriene A4 by rabbit blood cells: lack of relevant LTC4-synthase activity in rabbit platelets.
The objective of this study was to determine the transcellular metabolism of leukotriene A4 by rabbit blood cells. mixed peripheral blood leukocyte preparations with and without platelets in a ratio of 1:40 were challenged with the Ca(2+)-ionophore A23187. 5-Lipoxygenase metabolites production was assessed by RP-HPLC coupled with diode-array UV detection. In light of the observation that leukotriene C4 production in leukocyte-platelet coincubation was the same as with leukocytes alone, mixed coincubation of human and rabbit blood cells was tested. Rabbit leukocytes with human platelets resulted in a significant increase of leukotriene C4 production, while no changes were observed in human leukocytes with or without rabbit platelets. In agreement with these results, intact rabbit platelets or rabbit platelet lysates, unlike human platelets, were not able to convert synthetic leukotriene A4 free acid to leukotriene C4. These data provide evidence that rabbit leukocytes are able to make a significant amount of leukotriene A4 available for transcellular metabolism, while rabbit platelets, unlike human platelets, lack leukotriene C4-synthase activity.


Chemical mismanagement and skin burns among hospitalized and outpatient department patients.
Purpose. This article attempts to elucidate the nature of chemicals causing major and minor skin burns, and their associated characterization across different industries, using Fujian provincial hospitals' admission and outpatient department records. Materials and methods. Data were collected from the provincial hospitals of Fujian through a questionnaire, sent via email, from June 1, 2017 to November 30, 2017. The collected responses were statistically analyzed using SPSS version 19 through the interquartile range, median, Mann-Whitney U test and Fisher's exact test with two-tailed significance. Results and conclusions. The results of 306 collected responses reveal that the majority of skin burn cases are due to a lack of technical education and professional training among workers handling chemicals. This study suggests that management's effective supervision and governmental regulations may help to prevent chemical skin burns at work, and can further be controlled by hiring professional workers alongside providing training to them in chemical handling as well as using protective equipment and developing appropriate management policies to improve victims' well-being and quality of life. Findings will help workers, doctors, hospitals, industries, government and other stakeholders to understand and control chemical hazards on site to minimize the risks of chemical skin burn incidents.


Systemic mastocytosis with associated clonal hematological non-mast cell lineage disease: clinical significance and comparison of chomosomal abnormalities in SM and AHNMD components.
Some patients with systemic mastocytosis have concurrent hematological neoplasms, designated in the World Health Organization (WHO) classification as systemic mastocytosis with associated clonal hematological non-mast cell lineage disease (SM-AHNMD). In this study, we analyzed 29 patients with SM-AHNMD and compared them to 40 patients with pure SM. The AHNMDs were classified as chronic myelomonocytic leukemia (CMML) (n = 10), myelodysplastic syndrome (MDS) (n = 7), myeloproliferative neoplasms (n = 4), B-cell lymphoma/leukemia/plasma cell neoplasms (n = 7), and acute myeloid leukemia (n = 1). Patients with SM-AHNMD were older, more frequently had constitutional symptoms and hematological abnormalities, less often had skin lesions, and had an inferior overall survival compared with pure SM patients (48 months vs. not-reached, P < 0.001). Karyotypic abnormalities were detected in 9/28 (32%) patients with SM-AHNMD but not in pure SM patients (P < 0.001). Combined imaging/ fluorescence-in-situ hybridization performed in four SM-AHNMD cases revealed shared abnormal signals in mast cells and myeloid cells in two patients with SM-CMML and one patient with SM-MDS, but not in the mast cells of a case SM-associated with chronic lymphocytic leukemia with ATM-deletion. Quantitative mutation analysis showed higher levels of mutant KIT D816V in SM-CMML and SM-MDS than in pure SM (P < 0.001). Our data indicate that the SM-AHNMD category in the WHO classification is heterogeneous, including clonally related and unrelated forms of AHNMD. The presentation, treatment, and outcome of patients with SM-AHNMD is often dictated by the type of AHNMD.


A symmetrical model for the domain structure of type I DNA methyltransferases.
Type I DNA methyltransferases are complex multisubunit enzymes that methylate a specific base in each half of an asymmetric bipartite DNA recognition sequence. The specificity (S) subunit contains two corresponding DNA sequence recognition domains, plus a number of conserved regions which interact with two modification (M) subunits to form a trimeric enzyme of the form M2S. The way in which the subunits interact with DNA in a pseudo-symmetric fashion has long been unclear. Analysis of internal sequence repeats in the S-subunit shows the occurrence of significant homologies between the central conserved domain and sequences near the N and C termini. On the basis of this "split repeat", a "circular" organisation of the domains of this subunit is proposed that provides the required symmetry for interacting with the M-subunits and with the target DNA sequence. In the proposed model, one M-subunit interacts with the N and C-terminal conserved regions of the S-subunit, which are thereby brought into close proximity. The second M-subunit makes equivalent contacts with repeated sequences in the central conserved domain. The model suggests a more general scheme for the imposition of pseudo-dyad symmetry on protein subunits that have internal repeats by making equivalent contacts with additional subunits.


Dynamic corticostriatal activity biases social bonding in monogamous female prairie voles.
Adult pair bonding involves dramatic changes in the perception and valuation of another individual. One key change is that partners come to reliably activate the brain's reward system, although the precise neural mechanisms by which partners become rewarding during sociosexual interactions leading to a bond remain unclear. Here we show, using a prairie vole (Microtus ochrogaster) model of social bonding, how a functional circuit from the medial prefrontal cortex to nucleus accumbens is dynamically modulated to enhance females' affiliative behaviour towards a partner. Individual variation in the strength of this functional connectivity, particularly after the first mating encounter, predicts how quickly animals begin affiliative huddling with their partner. Rhythmically activating this circuit in a social context without mating biases later preference towards a partner, indicating that this circuit's activity is not just correlated with how quickly animals become affiliative but causally accelerates it. These results provide the first dynamic view of corticostriatal activity during bond formation, revealing how social interactions can recruit brain reward systems to drive changes in affiliative behaviour.


Serum and plasma 5-hydroxyindoleacetic acid as an alternative to 24-h urine 5-hydroxyindoleacetic acid measurement.
Neuroendocrine tumours are slow growing tumours known to secrete a variety of vasoactive peptides which give rise to symptoms of the carcinoid syndrome. The diagnosis and monitoring of patients with neuroendocrine tumours is undertaken in many centres using 24 h urinary measurement of 5-hydroxyindoleacetic acid. However, 5-hydroxyindoleacetic acid can also be quantified in plasma and serum. We measured 5-hydroxyindoleacetic acid concentration in 134 paired EDTA plasma and urine samples from 108 patients with known neuroendocrine tumours and 26 healthy volunteers. We also compared 5-hydroxyindoleacetic acid concentrations in paired serum and plasma samples (n = 63), then analysed paired urine and serum samples (n = 97). Furthermore, we examined the impact of renal impairment on serum 5-hydroxyindoleacetic acid by analysing 5-hydroxyindoleacetic acid in patients without neuroendocrine tumours in different stages of chronic kidney disease, as indicated by the estimated glomerular filtration rate. Plasma and urine 5-hydroxyindoleacetic acid had very similar diagnostic sensitivities and specificities, with areas under the curve on ROC analysis of 0.917 and 0.920, respectively. Serum and plasma 5-hydroxyindoleacetic acid values showed good correlation but serum results demonstrated a positive bias, indicating the necessity for different serum and plasma reference intervals. There was an inverse correlation between estimated glomerular filtration rate and serum 5-hydroxyindoleacetic acid concentration, with 5-hydroxyindoleacetic acid increasing once the estimated glomerular filtration rate falls below 60 mL/min/1.73 m(2). The measurement of both serum and plasma 5-hydroxyindoleacetic acid can be used for the diagnosis and monitoring of patients with neuroendocrine tumours. Provided renal function is taken into consideration, either of these tests should be incorporated into standard practice as an alternative assay to urinary 5-hydroxyindoleacetic acid.


Doppler echocardiography and myocardial dyssynchrony: a practical update of old and new ultrasound technologies.
Morbidity and mortality rates are higher in patients with severe left ventricular (LV) systolic dysfunction and ECG-derived prolonged QRS interval than in those with normal QRS duration. QRS duration is currently used on the grounds that it reflects the presence of ventricular dyssynchrony. However, 30-40% of patients selected on the basis of a prolonged QRS do not receive benefit by cardiac resynchronization therapy (CRT) since they do not show any significant inverse LV remodeling and QRS duration does not accurately distinguish responders to CRT. Consequently, mechanical dyssynchrony (particularly intra-ventricular dyssynchrony) seems to be much more important than electrical dyssinchrony. Pre- and post-echocardiographic assessment should require the combination of conventional and specific applications ranging from M-mode and pulsed/continuous Doppler, to pulsed Tissue Doppler, the off-line analysis of colour Tissue Velocity Imaging, Strain Rate Imaging, and real time three-dimensional reconstruction However, there is not no consensus about the best approach and the best ultrasound parameter for selecting candidates to CRT and ECG representation of abnormal cardiac conduction still remains as the main criterion in guidelines. This review is a practical update of ultrasound methods and measurements of atrio-ventricular, inter-ventricular and intra-ventricular dyssynchrony and describes experiences which used either conventional Doppler echocardiography and more advanced techniques. By these experiences, the global amount of LV dyssynchrony seems to be critical: the greater intra-ventricular dyssynchrony, the higher the possibility of significant LV inverse remodeling. After CRT, it is necessary also to evaluate the optimal atrio-ventricular delay and ventricular-ventricular delay setting that maximizes LV systolic function.


Changes in the cortical silent period during force control.
The contribution of gamma-aminobutyric acidergic inhibitory neural circuits in the primary motor cortex, as estimated by the cortical silent period, during weak and strong force output has not been defined. The aim of this study was to investigate whether cortical silent period is modulated with change from weak to strong force control. Eleven healthy right-handed adults participated in this study. With the aid of visual feedback, participants were asked to control the force of abduction of the right index finger to 10%, 20%, 40%, 60%, 80%, and 100% of the maximum voluntary contraction. Single pulse transcranial magnetic stimulation was delivered to the left primary motor cortex region during force control tasks. The averaged actual force output level, background electromyography amplitude, and cortical silent period duration were compared between conditions, and correlation analysis was conducted. There were significant main effects of target force on background electromyography, and cortical silent period duration; with increased force, the actual force output level and background electromyography gradually increased, while cortical silent period duration gradually decreased. There were significant negative correlations between cortical silent period and force and cortical silent period and background electromyography. These findings indicate that the excitability of gamma-aminobutyric acidergic inhibitory neural circuits in primary motor cortex decreases in response to increased force output, mediated via increased corticospinal and motoneuron excitability. These results may facilitate understanding of the role of the gamma-aminobutyric acidergic circuit in primary motor cortex in force control, as well as of the mechanism underlying motor dysfunction in stroke-induced palsy, dystonia, and cerebellar ataxia.


Effect of electromyography on serum creatine kinase values in clinically normal dogs and horses.
The effect of needle electromyography (EMG) on serum creatine kinase (CK) activity was determined, using clinically normal dogs (males and females; n = 8) and horses (females; n = 8). All animals appeared normal on EMG evaluation. Serum CK was measured before and 4, 24, and 48 hours after EMG. Except for a single 24-hour sample in a dog, the animals did not have abnormally increased serum CK activity after EMG. For dogs and horses, mean values were increased, but within normal range at 4 and 24 hours and returned to base-line values by 48 hours after EMG. For dogs, but not for horses, these CK increases at 4 and 24 hours were significant (P less than 0.05). Most dogs and horses, without neuromuscular disease, did not have serum CK activity above the normal range after EMG.


Stability in lobar ventilation distribution during change in thoracic configuration.
Stability in lobar ventilation was examined in dogs during bilateral electrophrenic respiration (BEPR) and positive pressure-assisted ventilation (PPAV). Bilateral prior ligation of the lower and middle lobe pulmonary arteries monitoring of upper lobe ventilation as alveolar minute ventilation (VA), middle and lower lobe ventilation as dead space (VD), and VD/VT ratio, both calculated by the Bohr equation. As documented by chest films, transverse and anteroposterior thoracic diameters during BEPR decreased below FRC values whereas thoracic cephalocaudal dimension greatly increased. During PPAV, all thoracic dimensions increased. Despite these dissimilar regional chest movements, VA, VD, and VD/VT ratio were comparable between PPAV and BEPR under conditions of matched tidal volume and respiratory frequency. Stability in upper lobe ventilation during BEPR was maintained by caudal displacement despite the compression of the rib cage, as documented by tantalum bronchography. Lobar-interdependence appears to be the mechanism transmitting negative pleural pressure developed by the diaphragm to the upper lobes via lower and middle lobe inflation.


UPS writes a new saga of SAGA.
SAGA (Spt-Ada-Gcn5-Acetyltransferase), an evolutionarily conserved transcriptional co-activator among eukaryotes, is a large multi-subunit protein complex with two distinct enzymatic activities, namely HAT (Histone acetyltransferase) and DUB (De-ubiquitinase), and is targeted to the promoter by the gene-specific activator proteins for histone covalent modifications and PIC (Pre-initiation complex) formation in enhancing transcription (or gene activation). Targeting of SAGA to the gene promoter is further facilitated by the 19S RP (Regulatory particle) of the 26S proteasome (that is involved in targeted degradation of protein via ubiquitylation) in a proteolysis-independent manner. Moreover, SAGA is also recently found to be regulated by the 26S proteasome in a proteolysis-dependent manner via the ubiquitylation of its Sgf73/ataxin-7 component that is required for SAGA's integrity and DUB activity (and hence transcription), and is linked to various diseases including neurodegenerative disorders and cancer. Thus, SAGA itself and its targeting to the active gene are regulated by the UPS (Ubiquitin-proteasome system) with implications in diseases.


Molecular modelling of protein-carbohydrate interactions. Understanding the specificities of two legume lectins towards oligosaccharides.
By means of a series of new molecular modelling tools, the conformational behaviour of mannose-containing di- and trisaccharides bound to either concanavalin A or Lathyrus ochrus isolectin I (LOLI) has been assessed. Tools for estimating and analysing either the 'rigid' or the 'relaxed' potential energy surfaces, representing the conformational space available for carbohydrates once interacting with lectins, are reported for the first time. Restrictions of conformational space are predicted to occur with different magnitudes, depending on the nature of the glycosidic linkages, as well as the size of the carbohydrates. Results from these molecular modelling studies are compared to existing structural data. Not only could the observed conformations and orientations of carbohydrates in crystalline lectin-oligosaccharides complexes be reproduced, but several other likely situations were also predicted to occur. Entropy calculations have been performed for comparison with experimental thermodynamics data. The results of the stimulation can also help giving an explanation of some observed affinity constants at the molecular level.


First stereoselective total synthesis of brevipolide M.
The first stereoselective total synthesis of a cytotoxic brevipolide M, which shares a pyrone framework bearing a tetrahydrofuran moiety and a cinnamate group with the readily available (-)-DET, is described. The key steps involved in the synthesis are the epoxide-opening, Brown's allylation, and the RCM reaction to install an α,β-unsaturated lactone ring and the inversion of the C-6' stereogenic hydroxyl group using the Mitsunobu reaction.


APL1, a yeast gene encoding a putative permease for basic amino acids.
A Saccharomyces cerevisiae gene (1722 bp), encoding a protein (574 aa) highly homologous to the basic-amino-acid permeases LYP1 and CAN1, was sequenced. The gene, which was named APL1 (Amino-acid Permase Like), is located 881 bp upstream from LYP1 (lysine-specific permease), and in head-to-head orientation to it. These sequence data have been deposited in the EMBL/GenBank/DDBJ nucleotide sequence data libraries under Accession Number X74069.