Isolation of BM mesenchymal stem cells by plastic adhesion or negative selection: phenotype, proliferation kinetics and differentiation potential.
BM mesenchymal stem cells (MSC) have the capacity for renewal and the potential to differentiate into multiple tissues. In this study, we compared different enrichment methods to obtain MSC from BM. Three different methods were compared with a view to obtaining MSC more rapidly from BM: negative selection (RosetteSep and MACS) and plastic adhesion. The three cell fractions were grown in complete alpha-minimum essential medium in order to evaluate their proliferative capacity, their phenotype during culture and their potential to differentiate into adipocytes, osteocytes and chondrocytes. Identification of MSC was performed by immunofluorescence with putative mesenchymal markers SH2 and SH3 but also with hematopoietic markers. After negative selection, only 1+/-0.2% and 2.9+/-0.8% of cells were recovered from BM with the RosetteSep and MACS methods, respectively. However, negative depletion permitted a homogeneous population of MSC, with more than 90% SH2+ and SH3+ cells, to be obtained rapidly and in large quantities after 10 days of culture. Similar homogeneity was observed after three passages if the plastic adhesion was used as selection method and after an average of 25-30 days of culture. Different levels of MSC maturity were also suggested by the variable level expression of Stro-1. Depleting selection by RosetteSep may represent an easy method of obtaining MSC rapidly from BM with the aim of potential therapeutic use.


Electron transport in Si nanochains/nanowires.
Electronic transport properties of a bundle of Si nanochains/nanowires were investigated. Si nanochains and nanowires were grown via a self-organized vapor-liquid-solid process and located on a pair of electrodes with a gap of several hundred nanometers. Unstable and a variety of current-voltage (I-V) characteristics were observed and some of those were Coulomb staircase-like. In addition, fluctuations which were seemingly random but partly and partially reproducible were observed in I-V curves of a parallel junction of a nanochain and a nanowire.


Dietary and hormonal regulation of L-type pyruvate kinase gene expression in rat small intestine.
L-type pyruvate kinase is an enzyme of the glycolytic pathway whose activity and mRNA levels fluctuate in the small intestine according to dietary status. Both the enzyme activity and mRNA concentration decline during fasting and increase upon refeeding either a glucose-rich or a fructose-rich diet. Using a single-strand M 13 phage complementary to L-type pyruvate kinase mRNA as probe, we determined the level of the mRNA in the small intestine of normal, adrenalectomized, thyroidectomized, diabetic and glucagon-treated or cAMP-treated animals refed either a glucose-rich or a fructose-rich diet. The specific mRNA is present in the small intestine of normal fasted rats and increases twofold and threefold on refeeding glucose and fructose respectively. However, the hormonal control of the gene expression differs according to the dietary carbohydrate. The L-type pyruvate kinase mRNA increase, induced by glucose feeding, is hormone-dependent and requires the presence of thyroid hormones and insulin. In fructose-fed rats a certain level of mRNA increase occurs regardless of the hormonal status of the animals, but the full induction of the mRNA by fructose requires the presence of glucocorticoids, thyroid hormones and insulin. Thus, the hormonal regulation of L-type pyruvate kinase gene expression in the small intestine is largely similar to that described in normal rat liver but the basal mRNA level and the stimulation of the mRNA increase by fructose are higher in the small intestine.


Kinematic design to improve ergonomics in human machine interaction.
This paper introduces a novel kinematic design paradigm for ergonomic human machine interaction. Goals for optimal design are formulated generically and applied to the mechanical design of an upper-arm exoskeleton. A nine degree-of-freedom (DOF) model of the human arm kinematics is presented and used to develop, test, and optimize the kinematic structure of an human arm interfacing exoskeleton. The resulting device can interact with an unprecedented portion of the natural limb workspace, including motions in the shoulder-girdle, shoulder, elbow, and the wrist. The exoskeleton does not require alignment to the human joint axes, yet is able to actuate each DOF of our redundant limb unambiguously and without reaching into singularities. The device is comfortable to wear and does not create residual forces if misalignments exist. Implemented in a rehabilitation robot, the design features of the exoskeleton could enable longer lasting training sessions, training of fully natural tasks such as activities of daily living and shorter dress-on and dress-off times. Results from inter-subject experiments with a prototype are presented, that verify usability over the entire workspace of the human arm, including shoulder and shoulder girdle.


Predicting accurate vibrational frequencies for highly anharmonic systems.
Improvements in the manner in which the potential energy surface (PES) is generated in the vibrational self-consistent field (VSCF) method have been implemented. The PES can now be computed over a flexible range of displacements and following normal mode displacement vectors expressed in internal rather than Cartesian coordinates, leading to higher accuracy of the calculated vibrational frequencies. The coarse-grained parallelization of the PES calculations, which is computationally by far the most expensive part of the VSCF method, enables the usage of higher levels of theory and larger basis sets. The new VSCF procedure is discussed and applied to three examples, H(3) (+), HNO(2), and HNO(3), to illustrate its accuracy and applicability.


Short-Term Pain Outcomes and Pain Medication Utilization Among Urine Toxicology-Identified Opioid and Marijuana Users After Elective Spine Surgery.
Postoperative pain outcomes may be influenced by preoperative substance use, which is often underreported due to associated stigma. This study examined the impact of urine toxicology-identified preoperative opioid and marijuana use on pain outcomes after elective spinal surgery. Patients undergoing elective spinal surgery between September 2020 and May 2022 were recruited for this prospective cohort study. Detailed chart review was completed to collect demographic, urine toxicology, Visual Analog Scale (VAS), and pain medication data. Comparisons between self-reported and urine toxicology-identified substance use, preoperative/postoperative VAS ratings, and postoperative pain medication use were made using χ2 tests, Student t-tests, and logistic regression, respectively. Models were adjusted for age, sex, and race. Among 111 participants (mean age 58 years, 59% female, 95% with ≥1 comorbidity), urine toxicology overestimated drug use (47% vs 16%, P < .001) and underestimated alcohol use (16% vs 56%, P < .001) at preoperative baseline relative to patient reports. Two weeks postoperatively, participants with preoperative opioid metabolites reported no significant improvements in pain from baseline (6.67 preoperative vs 5.92 postoperative, P = .288) unlike nonusers (6.56 preoperative vs 4.61 postoperative, P < .001). They also had worse postoperative VAS (5.92 vs 4.61, P = .030) and heavier reliance on opioid medications (odds ratio = 3.09, 95% CI = 1.21-7.89, P = .019). Conversely, participants with preoperative marijuana reported similar improvements in pain from baseline (users: 6.88 preoperative vs 4.36 postoperative, P = .001; nonusers: 6.49 preoperative vs 5.07 postoperative, P = .001), similar postoperative pain (4.36 vs 5.07, P = .238), and similar postoperative reliance on opioid medications (odds ratio = 0.96, 95% CI = 0.38-2.44, P = .928). Trends were maintained among the 83 patients who returned for the 3-month follow-up. Although urine toxicology-identified preoperative opioid use was associated with poor postoperative pain relief and reliance on postoperative opioids for pain management after elective spinal surgery, preoperative marijuana use was not. Preoperative marijuana use, hence, should not delay or be a contraindication to elective spinal surgery.


Topical corticosteroid use during pregnancy.
Some of my pregnant patients have been prescribed various potencies of topical corticosteroids. Do these carry the same fetal risks as systemic corticosteroids? Pregnant women can be reassured that there is no apparent increased risk of adverse fetal effects when using topical corticosteroids during pregnancy, although some data do suggest fetal growth restriction with more potent topical corticosteroids. Overall, women should be prescribed the lowest potency required whenever possible.


Systematic integration of machine learning algorithms to develop immune escape-related signatures to improve clinical outcomes in lung adenocarcinoma patients.
Immune escape has recently emerged as one of the barriers to the efficacy of immunotherapy in lung adenocarcinoma (LUAD). However, the clinical significance and function of immune escape markers in LUAD have largely not been clarified. In this study, we constructed a stable and accurate immune escape score (IERS) by systematically integrating 10 machine learning algorithms. We further investigated the clinical significance, functional status, TME interactions, and genomic alterations of different IERS subtypes to explore potential mechanisms. In addition, we validated the most important variable in the model through cellular experiments. The IERS is an independent risk factor for overall survival, superior to traditional clinical variables and published molecular signatures. IERS-based risk stratification can be well applied to LUAD patients. In addition, high IERS is associated with stronger tumor proliferation and immunosuppression. Low IERS exhibited abundant lymphocyte infiltration and active immune activity. Finally, high IERS is more sensitive to first-line chemotherapy for LUAD, while low IERS is more sensitive to immunotherapy. In conclusion, IERS may serve as a promising clinical tool to improve risk stratification and clinical management of individual LUAD patients and may enhance the understanding of immune escape.


Susceptibility Status of a Recently Introduced Population of Aedes albopictus to Insecticides Used by the Vector Control Program in Merida, Yucatan, Mexico.
In recent years, Aedes albopictus has become the most important invasive mosquito species worldwide. In 2018, Ae. albopictus was found in a suburban area of Merida, one of the cities with the highest number of arbovirus cases in Mexico in the last 10 years. As Ae. albopictus continues its range expansion, there is a need to monitor its susceptibility to existing insecticide classes, since countries like Mexico currently do not consider Ae. albopictus in its insecticide management programs. In order to determine its susceptibility to the insecticides usually applied by the vector control program in Mexico, the Centers for Disease Control and Prevention bottle bioassays were performed on individuals from established population of Ae. albopictus from Merida, Yucatan, Mexico. Results suggested that the population recently found in the suburban area of Merida is susceptible to permethrin, deltamethrin, chlorpyrifos, malathion, bendiocarb, and propoxur. Further studies of insecticide resistance using biochemical and molecular tools together with more knowledge of the biology and ecology of this species are necessary to generate specific and efficient control strategies in Mexico.


Methods and analysis of realizing randomized grouping.
Randomization is one of the four basic principles of research design. The meaning of randomization includes two aspects: one is to randomly select samples from the population, which is known as random sampling; the other is to randomly group all the samples, which is called randomized grouping. Randomized grouping can be subdivided into three categories: completely, stratified and dynamically randomized grouping. This article mainly introduces the steps of complete randomization, the definition of dynamic randomization and the realization of random sampling and grouping by SAS software.


Group C beta hemolytic Streptococci as a potential pathogen in patients presenting with an uncomplicated acute sore throat - a systematic literature review and meta-analysis.
Objective: The pathogenicity of beta-hemolytic Streptococcus group C (GCS) in patients attending for an uncomplicated acute sore throat is unknown and it was the objective to clarify this.Design: Systematic literature review with meta-analysis. Setting Medline and Scopus were searched from inception to February 2019, with searches of reference lists, Subjects case-control studies stating prevalence of GCS in patients as well as healthy controls presented for children and adults separately. Studies including patients already treated with antibiotics and studies focused on patients with HIV, malignancy or immunosuppression were not included. Main outcome measures Pooled prevalence of GCS was compared between patients and controls using chi-square and was further explored by calculating the positive etiologic predictive value (P-EPV) showing the post-test probability of a link between a sore throat and the bacterial finding. P-EPV for GCS was compared with that for group A Streptococci (GAS) using figures from the same publications and patients.Results: Eleven studies were included. The prevalence of GCS among patients versus controls was similar in children (3.15 versus 2.87%, p = .44) but for adults higher in patients (11%) than in controls (5.6%) (p < .0001). The P-EPV for finding GCS in children with a sore throat was 9.3% (0.0-41%). The corresponding P-EPV for GCS in adults with a sore throat was 53% (36-67%) while the corresponding P-EPV for GAS in adults was 94% (90-96%).Conclusions: GCS do not seem associated with the uncomplicated acute sore throat in children but there is support for an association in adults being weaker than for GAS. A possible consequence is to ignore GCS in otherwise healthy patients at their first visit for an uncomplicated sore throat. This would enable a stronger focus on the use of modern point of care tests (POCTs) to detect GAS.Key pointsThere is no current consensus on the pathogenicity of group C beta-hemolytic Streptococcus (GCS) in patients attending for an uncomplicated acute sore throat.This systematic literature review concludes it is unlikely that GCS is involved in the uncomplicated sore throat in otherwise healthy children.This meta-analysis found a moderate link between GCS and the uncomplicated sore throat in adults.The link in adults between GCS and the sore throat is much weaker than the corresponding link for group A beta-hemolytic Streptococcus.


Conceptualizing fairness in the secondary use of health data for research: A scoping review.
With the introduction of the European Health Data Space (EHDS), the secondary use of health data for research purposes is attracting more attention. Secondary health data processing promises to address novel research questions, inform the design of future research and improve healthcare delivery generally. To comply with the existing data protection regulations, the secondary data use must be fair, among other things. However, there is no clear understanding of what fairness means in the context of secondary use of health data for scientific research purposes. In response, we conducted a scoping review of argument-based literature to explore how fairness in the secondary use of health data has been conceptualized. A total of 35 publications were included in the final synthesis after abstract and full-text screening. Using an inductive approach and a thematic analysis, our review has revealed that balancing individual and public interests, reducing power asymmetries, setting conditions for commercial involvement, and implementing benefit sharing are essential to guarantee fair secondary use research. The findings of this review can inform current and future research practices and policy development to adequately address concerns about fairness in the secondary use of health data.


Substrate elasticity affects bovine satellite cell activation kinetics in vitro.
Satellite cells support efficient postnatal skeletal muscle hypertrophy through fusion into the adjacent muscle fiber. Nuclear contribution allows for maintenance of the fiber myonuclear domain and proficient transcription of myogenic genes. Niche growth factors affect satellite cell biology; however, the interplay between fiber elasticity and microenvironment proteins remains largely unknown. The objective of the experiment was to examine the effects of hepatocyte growth factor (HGF) and surface elasticity on bovine satellite cell (BSC) activation kinetics in vitro. Young's elastic modulus was calculated for the semimembranosus (SM) and LM muscles of young bulls (5 d; n = 8) and adult cows (27 mo; n = 4) cattle. Results indicate that LM elasticity decreased (P < 0.05) with age; no difference in Young's modulus for the SM was noted. Bovine satellite cells were seeded atop polyacrylamide bioscaffolds with surface elasticities that mimic young bull and adult cow LM or traditional cultureware. Cells were maintained in low-serum media supplemented with 5 ng/mL HGF or vehicle only for 24 or 48 h. Activation was evaluated by proliferating cell nuclear antigen (PCNA) immunocytochemistry. Results indicate that BSC maintained on rigid surfaces were activated at 24 h and refractive to HGF supplementation. By contrast, fewer (P < 0.05) BSC had exited quiescence after 24 h of culture on surfaces reflective of either young bull (8.1 ± 1.7 kPa) or adult cow (14.6 ± 1.6 kPa) LM. Supplementation with HGF promoted activation of BSC cultured on bioscaffolds as measured by an increase (P < 0.05) in PCNA immunopositive cells. Culture on pliant surfaces affected neither activation kinetics nor numbers of Paired box 7 (Pax7) immunopositive muscle stem cells (P > 0.05). However, with increasing surface elasticity, an increase (P < 0.05) in the numbers of muscle progenitors was observed. These results confirm that biophysical and biochemical signals regulate BSC activation.


Comparisons of the depressor, inotropic and renal effects of milrinone and CI-930 to different pure vasodilators and diuretics in conscious instrumented dogs.
The cardiovascular and renal effects of graded i.v. dosages of two low Km cAMP cGMP-inhibitable (cGi) phosphodiesterase (PDE) inhibitors: CI-930 and milrinone (both 10-300 micrograms/kg), and three pure vasodilators: fenoldopam (0.1-3 micrograms/kg), Na nitroprusside (3-100 micrograms/kg) and hydralazine (0.1-3 mg/kg), were compared in conscious dogs. Mean arterial pressure was decreased by CI-930 at 0.3 mg/kg, milrinone at doses greater than or equal to 0.1 mg/kg (both by approximately -17 mmHg [max. change]), nitroprusside at doses greater than or equal to 0.01 mg/kg (-60 +/- 5 mmHg, [mean +/- SEM, max. change]), fenoldopam at doses greater than or equal to 0.001 mg/kg, and hydralazine at all doses (both by approximately -26 mmHg). Heart rate was increased by milrinone and CI-930 at dosages greater than or equal to 0.03 mg/kg (both by approximately 57 beats/min), nitroprusside and hydralazine at all dosages (54 +/- 18 and 91 +/- 18 beats/min, respectively) and fenoldopam at 3 micrograms/kg (21 +/- 2 beats/min). The cGi PDE inhibitors at 0.01-0.3 mg/kg and the pure vasodilators (except fenoldopam) at all dosages increased dP/dt (approximately 1500 and 900 mmHg/s, respectively). Milrinone (greater than or equal to 0.1 mg/kg), CI-930 (greater than or equal to 0.03 mg/kg), nitroprusside (greater than or equal to 0.01 mg/kg) and hydralazine (0.3-1 mg/kg) decreased left ventricular end diastolic pressure (all by approximately -4 mmHg). None of the agents adversely affected urinary volume, Na+ and K+ excretion rates. In conclusion, all agents (except fenoldopam) induced positive inotropic and chronotropic effects, and preload and afterload reduction. The cardiac effects of the pure vasodilators may be reflexly induced, whereas those of the cGi PDE inhibitors may be primarily due to inhibition of cardiac cGi PDE.


Treatment of Primary Dorsal Wrist Ganglion-A Systematic Review.
Purpose The aim of this study was to compare the rates of recurrence and wound infection in patients with primary dorsal wrist ganglion treated with aspiration (with or without an injection of an additive), open excision, or arthroscopic resection. Methods This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines and registered on PROSPERO. Systematic electronic searches in PubMed (MEDLINE), EMBASE, Web of Science, and the Cochrane Library of Controlled Trials were performed on May 5, 2020, and June 1, 2021, respectively. All clinical studies written in English determining the recurrence and wound infection rates after treatment of primary dorsal wrist ganglion with aspiration, open excision, or arthroscopic resection in patients over the age of 16 years were eligible for inclusion. Quality assessment was guided by the Cochrane Collaboration's tool for randomized controlled trials (RCTs) and the methodological index for nonrandomized studies (MINORS) tool for observational studies. Results The literature searches resulted in 1,691 studies. After screening, five RCTs, enrolling 233 patients, and six observational studies, enrolling 316 patients with primary dorsal wrist ganglions were included. Quality assessment of the included RCTs and observational studies determined the existing level of evidence pertaining to primary dorsal wrist ganglion treatment to be low. About 11 studies reported on recurrence rate, which ranged between 7 and 72% for patients initially treated with aspiration (with or without an injection of an additive). In comparison, the recurrence rate for the open excision and arthroscopic resection groups ranged between 6 to 41% and 0 to 16%, respectively. Four studies investigated wound-related complications, for which zero infections were reported, irrespective of treatment. Conclusion The evidence summarized in this systematic review demonstrates a considerable variability in recurrence rate following aspiration and open or arthroscopic resection of a primary dorsal wrist ganglion. The greatest variability in recurrence was displayed among studies on aspiration. The overall infection rate after treatment of dorsal wrist ganglions seems to be low regardless of the treatment type. However, the divergent results of individual studies highlight a pressing need for prospective controlled trials assessing outcomes following dorsal wrist ganglion treatment. Level of Evidence Systematic review on level 1 to 4 clinical therapeutic studies.


[Antimicrobial resistance surveillance: VIRA STUDY 2006].
The objective of this study was to determine the current antimicrobial susceptibility patterns of the most frequent multi-resistant bacteria and to analyze any possible changes with respect to the two VIRA studies carried out in 2001 and 2004. In February 2006, the 40 participating hospitals sent the following microorganisms: non-penicillin-susceptible Streptococcus pneumoniae (92), methicillin-resistant Staphylococcus aureus (MRSA) (290), clinically significant coagulase-negative staphylococci (136), ampicillin-resistant Enterococcus faecium (89), ampicillin-resistant Haemophilus influenzae (67), ciprofloxacin-resistant Escherichia coli (365), Pseudomonas aeruginosa (181), and Acinetobacter baumannii (92). The hospitals provided epidemiological data on these microorganisms. Susceptibility was determined with a broth microdilution method. Among the non-penicillin-susceptible S. pneumoniae isolates, the proportion of those ones resistant to this antibiotic showed a significant (p < 0.001) decrease (59.8% in 2001, 30.2% in 2004 and 14.3% in 2006). Among MRSA, we detected one isolate nonsusceptible to linezolid, four resistant to quinupristin-dalfopristin and one strain with a vancomycin MIC of 4 microg/mL. The prevalence of extended-spectrum beta-lactamase-producing E. coli was 12.1%. Resistance of A. baumannii to imipenem varied from 27% in the 2001-2004 period to 47.8% in 2006 (p < 0.005). These results again emphasize that resistance surveillance systems are an important tool for preventing the emergence and spread of multi-resistant pathogens.


Starfish gonad: action and chemical identification of spawning inhibitor.
The gamete-shedding substance obtained from the radial nerves induces spawning when it is applied to the gonads of mature starfish in vivo and in vitro. A substance that inhibits the action of this spawning factor is present in both ovary and testis; it has been isolated from testis of Asterina pectinifera and chemically identified as L-glutamic acid.


HIV risk behavior among ethnically diverse adolescents living in low-income housing developments.
To describe patterns and predictors of HIV risk behaviors among ethnically diverse, low-income adolescents. Computer-assisted surveys were administered to 1172 adolescents between the ages of 12 and 17 years living in 15 low-income housing developments in three urban areas in the United States to characterize and identify predictors of HIV risk behavior. Data were analyzed using multinomial logistic regression to identify variables predictive of "no risk," "lower risk," and "higher risk" group classification. Most adolescents were not yet sexually active; nonetheless, a subset of youth reported high rates of HIV risk-related behaviors. HIV risk was highest among adolescents who were older, had weaker intentions to reduce risk, stronger beliefs that their sexual partners did not favor risk-reduction, lower risk-reduction behavioral skills, higher risk-reduction outcome expectation, and higher rates of substance use. HIV prevention efforts are needed that are tailored to ethnically diverse communities of adolescents, including those in early adolescence and those at highest risk.


Exosomes from Ub‑HBcAg‑overexpressing dendritic cells induce T‑lymphocyte differentiation and enhance cytotoxic T‑lymphocyte activity.
Hepatitis B virus (HBV) infection is a major public health concern. The clearance of HBV may involve cytotoxic T-lymphocyte (CTL) activity and T helper type 1 reactions. Exosomes generated from dendritic cells (DCs) can induce immunological responses capable of eradicating viruses. However, exosomes loaded with antigens have not yet demonstrated therapeutic potential in HBV infection. Therefore, the present study aimed to investigate the antiviral effects of DC-derived exosomes (Dexs) loaded with ubiquitinated HBV core antigen (Dexs-Ub-HBcAg). Murine bone marrow-derived DCs were loaded with a recombinant lentivector encoding the ubiquitinated form of HBcAg. High-purity Dexs were generated using differential velocity centrifugation. Splenic T-lymphocytes were stimulated with Dexs-Ub-HBcAg and the specific T-cell-mediated immune responses were examined. Cytokine expression was analyzed using enzyme-linked immunosorbent assays. T-lymphocyte proliferation was detected using a Cell Counting Kit-8 assay and HBcAg-specific CTL activity was determined using a lactate dehydrogenase release assay. The results revealed that Dexs-Ub-HBcAg effectively stimulated T-cell proliferation and induced the activation of antigen-specific CTLs to exhibit HBcAg-specific CTL immune responses in vitro. These results suggest the potential of Dexs-Ub-HBcAg for development as a future therapeutic option for the elimination of HBV.


[The expression and correlation analysis of TOX and inhibitory receptors on peripheral blood CD8+T cells in patients with aplastic anemia].
Objective: To investigate the expression levels of thymocyte selection related high mobility group proteins (TOX) and different inhibitory receptors in peripheral blood CD8+T cells of patients with aplastic anemia (AA), and to conduct correlation analysis. Methods: From September 2019 to November 2020, 27 AA patients in the Department of Hematology, General Hospital of Tianjin Medical University were retrospectively selected, including 21 males and 6 females, with a median age [M (Q1, Q3)] of 48 (30, 72) years. Thirty-three healthy controls, included 17 males and 16 females, with a median age of 46 (27, 69) years. The expression levels of TOX, programmed cell death receptor-1 (PD-1), T-cell immunoglobulin and mucin domain 3 (TIM-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), T-cell immune receptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT), perforin and granzyme B in peripheral blood CD8+T cells from AA patients and healthy controls were detected by flow cytometry. The correlation between TOX expression levels and different inhibitory receptors was analyzed using Pearson correlation analysis. Results: The expression levels of TOX, PD-1, TIM-3, CTLA-4, TIGIT, perforin, and granzyme B in peripheral blood CD8+T cells of AA patients were 47.33%(41.47%, 56.61%), (30.61±12.37)%, (39.94±10.84)%, (6.21±3.40)%, (51.45±20.21)%, (71.32±22.46)%, and (52.39±23.99)%, respectively, which were higher than those of healthy controls 27.32%(21.64%, 46.96%), (21.29±10.01)%, (21.11±3.00)%, (1.31±0.34)% (30.80±13.40)%, (46.72±22.53)%, (21.75±16.43)% (all P<0.05). The expression level of TOX in CD8+T cells was positively correlated with the expression levels of PD-1, TIM-3, CTLA-4, TIGIT, perforin, and granzyme B (r=0.49, 0.65, 0.70, 0.54, 0.58, 0.48, all P<0.05). Conclusion: The expression levels of TOX and different inhibitory receptors on peripheral blood CD8+T cells in AA patients are higher than those in the healthy control group, and the expression levels of TOX and different inhibitory receptors are positively correlated.


Specification of muscle neurotransmitter sensitivity by a Paired-like homeodomain protein in Caenorhabditis elegans.
The effects of neurotransmitters depend on the receptors expressed on the target cells. In Caenorhabditis elegans, there are two types of GABA receptors that elicit opposite effects: excitatory receptors that open cation-selective channels, and inhibitory receptors that open anion-selective channels. The four non-striated enteric muscle cells required for the expulsion step of the defecation behavior are all sensitive to GABA: the sphincter muscle expresses a classical GABA-sensitive chloride channel (UNC-49) and probably relaxes in response to GABA, while the other three cells express a cation-selective channel (EXP-1) and contract. Here we show that the expression of the exp-1 gene is under the control of dsc-1, which encodes a Paired-like homeodomain protein, a class of transcription factors previously associated with the terminal differentiation of neurons in C. elegans. dsc-1 mutants have anatomically normal enteric muscles but are expulsion defective. We show that this defect is due to the lack of expression of exp-1 in the three cells that contract in response to GABA. In addition, dsc-1, but not exp-1, affects the periodicity of the behavior, revealing an unanticipated role for the enteric muscles in regulating this ultradian rhythm.


Random walks of molecular motors arising from diffusional encounters with immobilized filaments.
Movements of molecular motors on cytoskeletal filaments are described by directed walks on a line. Detachment from this line is allowed to occur with a small probability. Motion in the surrounding fluid is described by symmetric random walks. Effects of detachment and reattachment are calculated by an analytical solution of the master equation in two and three dimensions. Results are obtained for the fraction of bound motors, their average velocity, displacement, and dispersion. The analytical results are in good agreement with results from Monte Carlo simulations and confirm the behavior predicted by scaling arguments. The diffusion coefficient parallel to the filament becomes anomalously large since detachment and subsequent reattachment, in the presence of directed motion of the bound motors, leads to a broadening of the density distribution. The occurrence of protofilaments on a microtubule is modeled by internal states of the binding sites. After a transient time, all protofilaments become equally populated.


Atypical responses of a large catchment river to the Holocene sea-level highstand: The Murray River, Australia.
Three-dimensional numerical modelling of the marine and fluvial dynamics of the lower Murray River demonstrate that the mid-Holocene sea-level highstand generated an extensive central basin environment extending at least 140 kilometres upstream from the river mouth and occupying the entire one to three kilometre width of the Murray Gorge. This unusually extensive, extremely low-gradient backwater environment generated by the two metre sea-level highstand captured most, if not all, of the fine-grained sediment discharged from the 1.06 million square kilometre Murray-Darling catchment. This material was sequestered within a >60 kilometre long, >10 metre thick valley-wide deposit of finely laminated mud. This previously unrecognised sediment trap persisted from 8,518 to 5,067 cal yr BP preventing sediment delivery to the marine environment. Its identification requires that mid-Holocene climate reconstructions for southeastern Australia based on fluctuations in the delivery of fine-grained sediment to the ocean offshore the lower Murray River's mouth must be re-evaluated.


Surgical and implantation reconstruction in a patient with giant-cell central reparative granuloma.
The giant-cell central reparative granuloma, unlike other giant-cell neoplasias, is mainly found in maxillary bones, particularly in the mandible. We report a patient study of giant-cell central reparative granuloma in the mandible extending from dental elements 34 to 44. The patient underwent excision of a neoplasm and reconstruction of the mandible via an autologous bone graft of the iliac crest. To restore fully, functionally, and aesthetically the masticatory apparatus after verification of graft stability, four osseointegrated implants were fixed, and an "overdenture" prosthesis was then applied, thus finally solving the problem.


Neurologic disorders in pregnancy.
Neurologic dysfunction, coma, and seizures are common in obstetric patients in the intensive care unit. To review common neurologic disorders resulting in critical illness in pregnancy. Obstetric disorders causing coma and seizures include eclampsia, acute fatty liver of pregnancy, and amniotic fluid embolism. Preexisting disorders such as epilepsy may worsen in one-third of pregnant patients, and seizures are common during labor. Changes in hemodynamics, blood volume, and hormonal effects on the vessel wall increase risk of bleeding from berry aneurysms and arteriovenous malformations during pregnancy and the postpartum period. Acute intermittent porphyria produces seizures and hypertension, closely mimicking eclampsia. Cerebral venous sinus thrombosis is common in postpartum patients, especially in developing countries. Brain tumors invariably enlarge during pregnancy because of fluid retention and the presence of estrogen and progesterone receptors on tumor cells. Infections such as cerebral malaria and acute viral hepatitis with fulminant hepatic failure are common causes of coma and seizures during pregnancy in tropical regions of Asia, Africa, and Latin America. Patients may be admitted to the intensive care unit with type II respiratory failure due to myasthenic crisis, Guillain-Barre syndrome and spinal cord disease. Relapses of multiple sclerosis are infrequent during pregnancy but increase in the postpartum period. In all instances, the effects of the disorders, diagnostic tests, and treatment on the fetus must be carefully weighed. Prompt delivery may be lifesaving for mother and fetus in conditions such as eclampsia and acute fatty liver of pregnancy; expectant treatment may be more appropriate in others.


[CYP2C8, PTGS-1, 2 gene polymorphisms prevalence associated with sensitivity to non-steroidal anti-inflammatory drugs among North Caucasus ethnic groups].
Find the prevalence of CYP2C8*3 (rs10509681; rs11572080), PTGS-1 (rs10306135; rs12353214) and PTGS-2 (rs20417) alleles and genotypes in four ethnic groups among Laks, Avars, Dargins and Kumyks. The study involved 400 volunteers from four ethnic groups living in Republic of Dagestan: 100 participants from each group. Carriage of polymorphic markers was determined by reverse transcription polymerase chain reaction. Minor allele frequency of the CYP2C8 (rs10509681) was 5.5% in Avars, 10% in Dargins, Laks and Kumyks 6.5% both; CYP2C8 (rs11572080) was 5.5% in Avars, 9.5% in Dargins, 6.5% in Laks, 8.5% in Kumyks; PTGS-1 (rs10306135) in Avars 10.5%, in Dargins 13.0%, in Laks 9.5% and Kumyks 7.5%; PTGS-1 (rs12353214) in Avars 9.0%, in Dargins 4.5%, in Laks 7.5%, in Kumyks 8.0%; PTGS-2 (rs20417) in Avars 1.0%, in Dargins 2.5%, in Laks 3.5%, in Kumyks 5.0%. There were no significant differences between groups. The study of CYP2C8 and PTGS-1 and 2 gene polymorphisms is promising for predicting the effectiveness and safety of non-steroidal anti-inflammatory drug therapy, due to the high prevalence of these polymorphisms in ethnic groups in the North Caucasus.


Rare Association of Leukocytoclastic Vasculitis in Visceral Leishmaniaisis.
A 30-year-old man presented with fever, hepatosplenomegaly, and a rash over his lower limbs (palpable purpura). Evaluation revealed pancytopenia and hypergammaglobulinemia. A subsequent bone marrow examination and serology confirmed visceral leishmaniasis (kala-azar), while the biopsy of skin lesion suggested leukocytoclastic vasculitis. No alternate cause of vasculitis was forthcoming, and the patient was treated with conventional amphotericin B for 14 days after which resolution of symptoms (including the rash) was noted. Cutaneous vasculitis is an extremely rare complication following visceral leishmaniasis with no known cases reported thus far. Hence, a high index of suspicion is warranted in achieving timely diagnosis and initiation of appropriate therapy.


Prediction of the Pharmacokinetics of Pravastatin as an OATP Substrate Using Plateable Human Hepatocytes With Human Plasma Data and PBPK Modeling.
Plateable human hepatocytes with human plasma were utilized to generate the uptake transporter kinetic data for pravastatin, an organic anion-transporting polypeptide (OATP) transporter substrate. The active hepatic uptake of pravastatin was determined with a Jmax value of 134.4 pmol/min/million cells and Km of 76.77 µM in plateable human hepatocytes with human plasma. The physiologically-based pharmacokinetic (PBPK) model with incorporation of these in vitro kinetic data successfully simulated the i.v. pharmacokinetic profile of pravastatin without applying scaling factor (the mean predicted area under the curve (AUC) is within 1.5-fold of the observed). Furthermore, the PBPK model also adequately described the oral plasma concentration-time profiles of pravastatin at different dose levels. The current investigation demonstrates an approach allowing us to build upon the translation of in vitro OATP uptake transporter data to in vivo, with a hope of utilizing the in vitro data for the prospective human pharmacokinetic (PK) prediction.


Novel multifunctional hybrids of single-walled carbon nanotubes with nucleic acids: synthesis and interactions with living cells.
Novel hybrids of fluorescein-labeled poly(ethylene glycol)-modified single-walled carbon nanotubes (SWCNTs) with nucleic acids were prepared. 5'-Pyrene conjugates of oligodeoxyribonucleotides were used to construct the noncovalent hybrids, with the pyrene residues acting as anchor groups, immobilizing an oligonucleotide on the SWCNT surface. The hybrid formation characteristics were studied using ζ-potential measurements and adsorption isotherm plots. Transmission electron microscopy (TEM) of the samples stained with contrast agents proved that the pyrene conjugates of oligonucleotides were adsorbed onto the surfaces of the functionalized SWCNTs. On the basis of the MTT assay, the functionalized SWCNTs and their hybrids with oligonucleotides exhibited low toxicity toward HeLa, KB-3-1, and KB-8-5 cells. A TEM study of ultrathin sections of cells treated with SWCNTs revealed that the nanotubes directly interacted with the cellular surface.


Interferon effect on cytotoxicity of peripheral blood and tumor-associated lymphocytes against human ovarian carcinoma cells.
A study was done to investigate the tumoricidal activity of peripheral blood lymphocytes (PBL) and tumor-associated lymphoid cells (TAL) against freshly isolated tumor cells in human ovarian carcinoma. TAL and carcinoma cells were purified by density and velocity sedimentation on discontinuous Ficoll-Hypaque gradients and fetal bovine serum. Purified carcinoma cells from 23 ascitic and 3 solid tumors were used as targets in a 4- or a 20-hour 51Cr release assay. K562 cells were used to measure natural killer (NK) activity. Freshly purified ovarian carcinoma cells were relatively resistant to lysis by normal unstimulated PBL. Cytolytic activity of ovarian cancer PBL and TAL did not exceed that of control PBL: Only one PBL preparation had high levels of cytotoxicity (36.2 and 42.9% specific lysis after 4 and 20 hr at an effector-to-target cell ratio of 50:1) against autologous cancer cells but not against allogeneic targets (less than 5% specific lysis). TAL and, to a lesser extent, ovarian cancer PBL showed impaired NK activity against K562 compared to the activity seen in controls. In vitro exposure to partially purified human fibroblast interferon (IFN) (1,000 U/ml for 1-18 hr) augmented NK activity against K562 of PBL and TAL. When ovarian carcinoma cells were used as targets, IFN enhanced the cytotoxicity of normal PBL in a 4- and 20-hour assay; stimulation by IFN was less frequently observed with ovarian cancer PBL and TAL in a 4-hour assay, but after 20 hours effector cells from tumor-bearing subjects showed IFN-boosted cytotoxicity against carcinoma cells similar to the degree of cytotoxicity seen in controls. IFN enhanced the cytotoxicity of PBL and TAL against both autologous and allogeneic carcinoma cells. Thus PBL and TAL are rarely cytotoxic against 51Cr-labeled fresh autologous carcinoma cells, but in vitro exposure to IFN induced low levels of killing of ovarian tumor cells.


The influence of the human becoming theory on teaching-learning stories in Hangzhou, China.
As a nurse educator, human becoming theory was used to enhance my understanding of my experience with students in Hangzhou, China. I describe my initial tension in living simultaneously the uncertainty and the certainty when I was faced with a strange but yet familiar teaching situation. The tension has however enabled me to cross from a traditional teaching approach to a human becoming teaching-learning paradigm where the students were given opportunities to share their practice encounters with patients and families by narrating their lived experiences in a clinical reasoning course. As their meanings of nursing surfaced, the students began to learn about who they were, who they are becoming, and who they want to be as nurses, teachers, and human beings.


Bioinformatics Analysis Identifies Molecular Markers Regulating Development and Progression of Endometriosis and Potential Therapeutic Drugs.
Endometriosis, a common disease that presents as polymorphism, invasiveness, and extensiveness, with clinical manifestations including dysmenorrhea, infertility, and menstrual abnormalities, seriously affects quality of life in women. To date, its underlying etiological mechanism of action and the associated regulatory genes remain unclear. This study aimed to identify molecular markers and elucidate mechanisms underlying the development and progression of endometriosis. Specifically, we downloaded five microarray expression datasets, namely, GSE11691, GSE23339, GSE25628, GSE7305, and GSE105764, from the Gene Expression Omnibus (GEO) database. These datasets, obtained from endometriosis tissues, alongside normal controls, were subjected to in-depth bioinformatics analysis for identification of differentially expressed genes (DEGs), followed by analysis of their function and pathways via gene ontology (GO) and KEGG pathway enrichment analyses. Moreover, we constructed a protein-protein interaction (PPI) network to explore the hub genes and modules, and then applied machine learning algorithms support vector machine-recursive feature elimination and least absolute shrinkage and selection operator (LASSO) analysis to identify key genes. Furthermore, we adopted the CIBERSORTx algorithm to estimate levels of immune cell infiltration while the connective map (CMAP) database was used to identify potential therapeutic drugs in endometriosis. As a result, a total of 423 DEGs, namely, 233 and 190 upregulated and downregulated, were identified. On the other hand, a total of 1,733 PPIs were obtained from the PPI network. The DEGs were mainly enriched in immune-related mechanisms. Furthermore, machine learning and LASSO algorithms identified three key genes, namely, apelin receptor (APLNR), C-C motif chemokine ligand 21 (CCL21), and Fc fragment of IgG receptor IIa (FCGR2A). Furthermore, 16 small molecular compounds associated with endometriosis treatment were identified, and their mechanism of action was also revealed. Taken together, the findings of this study provide new insights into the molecular factors regulating occurrence and progression of endometriosis and its underlying mechanism of action. The identified therapeutic drugs and molecular markers may have clinical significance in early diagnosis of endometriosis.


USING HITCHHIKING GENES TO STUDY ADAPTATION AND DIVERGENCE DURING SPECIATION WITHIN THE DROSOPHILA MELANOGASTER SPECIES COMPLEX.
Several studies of intraspecific and interspecific DNA sequence variation from Drosophila loci have revealed a pattern of low intraspecific variation from genomic regions of low recombination. The mechanisms consistently invoked to explain these patterns are the selective sweep of advantageous mutations together with genetic hitchhiking of linked loci. To examine the effect of selective sweeps on genetic divergence during speciation, we studied two loci in different genomic regions thought to be subject to selective sweeps. We obtained DNA sequences from 1.1kb pair portions of the fourth chromosome locus cubitus interruptus Dominant (ciD ) and from the asense locus near the telomere of the X chromosome. At ciD , we found very low variation among multiple lines of Drosophila mauritiana and D. sechellia. This finding is consistent with an earlier report of very low variation in D. melanogaster and D. simulans at ciD and supports the conclusion of selective sweeps and genetic hitchhiking on the nonrecombining fourth chromosome. The pattern of variation found at asense suggests that a selective sweep has occurred recently at the tip of the X chromosome in D. simulans, but not in D. melanogaster or D. mauritiana. The data from ciD and asense are compared with data from three X chromosome loci (period, zeste, and yolk protein 2) that experience normal levels of recombination. By examining estimated genealogies and the rates at which different classes of mutations have accumulated, we conclude that selective sweeps are common occurrences on the fourth chromosome but less common near the tip of the X chromosome. An interesting pattern of low variation at ciD among D. simulans, D. mauritiana, and D. sechellia suggests that a selective sweep may have occurred among these forms even after divergence into separate species had begun.


[Experience with treatment of thoracic empyema during seven years period].
The authors prospectively assembled group of 157 patients treated for empyema thoracic during seven years period. They followed applied methods of the diagnostics and therapy, the length of hospital stay after surgical intervention and its successfulness. The parameters were statistically evaluated. The results showed that surgical intervention substantially influences shortening of the hospital stay and successful cure. In the early stages of the disease thoracoscopic treatment is often sufficient to eliminate the infection. When is indicated later then three weeks after onset of the effusion, then facilitates early decontamination of the empyema cavity and possibility to perform lung decortication. In patients with thoracic empyema, where adequate effusion evacuation can not be reached, the conservative treatment results in prolongation of the hospitalization. Surgical intervention on the contrary the hospital stay, without increase in morbidity or mortality, shortens.


Hydrophobin gene deletion and environmental growth conditions impact mechanical properties of mycelium by affecting the density of the material.
Filamentous fungi colonize substrates by forming a mycelium. This network of hyphae can be used as a bio-based material. Here, we assessed the impact of environmental growth conditions and deletion of the hydrophobin gene sc3 on material properties of the mycelium of the mushroom forming fungus Schizophyllum commune. Thermogravimetric analysis showed that Δsc3 mycelium retained more water with increasing temperature when compared to the wild type. The Young's modulus (E) of the mycelium ranged between 438 and 913 MPa when the wild type strain was grown in the dark or in the light at low or high CO2 levels. This was accompanied by a maximum tensile strength (σ) of 5.1-9.6 MPa. In contrast, E and σ of the Δsc3 strain were 3-4- fold higher with values of 1237-2727 MPa and 15.6-40.4 MPa, respectively. These values correlated with mycelium density, while no differences in chemical composition of the mycelia were observed as shown by ATR-FTIR. Together, genetic modification and environmental growth conditions impact mechanical properties of the mycelium by affecting the density of the mycelium. As a result, mechanical properties of wild type mycelium were similar to those of natural materials, while those of Δsc3 were more similar to thermoplastics.


Systematic Full-Cycle Engineering Microbial Biofilms to Boost Electricity Production in Shewanella oneidensis.
Electroactive biofilm plays a crucial rule in the electron transfer efficiency of microbial electrochemical systems (MES). However, the low ability to form biofilm and the low conductivity of the formed biofilm substantially limit the extracellular electron transfer rate of microbial cells to the electrode surfaces in MES. To promote biofilm formation and enhance biofilm conductivity, we develop synthetic biology approach to systematically engineer Shewanella oneidensis, a model exoelectrogen, via modular manipulation of the full-cycle different stages of biofilm formation, namely, from initial contact, cell adhesion, and biofilm growth stable maturity to cell dispersion. Consequently, the maximum output power density of the engineered biofilm reaches 3.62 ± 0.06 W m-2, 39.3-fold higher than that of the wild-type strain of S. oneidensis, which, to the best our knowledge, is the highest output power density that has ever been reported for the biofilms of the genetically engineered Shewanella strains.


[Is prevention of thromboembolism in ambulatory and conservative therapy of rupture of the fibular ligament of the upper ankle joint necessary?].
In a prospective clinical study, 111 outpatients with tears of the lateral ankle ligaments were investigated for the occurrence of deep venous thrombosis (DVT). All patients had been treated by a plaster cast for 1 week and had not received any form of DVT prophylaxis. After removal of the plaster cast (mean 7.1 days), colour flow imaging of the veins of the injured leg was performed. A phlebography was undertaken whenever there was any suspicion of DVT. Risk factors for thrombosis [3, 10] were documented in all patients. Besides injury and immobilisation, a median of 1.2 (0-4) risk factors for DVT was involved. Only 31 patients had no additional risk factors at all. Median age of the patients was 26.1 years (16-53 median range). Only 1 patient over 40 years of age was diagnosed as having DVT, and none under 40. Therefore, medicamentous prophylaxis of DVT is not considered necessary in outpatients younger than 40 years with ankle ligament tears treated by bi-valved casts in cases when there are no additional risk factors (Table 4) for DVT.


What Does It Take to Complete the Cape Epic?
Reinpõld, K, Bossi, AH, and Hopker, JG. What does it take to complete the cape epic? J Strength Cond Res 36(12): 3513-3520, 2022-This study aimed to describe the racing and training demands of the Cape Epic. Six male mountain bike riders (age: 39 ± 7 years, height: 181 ± 3 cm, and body mass: 78.7 ± 8.1 kg) trained for 4.5 months and took part in the Cape Epic. Training and racing data (prologue, stage 1, and 2) were analyzed, and riders were tested in the laboratory on 3 distinct occasions for maximal oxygen uptake (V̇O 2 max), maximal work rate (Ẇmax), and power output associated with the respiratory compensation point (RCP PO ). Statistical significance was set at p ≤ 0.05. With race durations of 1.5 ± 0.2, 6.5 ± 1.2, and 6.4 ± 1.4 hours for, respectively, prologue, stage 1, and 2, normalized power was higher in prologue (3.73 ± 0.72 W·kg -1 ) compared with stages 1 (3.06 ± 0.59 W·kg -1 , p < 0.001) and 2 (2.94 ± 0.69 W·kg -1 , p < 0.001). Riders spent more time in power zones 1 and 2 (as %RCP PO ) and less time in zones 4 and 5, during stage 2 compared with prologue (all zones p ≤ 0.028). Despite no changes in V̇O 2 max or Ẇmax, RCP PO increased from midtraining (3.89 ± 0.61 W·kg -1 ) to prerace testing (4.08 ± 0.64 W·kg -1 , p = 0.048). No differences were found between base and build training phases for time in power zones. In conclusion, the Cape Epic requires an ability to sustain high submaximal power outputs for several hours as well as an ability to repeat high-intensity efforts throughout the race. A well-balanced program, incorporating a pyramidal intensity distribution, may be used as a starting point for the design of optimal training approaches.


Body weight and composition of Japanese quail (Coturnix coturnix japonica) at sexual maturity.
The influence of dietary protein (26%, 24%, 20%, 16%, and 14%) and restricted feeding (100%, 80%, and 60% of ad libitum) on body weight and body composition of Japanese quail (Coturnix coturnix japonica) at sexual maturity was examined in two similar experiments. Although less variable than chronological age, body weight at sexual maturity also differed significantly. In Experiment 1, there were no significant differences in breast weight, tibia length or carcass fat due to diet. In Experiment 2, differences in body composition were apparent as age at the onset of lay was increased by dietary manipulation. Early maturing quail tended to enter lay when a minimum chronological age or critical body lipid level was reached; late maturing quail entered lay when a critical lean body weight or skeletal size was reached. It is proposed that multiple threshold traits associated with growth and body composition are critical for the onset of sexual maturity.


The role of hepatic macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.
Nonalcoholic steatohepatitis (NASH) is becoming common chronic liver disease because of the increasing global prevalence of obesity and consequently Nonalcoholic fatty liver disease (NAFLD). However, the mechanism for progression of NAFLD to NASH and then cirrhosis is not completely understood, yet. The triggering of these hepatic diseases is thought from hepatocyte injury caused by over-accumulated lipid toxicity. Injured hepatocytes release damage-associated molecular patterns (DAMPs), which can stimulate the Kupffer cells (KCs), liver-resident macrophages, to release pro-inflammatory cytokines and chemokines, and recruit monocyte-derived macrophages (MDMs). The increased activation of KCs and recruitment of MDMs accelerate the progression of NAFLD to NASH and cirrhosis. Therefore, characterization for activation of hepatic macrophages, both KCs and MDMs, is a baseline to figure out the progression of hepatic diseases. The purpose of this review is to discuss the current understanding of mechanisms of NAFLD and NASH, mainly focusing on characterization and function of hepatic macrophages and suggests the regulators of hepatic macrophages as the therapeutic target in hepatic diseases.


[Association of rs2298212 polymorphism in OX40 gene with coronary atherosclerotic disease in Chinese Han population].
To study the association of the OX40 gene rs2298212G/A polymorphism with coronary atherosclerotic disease (CAD) in Chinese Han population. Five hundred and thirty six CAD patients and 544 age and ethnic matched controls of Chinese Han population were recruited from Qilu Hospital, Shandong University. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to genotype the selected single nucleotide polymorphism. Distributions of genotypic and allelic frequencies were analyzed by Chi-square test. The distribution of genotypic and allelic frequencies have no significant differences between the CAD cases and controls(P> 0.05), even after adjusting for age, gender, body mass index, systolic blood pressure, diastolic blood pressure, glucose, total cholesterol, and triglyceride. However, when substratification analysis of the involved coronary artery vessels was performed, significant difference was found between single-vessel and triple-vessel (P= 0.02, OR = 1.56, 95% CI: 1.08-2.26) involvement. The rs2298212G/A polymorphism in OX40 gene may be associated with the severity of coronary atherosclerotic disease.


Status and future needs of regional adult congenital heart disease centers in Japan.
Although the prevalence of adult congenital heart disease (ACHD) in Japan continues to rise, the number and geographic distribution of facilities potentially serving as regional ACHD centers remains unknown. We examined trends in ACHD care in Japan to identify needs and to determine potential regional responses to this growing patient population. A descriptive, cross-sectional, nationwide survey was conducted to assess the status and needs of cardiology specialists related to providing ACHD care. Questionnaires were mailed to 138 cardiology departments located in 8 geographical regions throughout Japan; respondents were asked to document the status and future direction of ACHD care for each facility. Of the 109 facilities that responded, approximately one-third currently treat or plan to treat all ACHD patients. Fourteen facilities (12.8%) fulfilled all criteria for becoming regional ACHD centers. Although each regional center was projected to serve a population of 9.1 million, in 2 regions, no centers possessed the necessary care structure. Our findings revealed a shortage of adult cardiologists dedicated to ACHD care. Moreover, basic as well as formal fellowship ACHD training was deemed necessary. In Japan, the number of potential regional ACHD centers has just reached international standards. However, based on the geographic gaps documented here, a strategy other than regional centralization might be required to deliver adequate ACHD care to rural areas.


Retro-enantio isomer of angiopep-2 assists nanoprobes across the blood-brain barrier for targeted magnetic resonance/fluorescence imaging of glioblastoma.
Glioblastoma (GBM), one of the most common primary intracranial malignant tumours, is very difficult to be completely excised by surgery due to its irregular shape. Here, we use an MRI/NIR fluorescence dual-modal imaging nanoprobe that includes superparamagnetic iron oxide nanoparticles (SPIONs) modified with indocyanine (Cy7) molecules and peptides (ANG or DANG) to locate malignant gliomas and guide accurate excision. Both peptides/Cy7-SPIONs probes displayed excellent tumour-homing properties and barrier penetrating abilities in vitro, and both could mediate precise aggregation of the nanoprobes at gliomas sites in in vivo magnetic resonance imaging (MRI) and ex vivo near-infrared (NIR) fluorescence imaging. However, compared with ANG/Cy7-SPIONs probes, DANG/Cy7-SPIONs probes exhibited better enhanced MR imaging effects. Combining all these features together, this MRI/NIR fluorescence imaging dual-modal nanoprobes modified with retro-enantio isomers of the peptide have the potential to accurately display GBMs preoperatively for precise imaging and intraoperatively for real-time imaging.


Increased intramyocellular lipid accumulation in HIV-infected women with fat redistribution.
The human immunodeficiency virus (HIV)-lipodystrophy syndrome is associated with fat redistribution and metabolic abnormalities, including insulin resistance. Increased intramyocellular lipid (IMCL) concentrations are thought to contribute to insulin resistance, being linked to metabolic and body composition variables. We examined 46 women: HIV infected with fat redistribution (n = 25), and age- and body mass index-matched HIV-negative controls (n = 21). IMCL was measured by 1H-magnetic resonance spectroscopy, and body composition was assessed with computed tomography, dual-energy X-ray absorptiometry (DEXA), and magnetic resonance imaging. Plasma lipid profile and markers of glucose homeostasis were obtained. IMCL was significantly increased in tibialis anterior [135.0 +/- 11.5 vs. 85.1 +/- 13.2 institutional units (IU); P = 0.007] and soleus [643.7 +/- 61.0 vs. 443.6 +/- 47.2 IU, P = 0.017] of HIV-infected subjects compared with controls. Among HIV-infected subjects, calf subcutaneous fat area (17.8 +/- 2.3 vs. 35.0 +/- 2.5 cm2, P < 0.0001) and extremity fat by DEXA (11.8 +/- 1.1 vs. 15.6 +/- 1.2 kg, P = 0.024) were reduced, whereas visceral abdominal fat (125.2 +/- 11.3 vs. 74.4 +/- 12.3 cm2, P = 0.004), triglycerides (131.1 +/- 11.0 vs. 66.3 +/- 12.3 mg/dl, P = 0.0003), and fasting insulin (10.8 +/- 0.9 vs. 7.0 +/- 0.9 microIU/ml, P = 0.004) were increased compared with control subjects. Triglycerides (r = 0.39, P = 0.05) and extremity fat as percentage of whole body fat by DEXA (r = -0.51, P = 0.01) correlated significantly with IMCL in the HIV but not the control group. Extremity fat (beta = -633.53, P = 0.03) remained significantly associated with IMCL among HIV-infected patients, controlling for visceral abdominal fat, abdominal subcutaneous fat, and antiretroviral medications in a regression model. These data demonstrate increased IMCL in HIV-infected women with a mixed lipodystrophy pattern, being most significantly associated with reduced extremity fat. Further studies are necessary to determine the relationship between extremity fat loss and increased IMCL in HIV-infected women.


[Effect of somatostatin on splanchnic hemodynamics in liver cirrhosis].
The effect of somatostatin on splanchnic haemodynamics in patients with liver cirrhosis is not clearly defined, as some Authors reported a decrease in portal pressure and in liver blood flow during i.v. administration of this hormone, while others did not. In 19 subjects with liver cirrhosis and portal hypertension the following parameters were measured before and during i.v. infusion of somatostatin (7.5 micrograms/min): porto-hepatic gradient, effective hepatic plasma flow, specific splenic blood flow, cardiac output. Moreover the gastrin-G-17 plasma levels, those of insulin and growth hormone were measured. Effective hepatic plasma flow decreased significantly during somatostatin infusion (P less than 0.05), averaging a 15% decrease. Porto-hepatic gradient, specific splenic blood flow, cardiac output did not vary significantly. Gastrin, insulin and growth hormone plasma levels decreased significantly (P less than 0.02, 0.01, 0.05). These data indicate that somatostatin infused at the dose of 7.5 micrograms/min provokes endocrine effects, but as far as the splanchnic circulation is concerned, it induces a slight decrease in liver blood flow without affecting portal hypertension.


Effects of human cumulus cells on in vitro fertilization outcomes and its significance in short-term insemination.
To observe the effects of cumulus cells on in vitro fertilization. Oocytes were retrieved from 47 patients (> 10/patient) who underwent short-term insemination from August 2009 to June 2010. The oocytes from each patient were divided into a cumulus cell-free group (cumulus cells were removed from the incubation medium 4 hours after coincubation of male and female gametes) with 389 oocytes and a cumulus cell group (cumulus cells were retained with the gametes until fertilization was evaluated 16-18 hours after co-incubation) with 402 oocytes. Polyspermic fertilization was 0.96 +/- 1.14 in the cumulus cell-free group and 0.47 +/- 0.72 in the cumulus cell group with p < 0.05. There were no significant differences in normal fertilization (5.96 ğ 1.73 vs. 6.55 +/- 3.72), 1PN fertilization (0.06 +/- 0.25 vs. 0.09 +/- 0.28), fertilization failure (1.34 +/- 1.17 vs. 1.45 +/- 1.84), cleavage (6.06 +/- 2.04 vs. 6.51 +/- 3.94), high-quality embryo (3.94 +/- 1.79 vs. 4.74 +/- 3.45) and usable embryo (5.06 +/- 1.86 vs. 5.68 +/- 3.98) between cumulus cell-free group and cumulus cell group, all with p > 0.05. In our study short-term insemination (4 hours) causes a statistical increase in polyspermic fertilization. In order to ensure correct oocyte fertilization and reduction of polyspermic fertilization, it is better to retain the cumulus cells for 16-18 hours.


Durian-Inspired Design of Bismuth-Antimony Alloy Arrays for Robust Sodium Storage.
Sodium-ion batteries have attracted widespread attention for cost-effective and large-scale electric energy storage. However, their practical deployment has been largely retarded by the lack of choice of efficient anode materials featuring large capacity and electrochemical stability and robustness. Herein, we report a durian-inspired design and template-free fabrication of a robust sodium anode based on triangular pyramid arrays of Bi0.75Sb0.25 alloy electrodeposited on Cu substrates. The Bi0.75Sb0.25 arrays exhibit an appreciable electrochemical robustness for sodium storage, sustaining a reversible capability 335 mAh g-1 at a high rate of 2.5 A g-1 and 87% of the initial capacity over 2000 cycles. We further demonstrate the applicability of the Bi0.75Sb0.25 array anode in sodium full cells by pairing it with a Na3V2(PO4)3/C cathode. This full cell achieves a high specific energy of 203 Wh kg-1 (based on both active electrodes). Such an enhanced performance is attributed to the thorny-durian-like architecture and bimetallic alloy composition. The pyramid tip induces ion enrichment for rapid charge-transfer reaction, while the alloy design reduces the electrode volume swelling for stable Na cycling.


Arterial embolization of a bleeding gastric Dieulafoy lesion: a case report.
Dieulafoy's lesion is one of an unusual cause of upper gastrointestinal bleeding (U GIB). Endoscopic intervention has always been a preferred non-surgical method in treating UGIB including bleeding from Dieulafoy's lesion. Owing to recent advances in angiography, arterial embolization has become a popular alternative in non- variceal UGIB especially in cases with failed endoscopic treatment. However, managing bleeding Dieulafoy's with selective arterial embolization as the first line of treatment has not been exclusively practiced. We hereby, report a case of bleeding Dieulafoy lesion which had been primarily treated with arterial embolization.


[Diagnosed morbidity in primary health care in the sanitary region of Sousse (Tunisia)].
Primary health care is one of the pillars of the Tunisian health care system. However, we have very little information about the specificities of general practice and the patterns of the morbidity encountered in this field. This study was interested on the diagnosed morbidity in primary health care settings. We aimed to illustrate the patterns of morbidity in general practice and identify the main diagnoses which are established by the general practitioners (GPs). The study design was descriptive and cross-sectional. 85 (out of 92) primary health centres of the province of Souse (Tunisia) have been included during one year, from June 2002 to May 2003. We have targeted a representative sample of 16.271 encounters in these primary care settings. On the methodological plan, we proceeded by a poll to two degrees; the first concerned the weeks within every season: 3 weeks were drawn out by lot; the second interested the encounters, proceeding by a systematic pull and the step of poll was fixed to 5. The International Classification of Primary Care (ICPC) was used to code recorded data. The main results of this study showed that among the 16.271 patient-doctor encounters we registered 24.882 reasons for encounter (RFE) (1.9 +/- 0.8 per encounter), 18.097 diagnoses (1.3 +/- 0.5 per encounter), and 40.190 procedures (3.2 +/- 1.9 per encounter). In this paper we have only explored the results of encounters related to the decision of general practitioners, i.e. the diagnosed morbidity. With regard to sex distribution there was a predominance of females (62%). The study population was relatively young as 50% were aged less than 25 years. According to ICPC chapters, we found that respiratory diseases were the main established diagnoses (43%) followed by digestive (10.1%), locomotive (8.9%) cardiovascular affections (8.7%) and skin diseases (8.4%). These five affections constituted alone about 80% of the total.


Radiation therapy of craniopharyngioma.
The histories of 32 patients with craniopharygioma who had received radiotherapy after surgery were reviewed to assess the effect and adequacy of the radiation dose. The survival rates were 69% at 5 years and 60% at 10 years in all cases, but depended markedly on sex and age. Symptomatic improvement and histological changes in the irradiated tumor are also discussed. Radiation therapy with a dose ranging from 5500 to 6000 rads (approximately 1700 rets) after the first surgical intervention definitely improves the prognosis.


Communication: Light driven remote control of microgels' size in the presence of photosensitive surfactant: Complete phase diagram.
Here we report on a light triggered remote control of microgel size in the presence of photosensitive surfactant. The hydrophobic tail of the cationic surfactant contains azobenzene group that undergoes a reversible photo-isomerization reaction from a trans- to a cis-state accompanied by a change in the hydrophobicity of the surfactant. We have investigated light assisted behaviour and the complex formation of the microgels with azobenzene containing surfactant over the broad concentrational range starting far below and exceeding several times of the critical micelle concentration (CMC). At small surfactant concentration in solution (far below CMC), the surfactant in the trans-state accommodates within the microgel causing its compaction, while the cis-isomer desorbs out of microgel resulting in its swelling. The process of the microgel size change can be described as swelling on UV irradiation (trans-cis isomerization) and shrinking on irradiation with blue light (cis-trans isomerization). However, at the surfactant concentrations larger than CMC, the opposite behaviour is observed: the microgel swells on blue irradiation and shrinks during exposure to UV light. We explain this behaviour theoretically taking into account isomer dependent micellization of surfactant within the microgels.


Failure morphology of all-ceramic prostheses.
The aim of this study is to investigate the internal morphology of all-ceramic prostheses before seating. Micro X-ray CT was used to inspect three dimensionally the locations and sizes of pores within experimentally fabricated all-ceramic crowns as well as measure the veneer and core thickness. Scanning electron microscopy (SEM) was used to examine the fracture sites of clinically failed prostheses. Micro X-ray CT analysis revealed the distribution patterns of pores within the all-ceramic prostheses, and SEM fractographic analysis indicated a strong relationship between the existence of pores and crack propagation. Therefore, micro X-ray CT is a useful tool for nondestructive inspection of the internal morphology of all-ceramic prostheses to identify the critical defects before seating.


Ligands of peroxisome proliferator-activated receptor-gamma increase the generation of vascular endothelial growth factor in vascular smooth muscle cells and in macrophages.
Peroxisome proliferator-activated receptors-gamma (PPARgamma) are ligand-inducible transcription factors of the nuclear hormone receptor superfamily. We examined the effect of PPARgamma activation on the generation of vascular endothelial growth factor (VEGF), one of the major angiogenic agents. Rat vascular smooth muscle cells (VSMC) and murine macrophages RAW264.7 were incubated for 24 h with PPARgamma activators: prostaglandin J2 and ciglitazone. PPARgamma were expressed in VSMC and RAW cells and their activity was upregulated in the presence of PGJ2 and ciglitazone. Incubation of the cells with PPARgamma activators significantly augmented the release of VEGF protein into the media, both in resting and in IL-1beta- or LPS-stimulated cultures. The higher protein generation was connected with the increased expression of mRNA and transcriptional activation of VEGF promoter. We conclude that the activation of PPARgamma upregulates the generation of VEGF and may be involved in the regulation of angiogenesis.


An improved method of diet preparation for toxicological feeding experiments.
Groups of 30 rats each were fed 1 of 4 diets to determine feeding preference for freeze-dried meal compared to dry meal, and to determine if 3% agar is a desirable component of freeze-dried meal. The diets were: dry meal, meal + distilled water(freeze-dried), meal + 3% agar in distilled water(freeze-dried), and meal + 3% agar in distilled water(gel). Diet preparation, and the method for introducing a toxin in a toxicological study, is described. Feed consumption, bodyweight, and observational data were collected. Rats ate freeze-dried meal in amounts comparable to dry meal. There were no significant variations in feed conversion ratios among the dietary treatment groups. Agar is not required for freeze-dried diets, and we recommend that it be omitted to save resources and preparation time. Freeze-dried diets have a longer storage and cage life, thus the frequency of diet preparation, animal feeding and clean-up are reduced. For studies involving a toxin, these factors would reduce the potential for accidental exposure of personnel to potentially harmful materials.


Acetaminophen for self-reported sleep problems in an elderly population (ASLEEP): study protocol of a randomized placebo-controlled double-blind trial.
The prevalence of sleep disorders increases with age. Sleep disorders may have serious health implications and may be related to serious underlying diseases. Many older people use hypnotics, like benzodiazepines, although these medications have serious side effects and often lead to habituation. Acetaminophen is one of the most frequently used off-label drugs for sleep disorders, although little is known about its effects. Our objective is to investigate whether acetaminophen is effective in treating self-reported sleep disorders in older people. Participants, aged 65 years or older (n=150), who have sleep disorders will be randomized for treatment with either acetaminophen 1000 mg or placebo, once daily at bedtime in a double-blind design. Eligible patients should be able to give informed consent, should not be cognitively impaired (Minimal Mental State Examination (MMSE) score≥20), should not have pain, and should not use acetaminophen on a regular basis because of pain complaints. The study will take three weeks to complete. During these three weeks, the participants register their sleep behavior in a sleep diary. The participants will use the study medication during the second and third week. The primary endpoint will be the self-reported sleep disorders at the end of week three, as measured by means of the Insomnia Severity Index (ISI). To validate these subjective sleep parameters against objectively measured indices of the sleep-wake pattern, we will measure the periods of wakefulness and sleep in a subgroup of participants, using an actigraph worn on the wrist during the entire study period. The proposed study will contribute to our knowledge about the treatment of sleep disorders in an older population. There is a need for treatments for sleep disorders without serious adverse effects. Acetaminophen might be a simple and inexpensive alternative for the regimes that are currently used with older people. The Netherlands National Trial Register NTR2747.


Minimizing the Access Trauma of Laparoscopic Sleeve Gastrectomy: the Transoral Specimen Extraction Technique.
Laparoscopic sleeve gastrectomy has become a popular stand-alone procedure among bariatric surgeons. Recently, Natural Orifice Specimen Extraction laparoscopic surgery has been introduced to avoid minilaparotomy, possibly reducing postoperative pain, hospital stay, and improving QoL and cosmetics. Operative steps and preliminary results of NOSE sleeve gastrectomy are described and reported. Five patients underwent NOSE LSG from November 2014 to March 2015. Selection criteria were as follows: age <60 years, ASA score ≤III, BMI <50. Operative steps are the same of standard LSG, but the stomach transection that starts higher on the greater curvature. A 2–3 cm width opening is created on the exceeding antrum and the resected stomach sutured to the calibration probe tip, which is pull back allowing transoral specimen extraction. The exceeding antrum is stapler-trimmed, allowing breach closure and completion of tubulization. Mean age was 41.6 years (median 43), average weight was 123.6 Kg (median 114), mean BMI 43.6 Kg/m2 (median 44). Mean operation time was 72 min (median 75). Mean and median postoperative stay were 4.6 and 5. No intraoperative nor postoperative complications occurred. Postoperative day 1 mean and median VAS pain score at were 1.4 and 1, respectively. Follow-up ranged 1–5 months (mean and median 3), average weight loss was 19.8 Kg (median 19), and excess weight loss 36.2 % (median 32 %). NOSE LSG potential advantages are as follows: improved cosmetics, decreased postoperative pain, possible incisional hernia rate reduction. No objective data are available to confirm these theoretical benefits; larger observational studies and RCTs are mandatory before clinical validation.


Intragenic CAMTA1 rearrangements cause non-progressive congenital ataxia with or without intellectual disability.
Non-progressive congenital ataxias (NPCA) with or without intellectual disability (ID) are clinically and genetically heterogeneous conditions. As a consequence, the identification of the genes responsible for these phenotypes remained limited. Identification of a new gene responsible for NPCA and ID. Methods Following the discovery of three familial or sporadic cases with an intragenic calmodulin-binding transcription activator 1 (CAMTA1) rearrangement identified by an array-CGH and recruited from a national collaboration, the authors defined the clinical and molecular characteristics of such rearrangements, and searched for patients with point mutations by direct sequencing. Intragenic copy number variations of CAMTA1 were all located in the CG-1 domain of the gene. It segregated with autosomal dominant ID with non-progressive congenital cerebellar ataxia (NPCA) in two unrelated families, and was de novo deletion located in the same domain in a child presenting with NPCA. In the patients with ID, the deletion led to a frameshift, producing a truncated protein, while this was not the case for the patient with isolated childhood ataxia. Brain MRI of the patients revealed a pattern of progressive atrophy of cerebellum medium lobes and superior vermis, parietal lobes and hippocampi. DNA sequencing of the CG-1 domain in 197 patients with sporadic or familial non-syndromic intellectual deficiency, extended to full DNA sequencing in 50 patients with ID and 47 additional patients with childhood ataxia, identified no pathogenic mutation. The authors have evidence that loss-of-function of CAMTA1, a brain-specific calcium responsive transcription factor, is responsible for NPCA with or without ID. Accession numbers CAMTA1 reference sequence used was ENST00000303635. Protein sequence was ENSP00000306522.


Opioid, 5-HT1A and alpha 2 receptors localized to subsets of guinea-pig myenteric neurons.
The expression of mu opioid, alpha 2 and 5-hydroxytryptamine1A (5-HT1A) receptors on guinea-pig myenteric neurons was determined using receptor selective agonists during intracellular recordings in vitro. Agonists known to hyperpolarize myenteric neurons by increasing potassium conductance were tested: noradrenaline and UK 14304 (alpha 2 agonists); 5-HT, 8-hydroxydipropylaminotetralin, 5-carboxamidotryptamine (5-HT1A agonists); normorphine, [Met5]-enkephalin and D-Ala2-Phe4, Gly-ol5 enkephalin (mu agonists). The alpha 2 agonists hyperpolarized 46/67 AH cells; mu agonists hyperpolarized 11/66 AH cells and 5-HT1A agonists inhibited 28/57 AH cells. Hyperpolarizations to both alpha 2 and mu agonists were observed in 11/59 AH cells; hyperpolarizations to both alpha 2 and 5-HT1A agonists were observed in 23/49 AH cells. Hyperpolarizations mediated at alpha 2 receptors were observed in 11/54 S neurons and mu agonists hyperpolarized 17/45 S cells. alpha 2 and mu receptors were localized together on 10/43 S cells tested with receptor selective agonists. 5-HT1A-mediated hyperpolarizations were not observed in 36 S cells. Presynaptic inhibition of fast excitatory post-synaptic potentials (fast e.p.s.p.s., S neurons) was observed in all cells tested with alpha 2 agonists (n = 32); in 14/23 cells tested with 5-HT1A agonists and in 8/22 cells tested with mu agonists. Both alpha 2 and 5-HT1A agonists inhibited fast e.p.s.p.s in 15/23 cells, while alpha 2 and mu agonists both inhibited the fast e.p.s.p. in 8/21 cells. Inhibition of fast e.p.s.p.s by mu and 5-HT1A agonists occurred together in 2/19 cells. Slow non-cholinergic e.p.s.p.s were inhibited by alpha 2 agonists in 19/19 cells and by 5-HT1A agonists in 19/21 cells. alpha 2- and 5-HT1A-mediated inhibition of slow e.p.s.p.s occurred together in 12/14 cells. These data allow AH neurons to be divided into two groups: those expressing alpha 2 and 5-HT1A receptors and those expressing alpha 2 and mu receptors. alpha 2 and mu receptors coexist on S neurons which do not express 5-HT1A receptors. Terminals that release acetylcholine express either alpha 2 and mu or alpha 2 and 5-HT1A receptors, consistent with the idea that they are provided by AH cells. Terminals that release mediators of the slow e.p.s.p. express primarily alpha 2 and 5-HT1A receptors.


Knee measurements among children with normal alignment, physiologic and pathologic bowing aged 0-3 years old: a systematic review.
Distinguishing physiologic and pathologic genu varus is challenging among children below age 3. They can be assessed by measuring intercondylar distance (ICD), clinical tibiofemoral angle (cTFA) or radiologic TFA (rTFA). We aim to determine the knee measurement values among three groups of children. Medline (1946-) and EMBase (1947-) were searched until 31 July 2020 using a search strategy. Studies with original data which reported knee measurements among children with normal alignment, physiologic and pathologic bowing between the ages of 0-3 years were included. In total 1897 studies were identified, and 16 studies included after title and abstract screening. These studies involved 1335 patients with normal alignment, 286 with physiologic and 184 with pathologic bowing. Five studies provided data on ICD, seven on cTFA and eight on rTFA which were pooled for meta-analyses. Normal children had neither measurable ICD nor demonstrable varus on cTFA after 19 months old. The mean (95% confidence interval) ICD for children with pathologic genu varus at 18 months was 4.41 (4.19-4.63). The rTFA for children with pathologic compared to the physiologic bowing by age groups was; 11-20 months: 24.74°(23.22°-26.26°) vs. 19.44°(17.05°-21.84°), 21-30 months: 20.35°(18.13°-22.56°) vs. 14.72°(12.32°-17.12°) and 12-36 months: 32.60°(26.40°-38.80°) vs. 19.14°(17.78°-20.50°). Children above the age of 18 months with genu varus should be closely monitored clinically using ICD or cTFA. An ICD of more than 4 cm may warrant further investigation for pathologic cause. rTFA has limited use in the detection of pathologic varus.


A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma.
Local radiotherapy (RT) alone was compared with radiotherapy plus continuous oral chlorambucil (RT+CHL) for the treatment of localised, low grade non-Hodgkins lymphoma (NHL) in a prospective randomised study of 148 patients. After a maximum of 18 years follow up there was no significant difference in overall survival or disease free survival between the two treatment groups. Age greater than 50 years and low serum albumin at diagnosis correlated with a poor prognosis in the series overall. Over one third of patients with localised, low grade NHL may be cured by RT alone and adjuvant chlorambucil as initial therapy confers no survival advantage.


Survival analysis in the presence of competing risks.
Survival analysis in the presence of competing risks imposes additional challenges for clinical investigators in that hazard function (the rate) has no one-to-one link to the cumulative incidence function (CIF, the risk). CIF is of particular interest and can be estimated non-parametrically with the use cuminc() function. This function also allows for group comparison and visualization of estimated CIF. The effect of covariates on cause-specific hazard can be explored using conventional Cox proportional hazard model by treating competing events as censoring. However, the effect on hazard cannot be directly linked to the effect on CIF because there is no one-to-one correspondence between hazard and cumulative incidence. Fine-Gray model directly models the covariate effect on CIF and it reports subdistribution hazard ratio (SHR). However, SHR only provide information on the ordering of CIF curves at different levels of covariates, it has no practical interpretation as HR in the absence of competing risks. Fine-Gray model can be fit with crr() function shipped with the cmprsk package. Time-varying covariates are allowed in the crr() function, which is specified by cov2 and tf arguments. Predictions and visualization of CIF for subjects with given covariate values are allowed for crr object. Alternatively, competing risk models can be fit with riskRegression package by employing different link functions between covariates and outcomes. The assumption of proportionality can be checked by testing statistical significance of interaction terms involving failure time. Schoenfeld residuals provide another way to check model assumption.


Hepatic fibrosis 2006: report of the Third AASLD Single Topic Conference.
The Third American Associated for the Study of Liver Diseases (AASLD)-sponsored Single Topic Conference on hepatic fibrosis was held in June 2006. The conference was both international, with 6 countries represented, and cross-disciplinary, linking the basic molecular and cellular biology of fibrogenic cells to clinical trial design for emerging antifibrotic therapies. The specific goals of the conference were: (1) to consolidate knowledge about the natural history of fibrosis; (2) to clarify potential endpoints and markers; (3) to emphasize new antifibrotic targets developed on the basis of advances in basic science; and (4) to understand current critical issues pertaining to clinical trial design. Given the tremendous growth of the field and the constraints of a 2-day format, the selection of speakers was a challenge. A number of topics not included in the oral presentations were featured at poster sessions, lending breadth and depth to the meeting as a whole. Surprising new themes emerged about molecular, clinical, and regulatory aspects of the field, and a consensus emerged that hepatic fibrosis has matured into an integrated discipline that promises to significantly improve the prognosis of patients with fibrosing liver disease.


Class II antigen expression of epidermal Langerhans cells in renal allograft recipients.
This study was designed to investigate the influence of systemic immunosuppressive therapy on the HLA-DR expression of epidermal Langerhans cells. Fifteen renal allograft recipients immunosuppressed with cyclosporin A and steroids were studied. Skin biopsies were taken from the upper arm prior to transplantation and at different intervals during the post-transplantation period. The epidermis was separated from the dermis, and the epidermal sheet was subjected to immunohistochemistry in order to make the HLA-DR antigens on the Langerhans cells visible. Following 2 days of immunosuppression, the number of Langerhans cells expressing HLA-DR antigens started to decrease and after 1 week, only 60% of the initial number of positive cells were detected. The number of positive cells remained low throughout the experimental period. It is suggested that systemic immunosuppressive therapy will suppress the expression of HLA-DR antigens on epidermal Langerhans cells, something which may mirror a systemic effect on other antigen-presenting cells.


Lactate-induced anxiety after imipramine and diazepam treatment.
To examine the effect of treatment on lactate-induced anxiety in a controlled study, we infused 44 panic disorder patients with lactate and placebo before and after eight weeks of double-blind treatment with imipramine, diazepam, or placebo. During treatment, both imipramine and diazepam groups improved more than the placebo group. After treatment, patients in both the imipramine and diazepam groups had significantly less anxiety than the placebo patients when reinfused with lactate. In addition, imipramine decreased posttreatment panic attack frequency and diazepam decreased the perceived severity of posttreatment lactate-induced panic attacks. This study demonstrates that diazepam, like imipramine, is an effective treatment for panic disorder, and that both imipramine and diazepam blunt lactate-induced anxiety in a placebo controlled study.


Decreased glutamate release correlates with elevated dynorphin content in the hippocampus of aged rats with spatial learning deficits.
The effects of aging on extracellular glutamate and tissue dynorphin content in the hippocampus were examined in Fischer-344 rats. Young adult (4-month-old) and aged (24-month-old) rats were trained to find a hidden platform in the Morris water task. Aged rats were unable to acquire the spatial learning task as rapidly as young controls. Following behavioral testing, an in vivo microdialysis perfusion method was used to determine extracellular glutamate levels in the hippocampus. There was a 25-35% reduction in extracellular glutamate concentration in both dorsal and ventral hippocampus of aged rats compared to young rats, in the absence of any change in tissue glutamate levels. Radioimmunoassay showed an increase in dynorphin A(1-8)-like immunoreactivity [DYN-A(1-8)LI] in both dorsal and ventral hippocampus, but not striatum, of aged rats. Immunocytochemistry indicated that this increase was localized to the dentate granule cells and mossy fibers. Furthermore, among the aged rats the increase in DYN-A(1-8)LI was inversely correlated with the decrease in extracellular glutamate. These results suggest that the disregulation of dynorphin observed in cognitively impaired aged rats is related to reduced excitatory transmission within the hippocampal formation.


Malpractice Lawsuits Relating to Mechanical Thrombectomy for Acute Ischemic Stroke: A Systematic Review.
Medical-legal claims for malpractice relating to the use of alteplase for acute ischemic stroke (AIS) are usually for failure to treat rather than for complications. The advent of mechanical thrombectomy (MT) as a standard of AIS treatment has added a new dimension to the medical-legal landscape as there is a need for the delivery of a higher level of care creating the potential for delays and errors associated with such treatment. Information on causes of malpractice related to mechanical thrombectomy (MT) is currently lacking. We conducted a systematic review of legal databases (Westlaw, LexisNexis, Google Scholar Case Law, and VerdictSearch) to identify medical malpractice cases with and without verdicts filed in the United States up to March 31, 2021 which pertained to performance or non-performance of MT for AIS. We collected various case characteristics, case outcomes, and root causes for malpractice claims. We found 25 cases, 16 of which alleged failure to treat with MT, 8 for harm due to delay in treatment and 1 case that alleged complications. Root causes included delay in vascular imaging, communication breakdowns, and transportation delays. Eight cases had an outcome in favor of the defendant, 9 in favor of the plaintiff, and 8 remained to be determined. As with alteplase, malpractice allegations regarding MT for AIS are largely for failure to treat or delay in treatment as opposed to complications. Addressing root causes of diagnostic delay, communication breakdowns, and transportation delays may reduce subsequent malpractice risk.


Actinomyces-Related Tubo-Ovarian Abscess in a Poorly Controlled Type II Diabetic With a Copper Intrauterine Device.
The historic association of Actinomyces israelii infection with intrauterine devices (IUDs) has long been recognized. In recent years, the risk of developing pelvic inflammatory disease with a copper or levonorgestrel IUD has been less than 1% in women who are low risk for sexually transmitted infections. IUD-related pelvic infections secondary to actinomyces have largely vanished from contemporary practice. A 49-year-old using a copper IUD for contraception with poorly controlled type II diabetes mellitus was admitted for suspected tubo-ovarian abscess on the basis of abdominopelvic pain, leukocytosis, and computed tomography findings. After she was treated with intravenous and outpatient antibiotics with clinical improvement, repeat imaging 1 month later revealed a persistent complex left adnexal mass. Tumor markers were negative but given the persistence and complex nature of the mass, surgical management was recommended. A robotic-assisted hysterectomy with bilateral salpingo-oophorectomy was performed. Adhesiolysis, profuse irrigation, and ureteral stenting were required. Pathology revealed bilateral tubo-ovarian abscesses with actinomyces species identified on intraoperative culture. The patient had a total of 10 days of postoperative antibiotics and improved glucose control with no further signs of infection. Although actinomyces-related IUD PID is considered an outdated diagnosis, there are intermittent case reports of bizarre presentations in older women, often mimicking malignancy. Actinomyces should be a consideration in tubo-ovarian abscesses or pelvic inflammatory disease in patients with an IUD in place, particularly those who have poor glucose control or are otherwise immunosuppressed. Early identification and treatment of actinomyces tubo-ovarian abscesses may reduce surgical morbidity and overall improve patient outcomes and safety.


Hospital Use in the Last Year of Life for Children With Life-Threatening Complex Chronic Conditions.
Although many adults experience resource-intensive and costly health care in the last year of life, less is known about these health care experiences in children with life-threatening complex chronic conditions (LT-CCCs). We assessed hospital resource use in children by type and number of LT-CCCs. A retrospective analysis of 1252 children with LT-CCCs, ages 1 to 18 years, who died in 2012 within 40 US children's hospitals of the Pediatric Health Information System database. LT-CCCs were identified with International Classification of Diseases, 9th Revision, Clinical Modification codes. Using generalized linear models, we assessed hospital admissions, days, costs, and interventions (mechanical ventilation and surgeries) in the last year of life by type and number of LT-CCCs. In the last year of life, children with LT-CCCs experienced a median of 2 admissions (interquartile range [IQR] 1-5), 27 hospital days (IQR 7-84), and $142 562 (IQR $45 270-$410 087) in hospital costs. During the terminal admission, 76% (n = 946) were mechanically ventilated; 36% (n = 453) underwent surgery. Hospital use was greatest (P < .001) among children with hematologic/immunologic conditions (99 hospital days [IQR 51-146]; cost = $504 145 [IQR $250 147-$879 331]) and children with ≥3 LT-CCCs (75 hospital days [IQR 28-132]; cost = $341 222 [IQR $146 698-$686 585]). Hospital use for children with LT-CCCs in the last year of life varies significantly across the type and number of conditions. Children with hematologic/immunologic or multiple conditions have the greatest hospital use. This information may be useful for clinicians striving to improve care for children with LT-CCCs nearing the end of life.