Glenoid Pathology, Skeletal Immaturity, and Multiple Preoperative Instability Events Are Risk Factors for Recurrent Anterior Shoulder Instability After Arthroscopic Stabilization in Adolescent Athletes.
To identify risk factors for recurrent shoulder instability after arthroscopic stabilization in adolescent athletes. A retrospective case-control study was undertaken of all patients younger than 18 years undergoing arthroscopic shoulder stabilization for anterior instability between 2009 and 2016. Two patient cohorts were identified: (1) patients with recurrent instability (frank dislocations or subluxations) after arthroscopic stabilization and (2) an age- and sex-matched cohort of patients with no recurrent instability at a minimum of 2 years' follow-up from index surgery. Patient demographic, injury, radiographic, and surgical variables were recorded. Variables with P < .10 on univariate analysis were entered into a binary logistic multivariate regression analysis. We identified 35 patients (20.5%) in whom arthroscopic stabilization failed at a mean of 1.2 ± 1.0 years after their index surgical procedure. A separate age- and sex-matched cohort of 35 patients with no evidence of recurrent instability was identified (mean follow-up, 5.4 ± 2.0 years; minimum follow-up, 2 years). Univariate analysis identified increased glenoid bone loss (P = .039), decreased glenoid retroversion (P = .024), and more than 1 instability event prior to surgery (P = .017) as significant risk factors for recurrent instability. Multivariate regression analysis revealed that glenoid retroversion less than 6°, skeletal immaturity, and more than 1 prior instability event significantly and independently predicted future recurrence. The risk of recurrence after arthroscopic stabilization was increased by 3 times in patients with 2 risk factors and by 4 times in patients with all 3 risk factors. Anterior glenoid bone loss, glenoid version, skeletal immaturity, and multiple preoperative instability events are risk factors for failed arthroscopic stabilization in adolescent athletes with anterior instability. Level III, case-control study.


Bis[μ(3)-N'-oxidopyridine-2-carbox-imidamidato(2-)]bis-[μ(2)-N'-oxido-pyridine-2-carboximidamidato(1-)]tetra-pyridine-tetra-nickel(II) dinitrate.
The title compound, [Ni(4)(C(6)H(5)N(3)O)(2)(C(6)H(6)N(3)O)(2)(C(5)H(5)N)(4)](NO(3))(2), is a tetra-nuclear nickel complex containing a single-decker cation, located on an inversion center. The two unique Ni(II) cations are N,N',N'',O-chelated by carbox-imid-amid-ate(2-) and carboximidamidate(1-) anions, forming a distorted four-coordinate planar structure, while the other two Ni(II) atoms are N,N',O,O'-chelated by the same bridging ligands and two pyridine mol-ecules, affording six-coordinated metals in an octa-hedral geometry. The cation is isostructural with the complex crystallized with perchlorate counter-ions in place of nitrate.


Bacteriological Profile and Antimicrobial Susceptibility Pattern in Chronic Suppurative Otitis Media: A 1-Year Cross-Sectional Study.
Inadequate antibiotic treatment, misuse/improper choice of antibiotic and poor compliance of patients have resulted in changes in susceptibility to antibiotics of the causative organisms and also development of resistance to commonly used antibiotics. Thus, this study aimed to identify the bacteriological profile and determine antibiotic susceptibility pattern in CSOM patients. This 1-year cross-sectional study was conducted on 120 clinically diagnosed cases of CSOM attending ear, nose, and throat outpatient department. Ear discharges obtained were processed for bacterial culture (aerobic and anaerobic). Antimicrobial susceptibility testing was done by Kirby-Bauer disc diffusion method. Demographic and clinical characteristics of the patients were recorded. Of total 120 cases, pathogens were isolated from 116 cases. The commonest aerobic organism isolated was Pseudomonas aeruginosa (38.79%) followed by Staphylococcus aureus (32.75%). Staphylococcus aureus showed maximum sensitivity to erythromycin (71.05%), followed by cotrimoxazole (63.15%) and ampicillin (55.26%). Maximum resistance was observed for ciprofloxacin (78.9%), followed by amoxiclave (55.26%). Pseudomonas aeruginosa showed maximum sensitivity to piperacillin (91.11%) followed by gentamicin (71.11%), amikacin (71.11%), moderate sensitivity to ceftazidime (51.11%); however resistance to carbpenicillin (60%). Ciprofloxacin was the most prescribed topical agent showing an increase in resistance to common organisms of CSOM. Hence, it is mandatory to study each case of CSOM bacteriologically to formulate local antibiotic policy for appropriate use of antibiotics. This will certainly help in achieving a safe ear and to control the organisms developing resistance to prevalent antibiotics.


Is it the egg or the endometrium? Elevated progesterone on day of trigger is not associated with embryo ploidy nor decreased success rates in subsequent embryo transfer cycles.
The purpose of our study was to determine if progesterone (P4) values on day of trigger affect certain cycle outcome parameters, ploidy status of embryos, as well as pregnancy outcomes in the subsequent first frozen embryo transfer cycle. Two hundred thirty-eight patients undergoing pre-gestational screening and freeze all protocol at our fertility center from 2013 to 2014 were included. Excluded patients were those whom had cancelled cycles prior to egg retrieval as well as cycles utilizing donor eggs. Once patients were identified as eligible for this study, frozen serum from the day of trigger was identified and analyzed using the Siemens Immulite 2000. Number of eggs retrieved, number of available embryos for biopsy, and number of euploid/aneuploid embryos were analyzed. The first frozen embryo transfer cycle was linked to the initial egg retrieval and outcomes including pregnancy rates, and live birth/ongoing pregnancy rates were calculated and analyzed. A discriminatory P4 value of 1.5 ng/ml was set. Group A had P4 values of less than 1.5 ng/ml and group B had P4 values greater than or equal to 1.5 ng/ml. T tests and chi-squared tests were used for statistical analysis. Group A had an average trigger P4 value of 0.87 +/- 0.3 and group B had an average trigger P4 of 2.1 +/- 0.8. Table 1 shows the baseline characteristics of both group A and group B. The only significant difference between the two groups was total gonadotropin dosage (IU) with a p value of 0.02 and estradiol (pg/ml) at trigger, also with a p value of 0.02 (Table 1). Number of eggs retrieved, number of embryos biopsied, number euploid/aneuploid, and non-diagnosis embryos were all non-significant. Chi-square analysis was used to compare pregnancy rates between the two groups after the first frozen embryo transfer cycle. Group A had a pregnancy rate of 72 % and Group B had a pregnancy rate of 66.7 %, which was not significant. Ongoing pregnancy/live birth rates were 65.6 % in group A and 66.67 % in group B, also not significant (Table 2). P4 values on day of trigger do not affect number of eggs retrieved and number of chromosomally normal embryos available for transfer in a subsequent embryo transfer cycle. Elevated P4 values (≥1.5 ng/ml) also do not affect pregnancy rates or live birth/ongoing pregnancy rates in the first subsequent frozen embryo transfer cycle.


Pathways to acute humoral rejection.
Acute humoral rejection, also known as acute vascular rejection, is a devastating condition of organ transplants and a major barrier to clinical application of organ xenotransplantation. Although initiation of acute humoral or vascular rejection is generally linked to the action of antibodies and complement on the graft, other factors such as ischemia, platelets, T cells, natural killer cells, and macrophages have also been implicated. Central to any understanding of the pathogenesis of acute humoral rejection, and to developing means of preventing it, is to know whether these factors injure the graft independently or through one or few pathways. We addressed this question by examining early events in a severe model of vascular rejection in which guinea pig hearts transplanted heterotopically into rats treated with cobra venom factor (CVF) develop disease over 72 hours. The early steps in acute vascular rejection were associated with expression of a set of inflammatory genes, which appeared to be controlled by availability of interleukin (IL)-1. Interruption of IL-1 signaling by IL-1 receptor antagonist (IL-1ra) averted expression of these genes and early tissue changes, including coagulation and influx of inflammatory cells. These findings suggest IL-1 plays an important role in initiation of acute humoral rejection.


Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons.
Heterotopic cardiac xenotransplantation from alpha1,3-galactosyltransferase gene-knockout (GalT-KO) swine to baboons was performed to characterize immunological reaction to the xenograft in the absence of anti-Gal antibody-mediated rejection. Eight baboons received heterotopic cardiac xenografts from GalT-KO porcine donors. All baboons were treated with chronic immunosuppressive therapy. Both histological and immunohistochemical studies were performed on biopsy and graftectomy samples. No hyperacute rejection was observed. Three baboons were euthanized or died 16 to 56 days after transplantation. The other five grafts ceased beating between days 59 and 179 (median, 78 days). All failing grafts exhibited thrombotic microangiopathy (TM) with platelet-rich fibrin thrombi in the microvasculature, myocardial ischemia and necrosis, and focal interstitial hemorrhage. TM developed in parallel with increases in immunoglobulin (IgM and IgG) and complement (C3, C4d, and C5b-9) deposition, as well as with subsequent increases in both TUNEL(+) endothelial cell death and procoagulant activation (increased expression of both tissue factor and von Willebrand factor and decreased expression of CD39). CD3(+) T-cell infiltration occurred in all grafts and weakly correlated with the development of TM. In conclusion, although the use of GalT-KO swine donors prevented hyperacute rejection and prolonged graft survival, slowly progressive humoral rejection--probably associated with non-Gal antibodies to the xenograft--and disordered thromboregulation represent major immunological barriers to long-term xenograft survival.


Fibonacci statistical convergence and Korovkin type approximation theorems.
The purpose of this paper is twofold. First, the definition of new statistical convergence with Fibonacci sequence is given and some fundamental properties of statistical convergence are examined. Second, we provide various approximation results concerning the classical Korovkin theorem via Fibonacci type statistical convergence.


The role of the IDEMV in predicting European stock market volatility during the COVID-19 pandemic.
The main purpose of this paper is to investigate whether the Infectious Disease EMV tracker (IDEMV) proposed by Baker et al. (2020) has additional predictive ability for European stock market volatility during the COVID-19 pandemic. The three European stock markets we consider are France, UK and Germany. Our investigation is based on the HAR and its augmented models. We find that the IDEMV has stronger predictive power for the France and UK stock markets volatilities during the global pandemic, and the VIX has also superior predictive ability for the three European stock markets during this period.


Management of infection following intra-abdominal trauma.
Intra-abdominal infections following abdominal trauma often involve the gastrointestinal aerobic and anaerobic bacterial flora. These organisms possess various virulence factors and exhibit potential synergy between them. The intra-abdominal infection is biphasic, with the Enterobacteriaceae as the major pathogens in the peritonitis stage, and the Bacteroides fragilis group predominant in the abscess stage. Experiments with animals and experience in human beings support the need to use single or combined antimicrobial agent therapy that is effective against both Enterobacteriaceae and the B fragilis group.


Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies.
Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.


Morphological study of the transition of haematopoietic sites in the developing mouse during the peri-natal period.
The transition of fetal haematopoietic sites in mice was examined histologically from 12.5-day embryos (E12.5) until 10 days of age (D10), and the expression of the adhesive molecules VCAM-1 and fibronectin was examined immunohistologically. Erythropoiesis occurred in the liver (E12.5-18.5), spleen (E18.5-D4) and bone marrow (D6-10), in that sequence. Even at D10, some erythropoiesis occurred in the liver, and more so in the spleen, although the active haematopoietic site was the bone marrow. Similarly, granulopoiesis of neutrophils occurred in the liver, spleen and bone marrow in turn. Granulopoiesis still occurred in the spleen at D10, but no neutrophils were found in the liver after D4. VCAM-1 appeared in the liver, spleen and bone marrow in parallel with active erythropoiesis and granulopoiesis. The co-expression of VCAM-1 and fibronectin was recognized in the endothelial cells of the sinus at the onset of haematopoiesis. This study showed that haematopoiesis in the liver, spleen and bone marrow overlapped peri-natally, although it shifted sequentially. VCAM-1 appears to be closely associated with erythropoiesis and granulopoiesis, and the co-expression of VCAM-1 and fibronectin plays a role in inducing haematopoietic stem cells to move to the tissues.


Identifying students who are off-track academically at the start of secondary school: The role of social-emotional learning trajectories.
Research shows that successfully transitioning from intermediate school to secondary school is pivotal for students to remain on track to graduate. Studies also indicate that a successful transition is a function not only of how prepared the students are academically but also whether they have the social-emotional learning (SEL) skills to succeed in a more independent secondary school environment. Yet, little is known about whether students' SEL skills are stable over time, and if they are not, whether a student's initial level of SEL skills at the start of intermediate school or change in SEL skills over time is a better indicator of whether the student will be off track academically in 9th grade. This study begins to investigate this issue. We use four years of longitudinal SEL data from students in a large urban district with a sample size of ~3,000 students per timepoint. We use several years of longitudinal SEL data to fit growth models for three constructs shown to be related to successfully transitioning to secondary school. In so doing, we examine whether a student's mean SEL score in 6th grade (status) or growth between 6th and 8th grade is more predictive of being off track academically in 9th grade. Results indicate that, while status is more frequently significant, growth for self-management is also predictive above and beyond status on that construct. Findings suggest that understanding how a student develops social-emotionally can improve identification of students not on track to succeed in high school.


Heterogeneity of coronary vasomotion.
Apart from local heterogeneities of myocardial blood flow, the regulation of vascular tone is equally complex. Changes in vascular tone are essential for the adaptation of coronary blood flow to varying metabolic demands. The majority of coronary vascular resistance is found in the microcirculation, that is, in vessels with less than 150-200 microns in diameter; therefore, understanding the regulatory mechanisms that exercise control of the tone of these vessels is paramount to our understanding the control of myocardial perfusion. Recently, it became evident that different regulatory systems such as metabolic, neurohumoral, myogenic, and flow-mediated mechanisms have preferential effects on particular microvascular segments. However, the significance of specific vasoactive mediators is still under investigation. Growth factors, which are synthesized in cells in the surrounding of vessels such as mast cells and cardiac myocytes, have recently been suggested to play a role in the coordination of endothelium-dependent and endothelium-independent vasoactive mechanisms. The aim of this review is, first, to focus on the heterogeneity of the regulation of coronary vascular resistance in general and, second, to discuss recent studies showing a possible role of growth factors, especially fibroblast growth factor (FGF), heparin, and endothelin, as modulators of microvascular tone.


Immunohistochemistry-Based Consensus Molecular Subtypes as a Prognostic and Predictive Biomarker for Adjuvant Chemotherapy in Patients with Stage II Colorectal Cancer.
For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial. Consensus molecular subtype (CMS) has been validated to be a prognostic tool for CRCs. In this study, CMS status was investigated as a prognostic biomarker for the efficacy of adjuvant chemotherapy for stage II colorectal cancer. The tissue microarray was retrospectively constructed of 165 nonconsecutive, primary, and sporadic stage II CRCs. CMS status was determined by immunohistochemistry staining of CDX2, HTR2B, FRMD6, and ZEB1, combining with microsatellite instability testing. The prognostic for adjuvant chemotherapy efficacy of CMS status was calculated by Kaplan-Meier curves and Cox regression analysis. Subgroup analyses were conducted according to tumor location. Kaplan-Meier curves indicated that CMS was associated with overall survival (OS) and disease-free survival for stage II CRCs. Cox regression analysis showed that CMS was an independent risk factor for OS. Among high-risk clinicopathological factors, patients with CMS2/3 (hazard ratio [HR]: 0.445, 95% confidence interval [CI]: 0.227-0.875), left-sided tumors (HR: 0.488, 95% CI: 0.247-0.968), or fewer than 12 lymph nodes examined (HR: 0.307, 95% CI: 0.097-0.974) had survival benefit from adjuvant chemotherapy. Subgroup analysis showed that adjuvant chemotherapy only improved OS for patients with left-sided tumors of CMS2/3 subtype. Regardless of CMS, right-sided tumors had no benefit from adjuvant chemotherapy. CMS is a better prognostic factor for adjuvant chemotherapy for stage II CRCs. Together with tumor location, CMS classification will aid in personalized treatment for stage II CRCs. For stage II colorectal cancer (CRC), the efficacy of adjuvant chemotherapy remains controversial, in that its minimal benefit (no more than 5% on average) is considered not worth the toxic effects of the drugs. There are still no effective prognostic and predictive biomarkers. This study showed that consensus molecular subtype (CMS) status is a predictive marker for adjuvant chemotherapy efficacy. Patients with left-sided tumors of CMS2/3 subtype have survival benefit by receiving adjuvant chemotherapy, which will aid in personalized treatment for stage II CRCs. Moreover, this test of CMS based on immunohistochemistry is cheap, not time consuming, and easily conducted in the laboratories of most hospitals.


A calorimetric study of Ca2+ binding to two major isotypes of bullfrog parvalbumin.
Microcalorimetric titrations of the two major isotypes of parvalbumin (PA1 and PA2) from bullfrog skeletal muscle with Ca2+ in the presence and absence of Mg2+ have been carried out at 25 degrees C and pH 7.0. The observed enthalpy titration curves were analyzed by the least-squares method. The measured enthalpy changes (delta H) of Ca2+ binding are -33.2 (PA1) and -16.3 kJ/mol site (PA2), and the entropy changes (delta S) are 28 (PA1) and 76 j/mol per K (PA2) in the absence of Mg2+. When 5 mM Mg2+ is present, the enthalpy change of PA2 (-26.7 kJ/mol) is about twice as large as that in the absence of Mg2+, whereas that of PA1 (-34.6 kJ/mol) is about the same. The entropy changes are 8 (PA1) and 29 J/mol per K (PA2). Both enthalpy and entropy changes are favorable for the Ca2+-binding reactions of PA1 and PA2 irrespective of the presence of Mg2+.


On the functionality of the N-terminal domain in xylanase 10A from Ruminococcus albus 8.
We analyzed the structure to function relationships in Ruminococcus albus 8 xylanase 10A (RalXyn10A) finding that the N-terminus 34-amino acids sequence (N34) in the protein is particularly functional. We performed the recombinant wild type enzyme's characterization and that of the truncated mutant lacking the N34 extreme (RalΔN34Xyn10A). The truncated enzyme exhibited about half of the activity and reduced affinity for binding to insoluble saccharides. These suggest a (CBM)-like function for the N34 motif. Besides, RalXyn10A activity was diminished by redox agent dithiothreitol, a characteristic absent in RalΔN34Xyn10A. The N34 sequence exhibited a significant similarity with protein components of the ABC transporter of the bacterial membrane, and this motif is present in other proteins of R. albus 8. Data suggest that N34 would confer RalXyn10A the capacity to interact with polysaccharides and components of the cell membrane, enhancing the degradation of the substrate and uptake of the products by the bacterium.


Public Health, Visual Rhetoric, and Latin America: Steinbeck's The Forgotten Village.
This essay analyzes the visualization of Euro-American medicine and indigenous healing in John Steinbeck's 1941 documentary-drama The Forgotten Village. The movie juxtaposes film and medical discourse as exemplifications of modern, visual culture by showing excerpts from hygiene films and foregrounding medical imagery (e.g., bacteria cultures). The film displaces indigenous medicine by privileging a Euro-American medical model, and the gaze of oppression is perpetuated through humanitarian medical intervention. In short, disease is not simply a material fact but embedded in discourses about community identity, moral values, and politics.


[Microtympanopuncture].
Tympanopuncture was made with a needle having a step gradation to its thin end. Such a needle abates traumaticity of this manipulation and extends its applicability. The above modification was called by the author microtympanopuncture. The review of 7000 cases of microtympanopuncture is given. Indications for this procedure and its possible complications are outlined. Microtympanopuncture can be made in outpatient setting and therefore must find wider application.


Precise injection of human mesenchymal stromal cells in the urethral sphincter complex of Göttingen minipigs without unspecific bulking effects.
To investigate if injection of cells in the urethral sphincter complex causes unspecific bulking effects. Human mesenchymal stromal cells were isolated, expanded, and characterized. For transurethral injection, cells were labeled with the fluorescent dye PKH26 and in magnetic resonance imaging associated experiments with superparamagnetic particles. Aliquots of cells in 250 µL solvent were injected under vision in the urethral sphincter of immuno-suppressed Göttingen minipigs. Sphincteric closure pressure was recorded by standard and high-definition urethral pressure profilometry prior to and after cell injection. The animals were sacrificed after surgery or after 3 weeks, 3, 6, or 12 months of follow-up. The localisation of the injected cells was explored by histochemistry. Sham-treated animals served as controls. PKH26-labeled cells survive injections in sphincter tissue samples by Williams cystoscopic injection needle well. In our animal study, the cellular depots were detected in the submucosa or in deeper zones of the sphincter, depending of the length of the injection needle (4-8 mm). Adverse effects associated with injection of cells or solvent such as a noteworthy bleeding, incontinence, or obstruction, were not recorded (n = 96 minipigs). However, a transient infiltration of macrophages was detected 3 weeks after cell injection. Changes in the urethral pressure profiles were not observed in cell-treated (n = 72) compared to sham-treated animals (n = 24). Injection of small aliquots of cells to investigate cell therapies in minipigs is a feasible and safe procedure, and it does not bias the intrinsic urethral wall pressure.


Growth of normal human T lymphocytes induced by monoclonal antibody to the T cell antigen receptor.
A monoclonal antibody (mAb) called 30-3D6 has been raised against the T cell antigen receptor analogue on a human T cell leukemia cell line HPB-ALL. This mAb comodulates the T3 molecule on HPB-ALL and precipitates the heterodimeric structure previously described as a T cell idiotypic receptor analogue on this cell line. 30-3D6 reacts with a variable percentage of normal T cells (up to 6%) depending on the donor and this number is stable on repeated sampling and is not affected by the temperature of the reaction. When normal T cells from a high frequency donor are stimulated with 30-3D6 and interleukin 2 in vitro the idiotype-positive (Id+) population can be expanded. Large numbers of greater than 90% Id+ T cells can be generated. Id cells are present in both the helper and cytotoxic suppressor subsets.


Phytochemical Profiling and Pharmacological Evaluation of Leaf Extracts of Ruellia tuberosa L.: An In Vitro and In Silico Approach.
The present study was designed to appraise the photoprotective, antioxidant, and antibacterial bioactivities of Ruellia tuberosa leaves extracts (RtPE, RtChl, RtEA, RtAc, RtMe, and RtHMe). The results showed that, RtHMe extracts of R. tuberosa was rich in total phenolic content, i. e., 1.60 mgGAE/g dry extract, while highest total flavonoid content was found in RtAc extract, i. e., 0.40 mgQE/g. RtMe showed effective antioxidant activity (%RSA: 58.16) at the concentration of 120 μL. RtMe, RtEA and RtHMe exhibited effective in vitro antibacterial activity against Gram-negative bacteria (E. coli). In silico docking studies revealed that paucifloside (-11.743 kcal/mol), indole-3-carboxaldehyde (-7.519 kcal/mol), nuomioside (-7.275 kcal/mol), isocassifolioside (-6.992 kcal/mol) showed best docking score against PDB ID 2EX8 [penicillin binding protein 4 (dacB) from Escherichia coli, complexed with penicillin-G], PDB ID 6CQA (E. coli dihydrofolate reductase protein complexed with inhibitor AMPQD), PDB ID 2Y2I [Penicillin-binding protein 1B in complex with an alkyl boronate (ZA3)] and PDB ID 2OLV (from S. aureus), respectively. Docked phytochemicals also showed good drug likeness properties.


[Regeneration of the liver under the influence of E. coli endotoxin].
Studies were conducted into regeneration of rat liver exposed to the action of E. coli endotoxin, following two-third resection. No accelerated regeneration was found to take place in the wake of two-third hepatectomy and following postoperative intraperitoneal administration of E. coli endotoxin. However, regeneration was accelerated with significance in response to preoperative administration of 0.1 mg/kg body weight of E. coli endotoxin (B 5:55 DIFCO).


Primary results of the HABIT Trial (heart failure assessment with BNP in the home).
This study was a multicenter, single-arm, double-blinded observational prospective clinical trial designed to monitor daily concentrations of B-type natriuretic peptide (BNP) and to determine how these concentrations correlate with acute clinical heart failure decompensation (ADHF) and related adverse clinical outcomes in at-risk HF patients. Although BNP at discharge is predictive of 30-day outcomes, outpatient serial testing may improve the risk of detecting early decompensation. A total of 163 patients with HF signs and symptoms of ADHF discharged from the hospital or in an outpatient setting measured their weight and BNP levels daily for 60 days with a finger-stick test. Patients and physicians were blinded to BNP levels. The composite outcome was ADHF events: cardiovascular death, admission for decompensated HF, or clinical HF decompensation requiring either parenteral HF therapy or changes in oral HF medications. A total of 6,934 daily BNP values were recorded, with a median of 46 measures per patient over a monitoring period of 65 days. Forty patients had 56 events. Correlations between BNP measures weakened over time, and the dispersion between BNP measures grew. During 10,035 patient-days, there were 494 (4.9%) days of weight gain (≥5 lbs). The hazard ratio per unit increase of ln BNP was 1.84, and the hazard ratio on a day of weight gain was 3.63. These effects retained significance when controlling for symptoms. When the monitoring period for each subject was broken into intervals based on ADHF events, there were 39 (18.4%) intervals of upward trending BNP corresponding to a risk increase of 59.8% and 64 (30.2%) downward trending intervals corresponding to a risk decrease of 39.0%. There were 94 (44.3%) intervals with 1 or more days of weight gain corresponding to a risk increase of 26.1%. This pilot study demonstrates that home BNP testing is feasible and that trials using home monitoring for guiding therapy are justifiable in high-risk patients. Daily weight monitoring is complementary to BNP, but BNP changes correspond to larger changes in risk, both upward and downward. (Heart Failure [HF] Assessment with B-type Natriuretic Peptide [BNP] In the Home [HABIT]; NCT00946231).


Does body appreciation or satisfaction buffer against idealised functionality-focused images of models?
Research suggests that greater levels of body appreciation and body satisfaction may protect women from negative outcomes when viewing media images of the thin-ideal. In this study, we compared the effectiveness of body appreciation and body satisfaction in ameliorating negative effects from viewing images of the traditional thin-ideal and the newer functional-ideal (i.e., models presented in active stances with a focus on the function of their body). A sample of 122 women (Mage = 24.43 years) from a regional university and the general community was recruited to complete an online study. Participants were randomly allocated to view images of models presented in either an active or posed stance, or images of scenery. Participants completed pre- and post-test measures of appearance and functionality satisfaction, as well as trait measures of body appreciation and satisfaction. Results showed that women had poorer outcomes after viewing the active but not the posed or scenery images. Neither body appreciation nor body satisfaction moderated effects. Active, functional images may be particularly insidious and further research is needed to identify effective protective strategies.


Factors Predictive of Weight Gain and Implications for Modeling in Type 2 Diabetes Patients Initiating Metformin and Sulfonylurea Combination Therapy.
The objectives of this study were to (a) assess the factors associated with weight gain in a population of type 2 diabetes patients escalating from metformin (M) to M+ sulfonylurea (M + S) and (b) evaluate whether healthcare resource utilization associated with being overweight or obese is underestimated in typical health economic evaluations. The study was a retrospective cohort study using UK Clinical Practice Research Datalink linked to Hospital Episode Statistics (CPRD/HES) data. The association between baseline phenotypic factors and weight gain was assessed using logistic regression. Hospitalization incidence rates per 1000 person-years for major diabetes-related complications according to body mass index (BMI) at baseline were estimated from the data (observed) and compared to those obtained from a validated diabetes model (predicted). 11,071 patients were included in the analysis; approximately 40% gained weight in the first year following escalation to M + S. Baseline age, HbA1c and gender were found to be predictors of weight gain [odds ratios 0.99 (1-year increment), 1.11 (1% increment) and 0.81 (female vs male), respectively, p < 0.001]. Observed vs predicted incidence rates of hospitalization were 265 vs 13 (normal), 297 vs 31 (overweight), 223 vs 50 (obese) and 378 vs 41 (severe obese). This analysis suggests there are identifiable patient characteristics predictive of weight gain that may be informative to clinical and economic decision making in the context of patients escalating from M to an M + S regimen. Hospital admissions in people with type 2 diabetes were generally under-predicted. A particular focus of future research should be the need for diabetes models to make the likelihood of experiencing an event conditional on BMI. Takeda Development Centre Europe Ltd., UK.


Effect of indomethacin on modest pressure natriuresis in chloralose-anesthetized, non-laparotomized dogs.
To determine if indomethacin (indo) would attenuate the effects of changed renal perfusion pressure on sodium excretion as reported by others, we performed clearance studies in chloralose-anesthetized dogs without the major stress of laparotomy. Mean renal arterial pressure was varied by a balloon-tipped catheter indwelling the aorta suprarenally. With pressure decreases to mean values above 85 mm Hg during isotonic saline infusion, sodium output decreased only by 10.7 +/- 2.4% per 10 mm Hg pressure decrease without indo pre-treatment but decreased by 22.0 +/- 3.8% per 10 mm Hg pressure decrease with indo pre-treatment. The greater, rather than lesser, pressure effect on excretory function after indo in these experiments with chloralose anesthesia suggest that renal prostaglandin (PG) activity does not mediate normally pressure natriuresis. Instead, the data suggest that, in the absence of major stress, the renal pressure effects on excretory function may become more sensitive after indo. In addition, we postulate that the normal acute pressure natriuresis may be modest and may average no more than 20% change for each 10 mm Hg change in mean pressure above 90 mm Hg when stress is minimal and when vasoactive preglomerular autoregulation is nearly perfect. This is a phenomenon which keeps intrarenal tissue pressure and urine output relatively constant with arterial pressure elevations.


NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)alpha-mediated cardiovascular effects.
Activation of peroxisome proliferator activated receptor (PPAR)alpha and its protective role in cardiovascular function has been reported but the exact mechanism(s) involved is not clear. As we have shown that PPARalpha ligands increased nitric oxide (NO) production and cardiovascular function is controlled by a balance between NO and free radicals, we hypothesize that PPARalpha activation tilts the balance between NO and free radicals and that this mechanism defines the protective effects of PPARalpha ligands on cardiovascular system. Systolic blood pressure (SBP) was greater in PPARalpha knockout (KO) mice compared with its wild type (WT) litter mates (130+/-10 mmHg versus 107+/-4 mmHg). L-NAME (100mg/L p.o.), the inhibitor of NO production abolished the difference between PPARalpha KO and WT mice. In kidney homogenates, tissue lipid hydroperoxide generation was greater in KO mice (11.8+/-1.4 pM/mg versus 8.3+/-0.6 pM/mg protein). This was accompanied by a higher total NOS activity (46+/-6%, p<0.05) and a approximately 3 fold greater Ca2+-dependent NOS activity in kidney homogenates of untreated PPARalpha WT compared with the KO mice. Clofibrate, a PPARalpha ligand, increased NOS activity in WT but not KO mice. Bezafibrate (30 mg/kg) reduced SBP in conscious rats (19+/-4%, p<0.05), increased urinary NO excretion (4.06+/-0.53-7.07+/-1.59 microM/24 h; p<0.05) and reduced plasma 8-isoprostane level (45.8+/-15 microM versus 31.4+/-8 microM), and NADP(H) oxidase activity (16+/-5%). Implantation of DOCA pellet (20mg s.c.) in uninephrectomized mice placed on 1% NaCl drinking water increased SBP by a margin that was markedly greater in KO mice (193+/-13 mmHg versus 130+/-12 mmHg). In the rat, DOCA increased SBP and NAD(P)H oxidase activity and both effects were diminished by clofibrate. In addition, clofibrate reduced ET-1 production in DOCA/salt hypertensive rats. Thus, apart from inhibition of ET-1 production, PPARalpha activation exerts protective actions in hypertension via a mechanism that involves NO production and/or inhibition of NAD(P)H oxidase activity.


Polyarthritis with atypical keratotic nodular dermatosis or polyarthritis with multiple keratoacanthoma. A case report.
We report an interesting case of generalized papular and nodular lesions with central keratinous plugs and severe hyperkeratotic-acanthotic histopathology with arthritis in a 19-year-old male patient who had suffered from a similar disease 2 years earlier. Papules and nodules erupted a few days after the arthritis and this was noticed during both episodes. On healing, nodules fell spontaneously leaving behind insignificant hyperpigmented scars.


Gas chromatography coupled to mass spectrometry analysis of volatiles, sugars, organic acids and aminoacids in Valencia Late orange juice and reliability of the Automated Mass Spectral Deconvolution and Identification System for their automatic identification and quantification.
Neutral volatiles and non-volatile polar compounds (sugars, organics acids and aminoacids) present in Valencia Late orange juice have been analysed by Gas Chromatography coupled to Mass Spectrometry (GC-MS). Before analysis, the neutral volatiles have been extracted by Headspace-Solid Phase Microextraction (HS-SPME), and the non-volatile polar compounds have been transformed to their corresponding volatile trimethylsilyl (TMS) derivatives. From the resulting raw GC-MS data files, the reliability of the Automated Mass Spectral Deconvolution and Identification System (AMDIS) to perform accurate identification and quantification of the compounds present in the sample has been tested. Hence, both raw GC-MS data files have been processed automatically by using AMDIS and manually by using Xcalibur™, the manufacturer's data processing software for the GC-MS platform used. Results indicate that the reliability of AMDIS for accurate identification and quantification of the compounds present in the sample strongly depends on a number of operational settings, for both the MS and AMDIS, which must be optimized for the particular type of assayed sample. After optimization of these settings, AMDIS and Xcalibur™ yield practically the same results. A total of 85 volatiles and 22 polar compounds have been identified and quantified in Valencia Late orange juice.


Skin-prick test preparations of Dermatophagoides pteronyssinus for prediction of a positive response to provocation testing.
Skin-prick testing (SPT) with allergen is widely used in the investigation of respiratory disease, yet its relationship to the results of provocation testing of the nose or bronchus remains obscure. We have studied this relationship by determining the concentration of Dermatophagoides pteronyssinus extract and the associated weal size which resulted in the lowest 'false positive' (FP) and highest 'true positive' (TP) rates when compared to the results of bronchial and nasal provocation testing. Subjects studied included those with both positive and negative bronchial or nasal provocation tests. For each of a series of concentrations of D. pteronyssinus extract, standardized in relation to content of Der pI antigen, receiver operating characteristic (ROC) curves of TP against FP rates were constructed. Optimal diagnostic concentrations for SPT were 0.112-1.122 x 10(6) IU of Der pI ml-1. However, at the lower end of this range the optimum weal areas for a positive test with the D. pteronyssinus extract were very small (less than 5 mm2). More appropriate concentrations for use in clinical practice were 0.56-1.122 x 10(6) IU Der pI ml-1 since at these concentrations more easily measurable weal areas of 5-10 mm2 (2.6-3.6 mm diameter) were almost equally predictive of a positive provocation test.


Measures of Connectivity and Dorsolateral Prefrontal Cortex Volumes and Depressive Symptoms Following Treatment With Selective Serotonin Reuptake Inhibitors in Adolescents.
Selective serotonin reuptake inhibitors (SSRIs) are considered a first-line pharmacological treatment for adolescent depression with moderate or higher levels of symptom severity. Thus, it is important to understand neurobiological changes related to SSRIs during the course of treatment for adolescents with depression. To examine neurobiological changes associated with SSRI treatment in adolescents with major depressive disorder (MDD) by measuring longitudinal changes in volume and resting-state functional connectivity (rsFC) in the dorsolateral prefrontal cortex (DLPFC), a core region of cognitive control. This cohort study was conducted with an open-label design. Adolescents with MDD and healthy controls were recruited at the Seoul National University Hospital (Seoul, South Korea). Adolescents with MDD were treated with escitalopram for 8 weeks. Data analysis was conducted between April 2021 and February 2022. Depressive symptoms were assessed using the Children's Depression Rating Scale-Revised. The outcome measure was defined as the change in Children's Depression Rating Scale-Revised scores from week 0 (before treatment) to week 8 (after treatment) or upon termination. Participants completed structural and resting-state functional magnetic resonance imaging (rsfMRI) assessments before (week 0) and after (week 8) SSRI treatment. Repeated measures analysis of variance and liner mixed model analyses were used to examine the longitudinal associations of SSRI treatment with DLPFC volume and rsFC between responders who showed at least a 40% decrease in depressive symptoms and nonresponders who did not. Ninety-five adolescents with MDD and 57 healthy controls were initially recruited. The final analyses of volume included 36 responders (mean [SD] age, 15.0 [1.6] years; 25 girls [69.4%]) and 26 nonresponders (mean [SD] age, 15.3 [1.5] years; 19 girls [73.1%]). Analyses of rsFC included 33 responders (mean [SD] age, 15.2 [1.5] years; 21 girls [63.6%]) and 26 nonresponders (mean [SD] age, 15.3 [1.5] years; 19 girls [73.1%]). The longitudinal associations of SSRI treatment were more evident in responders than in nonresponders. Responders showed significantly increased right DLPFC volume, decreased bilateral DLPFC rsFC with the superior frontal gyri, and decreased left DLPFC rsFC with the ventromedial PFC after treatment compared with before treatment. Furthermore, increased right DLPFC volume was correlated with decreased rsFC between the right DLPFC and superior frontal gyri after SSRI treatment. The preliminary results of this cohort study suggest that the DLPFC volumetric and rsFC changes may serve as potential neurobiological treatment markers that are associated with symptom improvement in adolescents with MDD.


Multifactorial Characteristics of Pediatric Dizziness and Imbalance.
To examine the relative prevalence of individual diagnoses in children and adolescents presenting with dizziness and/or imbalance, and to assess the proportion of patients assigned multiple contributing diagnoses. Retrospective cohort study. We retrospectively reviewed our internal database of all patients seen at our pediatric vestibular program between January 2012 and March 2019 to determine the incidence of common diagnoses and groups of diagnoses for patients ages 21 or younger. One thousand twenty-one patients were included with a mean age of 12.5 ± 4.9 years (range: 9 months-21 years). Of this total, 624 patients were female and 397 were male. Common diagnoses included vestibular migraine (VM; 35.0%), benign paroxysmal positional vertigo (BPPV; 21.6%), primary dysautonomia (15.7%), anxiety disorder (13.5%), and persistent postural perceptual dizziness (PPPD; 11.2%). A high proportion of patients (44.4%) received multiple contributing diagnoses. VM was frequently diagnosed with BPPV or PPPD, and 22 patients were diagnosed with all three concurrently. The causes of dizziness and imbalance in the pediatric population are diverse, and many patients have multiple diagnoses that are often interrelated. It is important that providers recognize that the causes of vestibular symptoms in children and adolescents may be multifactorial and may span across multiple specialties. 4 Laryngoscope, 131:E1308-E1314, 2021.


Acute kidney injury and renal regional oxygen saturation during aortic arch reconstruction in infants.
Acute kidney injury is a serious postoperative complication following cardiac surgery. The aortic arch repair technique using antegrade selective cerebral perfusion has been used, but it is unclear whether subdiaphragmatic organs such as the kidneys are perfused adequately. The authors compared intraoperative renal regional oxygen saturation using near-infrared spectroscopy between infants with and without postoperative acute kidney injury after undergoing aortic arch reconstruction. Retrospective medical records review. University medical center. Elective cardiac surgical infants. The author reviewed the perioperative clinical records of infants who underwent aortic arch reconstruction surgery using antegrade selective cerebral perfusion. During the operation, prestenotic (right radial or right brachial artery) and poststenotic (femoral or umbilical artery) invasive arterial blood pressure and cerebral and renal regional oxygen saturation were monitored continuously. Development of acute kidney injury within 72 hours of surgery was investigated. A total of 47 patients were enrolled in this study. Postoperative acute kidney injury occurred in 19 patients (40.4%). Intraoperative renal regional oxygen saturation was similar between patients with and without acute kidney injury. Intraoperative prestenotic and poststenotic mean arterial blood pressure and cerebral regional oxygen saturation also were similar between the 2 groups. The intraoperative renal tissue oxygen saturation was not different between the groups with or without postoperative acute kidney injury in infants who underwent aortic arch repair using antegrade selective cerebral perfusion.


Revision of subcutaneous implantable cardioverter defibrillator to intermuscular pocket to prevent inappropriate shocks.
Sensing and defibrillation threshold for a S-ICD are impacted by positioning at implant or revision. The intermuscular pocket prevents device migration and provides appropriate, stable sensing vectors.


Dietary exposure to 5-hydroxymethylfurfural from Norwegian food and correlations with urine metabolites of short-term exposure.
5-Hydroxymethylfurfural (HMF) is formed in carbohydrate-rich food during acid-catalysed dehydration and in the Maillard reaction from reducing sugars. HMF is found in mg quantities per kg in various foods. HMF is mainly metabolised to 5-hydroxymethyl-2-furoic acid (HMFA), but unknown quantities of the mutagenic 5-sulphoxymethylfurfural (SMF) may also be formed, making HMF potentially hazardous to humans. We determined the HMF content in Norwegian food items and estimated the dietary intake of HMF in 53 volunteers by means of 24h dietary recall. The estimated intakes of HMF were correlated with urinary excretion of HMFA. Coffee, prunes, dark beer, canned peaches and raisins had the highest levels of HMF. The 95th percentile of the estimated daily dietary intake of HMF and the 24h urinary excretion of HMFA were 27.6 and 28.6mg, respectively. Coffee, dried fruit, honey and alcohol were identified as independent determinants of urinary HMFA excretion. Most participants had lower estimated HMF intake than the amount of HMFA excreted in urine. In spite of this there was a significant correlation (r=0.57, P<0.001) between the estimated HMF intake and urinary HMFA. Further studies are needed to reveal alternative sources for HMF exposure.


Future Trends in Disability and Its Determinants Among Chinese Community Patients With Anxiety Disorders: Evidence From a 5-Year Follow-Up Study.
Background: Anxiety disorders (ADs) are a group of disorders with a high disability rate and bring a huge social burden. In China, information on future trends in the disability among community ADs patients and its determinants are rare. The objectives of this study are to describe the future trends in the disability among ADs patients living in community and to investigate the determinants of the disability. Methods: Participants diagnosed with 12-month ADs in the China Mental Health Survey (CMHS) were followed up by telephone from April to June 2018 to assess the future trends in the disability in a 5-year interval using the World Health Organization's Disability Assessment Schedule 2.0. The disability rate was reported and its determinants were analyzed by complex sample design multivariate logistic regression. Results: Totally 271 patients were interviewed by telephone and 33 informants finished proxy interviews. The disability rates were 45.9% and 14.3% among ADs patients at baseline and during the follow-up. Patients with general anxiety disorder (GAD) or agoraphobia with/without panic disorder (AGP) had the lower decrease and higher disability during the follow-up than patients with other subtypes. Patients aged in middle age (aged 40-49 years old, OR = 11.12, 95% CI: 4.16-29.72), having disability at baseline (OR = 7.18, 95% CI: 1.37-37.73), having comorbidity with three or more physical diseases (OR = 9.27, 95% CI: 2.48-34.71), and having comorbidity with other mental disorders (OR = 3.97, 95% CI: 1.13-13.96) had higher disability during the follow-up. Conclusions: The disability rate tends to decrease among ADs patients living in communities. Treatment priority should be given for ADs patients with disability and those in middle age. Treatments for the comorbidity of other mental disorders or physical diseases should be considered when treating anxiety.


A colorimetric titration method for quantification of millimolar glucose in a pH 7.4 aqueous phosphate buffer.
3-Pyridinylboronic acid is identified as a key sensing element for reversible sugar complexation in an aqueous solution at the physiological pH. The utility of a sensing element has been demonstrated through a simple colorimetric titration of glucose using absorption spectroscopy in the visible region. The mechanism of the high diol/triol binding affinity of pyridine boronic acid in the neutral pH is discussed based on the 1H and 11B NMR spectroscopic studies.


Knockdown of menin affects pre-mRNA processing and promoter fidelity at the interferon-gamma inducible IRF1 gene.
The tumor suppressor menin (MEN1) is mutated in the inherited disease multiple endocrine neoplasia type I, and has several documented cellular roles, including the activation and repression of transcription effected by several transcription factors. As an activator, MEN1 is a component of the Set1-like mixed lineage leukemia (MLL) MLL1/MLL2 methyltransferase complex that methylates histone H3 lysine 4 (H3K4). MEN1 is localized to the signal transducer and activator of transcription 1 (STAT1)-dependent gene, interferon regulatory factor 1 (IRF1), and is further recruited when IRF1 transcription is triggered by interferon-γ signaling. RNAi-mediated knockdown of MEN1 alters the H3K4 dimethylation and H3 acetylation profiles, and the localization of histone deacetylase 3, at IRF1. While MEN1 knockdown does not impact the rate of transcription, IRF1 heteronuclear transcripts become enriched in MEN1-depleted cells. The processed mRNA and translated protein product are concomitantly reduced, and the antiviral state is attenuated. Additionally, the transcription start site at the IRF1 promoter is disrupted in the MEN1-depleted cells. The H3K4 demethylase, lysine specific demethylase 1, is also associated with IRF1, and its inhibition alters H3K4 methylation and disrupts the transcription start site as well. Taken together, the data indicate that MEN1 contributes to STAT1-activated gene expression in a novel manner that includes defining the transcription start site and RNA processing.


Timing of midstream urine culture before endourological procedure-can we do better?-A comparative study.
Endourological procedures are the mainstay of treatment for stone disease in the upper urinary system. Infection is a common complication, and urine cultures (UC) are often obtained preoperatively. In this study, we sought to investigate the role of positive UC in the 90 days prior to surgery (90PreOp) in predicting postoperative infectious complications in comparison to a single positive preoperative UC (PreOP). We compared the correlation between positive PreOp UCs and positive 90PreOp UCs with postoperative urosepsis, and a positive UC obtain proximal to obstruction (Prox UC) during percutaneous nephrolithotomy, ureteroscopy and a placement of nephrostomy tube or ureteral stent. Data from 140 consecutive patients were collected. PreOp UCs were positive in 15 (11%) of patients versus 31 of 140 (22%) positive 90PreOp UCs. All six sepsis events had a positive 90PreOp UC, and five had a positive PreOp UC. Fourteen (93.3%) out of 15 positive Prox UC had a positive 90PreOp UC, whereas only 7 (38.9%) had a positive 90PreOp UC. Positive 90PreOp UC outperformed PreOp UC in predicting positive Prox UC, OR = 12.8 (95% CI 3.70-44.30, p < 0.001), versus OR of 88.9 (95% CI 11.0-720.7, p < 0.001); sensitivity 93%(95% CI 68-100%) versus 47%(95% CI 21-73%); as well as area under the ROC curve(AUC), 0.90 (CI 0.80-0.95) for 90PreOp versus 0.70 (CI 0.56-0.82) for positive Prox UC. Uropathogen persistence was better identified when using 90PreOp UC (27%) than using PreOp UC (12%). We suggest reviewing UCs taken within 90 days preoperatively as this was found superior to a single preoperative midstream UCs in predicting postoperative infectious sequela after stone procedure.


Psychometric evaluation of the Urgency NRS as a new patient-reported outcome measure for patients with ulcerative colitis.
The Urgency Numeric Rating Scale (NRS) was developed as a content-valid single-item patient-reported outcome measure to assess severity of bowel urgency. Here, we evaluated the psychometric properties of the Urgency NRS. Data were from a multicenter, randomized, placebo-controlled phase 3 trial in adults with moderately to severely active ulcerative colitis (NCT03518086). Patients completed the Urgency NRS using a daily electronic diary, from which weekly average Urgency NRS scores were calculated. Test-retest reliability, known-groups validity, construct validity, responsiveness, and score interpretation were assessed using the modified Mayo score, Inflammatory Bowel Disease Questionnaire (IBDQ), Patient Global Rating of Severity (PGRS), Patient Global Rating of Change (PGRC), and Geboes score. The study sample comprised 1,162 participants (40.2% female). Mean Urgency NRS score was higher (worse) at baseline than at week 12 (6.2 vs. 3.7). Test-retest reliability was strong, with intra-class correlation coefficients of 0.76-0.89. Baseline least-square mean Urgency NRS score was higher for participants with a PGRS score greater than the median (worse symptoms) than for those with a PGRS score less than or equal to the median (7.5 vs. 5.4; p < 0.0001), indicating good known-groups validity. Urgency NRS score was moderately correlated with IBDQ total and domain scores, PGRS, PGRC, and modified Mayo stool frequency, establishing its convergent validity. Correlations were weak for Geboes score and weak to moderate for modified Mayo endoscopic subscore and modified Mayo rectal bleeding, indicating that the Urgency NRS also had discriminant validity. Patients achieving clinical remission, clinical response, IBDQ remission, and PGRS score improvement showed significantly greater improvement on the Urgency NRS (p < 0.0001 for all), demonstrating responsiveness to change. A ≥ 3-point improvement in Urgency NRS score represented a meaningful improvement in bowel urgency and an Urgency NRS score of ≤ 1 point represented a bowel urgency remission threshold that was closely associated with clinical, endoscopic, and histologic remission. The Urgency NRS is a valid and reliable patient-reported outcome measure that is suitable for evaluating treatment benefits in clinical trials in patients with moderately to severely active ulcerative colitis.


High-Intensity Resistance and Impact Training Improves Bone Mineral Density and Physical Function in Postmenopausal Women With Osteopenia and Osteoporosis: The LIFTMOR Randomized Controlled Trial.
Optimal osteogenic mechanical loading requires the application of high-magnitude strains at high rates. High-intensity resistance and impact training (HiRIT) applies such loads but is not traditionally recommended for individuals with osteoporosis because of a perceived high risk of fracture. The purpose of the LIFTMOR trial was to determine the efficacy and to monitor adverse events of HiRIT to reduce parameters of risk for fracture in postmenopausal women with low bone mass. Postmenopausal women with low bone mass (T-score < -1.0, screened for conditions and medications that influence bone and physical function) were recruited and randomized to either 8 months of twice-weekly, 30-minute, supervised HiRIT (5 sets of 5 repetitions, >85% 1 repetition maximum) or a home-based, low-intensity exercise program (CON). Pre- and post-intervention testing included lumbar spine and proximal femur bone mineral density (BMD) and measures of functional performance (timed up-and-go, functional reach, 5 times sit-to-stand, back and leg strength). A total of 101 women (aged 65 ± 5 years, 161.8 ± 5.9 cm, 63.1 ± 10.4 kg) participated in the trial. HiRIT (n = 49) effects were superior to CON (n = 52) for lumbar spine (LS) BMD (2.9 ± 2.8% versus -1.2 ± 2.8%, p < 0.001), femoral neck (FN) BMD (0.3 ± 2.6% versus -1.9 ± 2.6%, p = 0.004), FN cortical thickness (13.6 ± 16.6% versus 6.3 ± 16.6%, p = 0.014), height (0.2 ± 0.5 cm versus -0.2 ± 0.5 cm, p = 0.004), and all functional performance measures (p < 0.001). Compliance was high (HiRIT 92 ± 11%; CON 85 ± 24%) in both groups, with only one adverse event reported (HiRIT: minor lower back spasm, 2/70 missed training sessions). Our novel, brief HiRIT program enhances indices of bone strength and functional performance in postmenopausal women with low bone mass. Contrary to current opinion, HiRIT was efficacious and induced no adverse events under highly supervised conditions for our sample of otherwise healthy postmenopausal women with low to very low bone mass. © 2017 American Society for Bone and Mineral Research.


An injectable hydrogel based on hyaluronic acid prepared by Schiff base for long-term controlled drug release.
Drug-loaded injectable hydrogels have been studied widely in biomedical technology while the stable long-term controlled drug release and cytotoxicity are challenges. In this work, an injectable hydrogel with good swelling resistance was in situ synthetized using aminated hyaluronic acid (NHA) and aldehyde β-cyclodextrin (ACD) via Schiff base reaction. The composition, morphology and mechanical property were characterized with FTIR, 13C NMR, SEM and rheology test, respectively. Voriconazole (VCZ) and Endophthalmitis was selected as a model drug and disease, respectively. The drug release, cytotoxicity and antifungal properties were detected in vitro. The results showed a long-term (> 60 days) drug release was realized, the NHA/ACD2/VCZ presented a zero-order release in the later stage. The cytotoxicity of NHA/ACD was detected by live/dead staining assay and Cell Counting Kit-8 (CCK-8). The survival rate of adult retina pigment epithelial cell line-19 (ARPE-19) was over 100 % after 3 d, it indicated a good cytocompatibility. The antifungal experiment presented samples had antifungal property. Biocompatibility in vivo proved NHA/ACD2 had no adverse effects on ocular tissues. Consequently, the injectable hydrogel based on hyaluronic acid prepared by Schiff base reaction provides a new option for long-term controlled drug release in the course of disease treatment from a material perspective.


Population pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass grafting.
Midazolam is commonly used for short-term postoperative sedation of patients undergoing cardiac surgery. The purpose of this multicenter study was to characterize the pharmacokinetics and intersubject variability of midazolam in patients undergoing coronary artery bypass grafting. With institutional review board approval, 90 consenting patients undergoing coronary artery bypass grafting were enrolled at three study centers. All subjects received sufentanil and midazolam via target-controlled infusions. After operation, midazolam was titrated to maintain deep sedation for at least 2 h. It was then titrated downward to decrease sedation for a minimum of 4 h more and was discontinued before tracheal extubation. Arterial blood samples were taken throughout the study and were assayed for midazolam and 1-hydroxymidazolam. Midazolam population pharmacokinetic parameters were estimated using NONMEM. Cross-validation was used to estimate the performance of the model. The pharmacokinetics of midazolam were best described by a simple three-compartment mammillary model. Typical pharmacokinetic parameters were V1 = 32.2 l, V2 = 53 l, V3 = 245 l, Cl1 = 0.43 l/min, Cl2 = 0.56 l/min, and Cl3 = 0.39 l/min. The calculated elimination half-life was 15 h. The median absolute prediction error was 25%, with a bias of 1.4%. The performance in the cross-validation was similar. Midazolam metabolites were clinically insignificant in all patients. The intersubject variability and predictability of the three-compartment pharmacokinetic model are similar to those of other intravenous anesthetic drugs. This multicenter study did not confirm previous studies of exceptionally large variability of midazolam pharmacokinetics when used for sedation in intensive care settings.


Accumulation of extracellular ATP protects against acute reperfusion injury in rat heart endothelial cells.
Ischemia-reperfusion provokes barrier failure of the coronary microvasculature, leading to myocardial edema development that jeopardizes functional recovery of the heart during reperfusion. Here, we tested whether adenosine 5'-triphosphate (ATP), either exogenously applied or spontaneously released during reperfusion, protects the endothelial barrier against an imminent reperfusion injury and whether interventions preventing ATP breakdown augment this protective ATP effect. Cultured microvascular coronary endothelial monolayers and isolated-perfused hearts of rat were used. After ischemic conditions were induced, reperfusion of endothelial monolayers activated the endothelial contractile machinery and caused intercellular gap formation. It also led to the release of ATP. When its breakdown was inhibited by 6-N,N-diethyl-beta,gamma-dibromomethylene-D-ATP (ARL 67156; 100 microM), a selective ectonucleotidase inhibitor, contractile activation and gap formation were significantly reduced. Reperfusion in the presence of exogenously added ATP (10 microM) plus ARL caused an additional reduction of both aforementioned effects. In contrast, elevation of ATP degradation by apyrase (1 U/ml), a soluble ectonucleotidase, or addition of adenosine (10 microM) provoked an increase in gap formation during reperfusion that could be completely inhibited by 8-phenyltheophylline (8-PT; 10 microM), an adenosine receptor antagonist. In Langendorff-perfused rat hearts, the reperfusion-induced increase in water content was significantly reduced by ARL plus ATP. Under conditions favouring ATP degradation, an increase in myocardial edema was observed that could be blocked by 8-PT. ATP, either released from cells or exogenously applied, protects against reperfusion-induced failure of the coronary endothelial barrier. Inhibition of ATP degradation enhances the stabilizing effect of ATP on barrier function.


Local Control after Locally Ablative, Image-Guided Radiotherapy of Oligometastases Identified by Gallium-68-PSMA-Positron Emission Tomography in Castration-Sensitive Prostate Cancer Patients (OLI-P).
Progression of prostate-specific antigen (PSA) values after curative treatment of prostate cancer patients is common. Prostate-specific membrane antigen (PSMA-) PET imaging can identify patients with metachronous oligometastatic disease even at low PSA levels. Metastases-directed local ablative radiotherapy (aRT) has been shown to be a safe treatment option. In this prospective clinical trial, we evaluated local control and the pattern of tumor progression. Between 2014 and 2018, 63 patients received aRT of 89 metastases (MET) (68 lymph node (LN-)MET and 21 bony (OSS-)MET) with one of two radiation treatment schedules: 50 Gy in 2 Gy fractions in 34 MET or 30 Gy in 10 Gy fractions in 55 MET. The mean gross tumor volume and planning target volume were 2.2 and 14.9 mL, respectively. The median follow-up time was 40.7 months. Local progression occurred in seven MET, resulting in a local control rate of 93.5% after three years. Neither treatment schedule, target volume, nor type of lesion was associated with local progression. Regional progression in the proximity to the LN-MET was observed in 19 of 47 patients with at least one LN-MET (actuarial 59.3% free of regional progression after 3 years). In 33 patients (52%), a distant progression was reported. The median time to first tumor-related clinical event was 16.6 months, and 22.2% of patients had no tumor-related clinical event after three years. A total of 14 patients (22%) had another aRT. In conclusion, local ablative radiotherapy in patients with PSMA-PET staged oligometastatic prostate cancer may achieve local control, but regional or distant progression is common. Further studies are warranted, e.g., to define the optimal target volume coverage in LN-MET and OSS-MET.


Evaluation of grey-scale standard display function as a calibration tool for diagnostic liquid crystal display monitors using psychophysical analysis.
The digital imaging and communications in medicine (DICOM) standard proposed the grey-scale standard display function (GSDF) as a calibration tool for making the gradation characteristic of a radiographic output image consistent. This is designed in such a manner that the contrast visually recognised by observers (called psychophysical contrast) becomes a constant for all digital driving levels. The DICOM standard calls such an ideal characteristic perceptual linearisation. The psychophysical gradient that can express the psychophysical contrast was introduced for the evaluation of the GSDF using a liquid crystal display monitor. Investigations regarding its ability to yield a constant psychophysical contrast, independent of the digital driving level change and under an actual observation environment, such as for clinical radiographic diagnosis in hospital, were carried out. The psychophysical gradients of the GSDF were obtained for two kinds of observation environment: one was a restricted environment such as in a dark room, under steady-state adaptation, using the sinusoidal grading pattern corresponding to the peak frequency of the human eye response. The other was an actual environment reflecting that encountered during clinical diagnosis in a hospital. As a result, the psychophysical gradient under the restricted environment became almost constant and independent of the change in digital driving level, i.e. perceptual linearisation could be satisfied. Furthermore, under the actual observation environment, the psychophysical gradient decreased gradually with the increase in digital driving level, i.e. the perceptual linearisation could not be satisfied. The percentage decrease in the value of the psychophysical gradient at the maximum luminance area was approximately 60% compared with that at the minimum luminance area. Accordingly, the GSDF is unsuitable as a calibration tool for the liquid crystal display monitor, which will be used in actual clinical diagnosis, as it cannot achieve 'perceptual linearisation' under the actual environment. For the purpose of clinical diagnosis, it is necessary to enlarge the physical gradient of GSDF further in the high digital driving level range (which relates to a high luminance area) to give an approximation that is as close to the idealised form as possible.


Pain management, morphine administration, and outcomes in preterm infants: a review of the literature.
Infants in the Neonatal Intensive Care Unit may experience a myriad of painful procedures and stressful experiences. Pain management for infants requiring mechanical ventilation is complex and challenging especially in the preterm population. Many infants may not receive analgesia, primarily due to the unknown long-term neurodevelopmental effects of morphine exposure on the developing brain. Currently, there is no consensus on how to treat pain related to mechanical ventilation due to conflicting scientific evidence lacks clarity and certainty about the role of morphine in pain in preterm infants. The Advance Practice Neonatal Nurse must make the best use of available information about morphine analgesia for the preterm infant, and use it to guide policy and practice for infants. The Advance Practice Neonatal Nurse must use his/her clinical expertise to judicially balance the risks and benefits of morphine analgesia, when used, and tailor the treatment plan to each infant's specific needs.


Stimulus-dependent myristoylation of a major substrate for protein kinase C.
Bacterial lipopolysaccharide (LPS), the major surface component of gram-negative bacteria, exerts a profound effect on the immune system by enhancing the release of proteins and arachidonic acid metabolites from macrophages (for review see ref. 1). The molecular mechanism(s) by which LPS induces these various secretory responses is unknown. We previously reported that LPS promotes the myristoylation of several macrophage proteins including one with a relative molecular mass (Mr) of 68K2. We have now found that by several criteria the 68K myristoylated protein is similar or identical to the 80/87K protein, a major specific substrate for protein kinase C (PKC) found in brain and fibroblasts (for review see refs 7,8). We have also found that the myristoylated PKC substrate is quantitatively associated with the membrane fraction. Myristoylation of the PKC substrate may target it to the membrane and constitute a transduction pathway for stimulus-response coupling.


[Evidence-based treatment and education programs--evaluation of complex interventions].
Patient education and treatment programmes are complex interventions that require a multiphased stepwise evaluation. The continuum of increasing evidence of effectiveness of structured treatment and teaching programmes for diabetes and hypertension as implemented in Germany is presented, and the indispensable components of the program and the conditions of their effective implementation are described.


Capturing the value of complementary and alternative medicine: including patient preferences in economic evaluation.
Complementary and alternative medicine (CAM) is growing in popularity among patients, for an increasing range of conditions. However, current provision of CAM in the National Health Service in the UK is limited, patchy and disparate, which results in considerable inequity and patient unease. This has led to an escalation in the debate about the role of CAM within the NHS. Lack of evidence about the cost effectiveness of CAM therapies compared with other forms of care is often cited as the main reason for the reluctance of funders to integrate CAM into mainstream service provision. Cost-effectiveness relies on evidence about costs and benefits. Cost data are relatively straightforward to collect but it has proved difficult to value the complete package of benefits offered by CAM, likely to be both process and outcome based, in a way that can be compared with alternatives. Stated preference discrete choice modelling (SPDCM), a method of healthcare evaluation growing in popularity, uses information about patient preferences to identify the important characteristics of an intervention or method of delivering care and how patients value these. SPDCM is a method that could be used to evaluate the 'added value' provided by CAM and thus supply evidence on cost-effectiveness that policy makers could use in configuring service provision.


The role of diacylglycerol and activation of protein kinase C in alpha 1A-adrenoceptor-mediated contraction to noradrenaline of rat isolated epididymal vas deferens.
1. The mechanism of contraction to noradrenaline (pEC50 5.6 +/- 0.1) in the rat epididymal vas deferens (mediated via alpha 1A-adrenoceptors) has been studied in functional experiments. 2. Contractions to noradrenaline at 10(-6) M were potentiated by the diacylglycerol (DAG) kinase inhibitor R 59022 (3 x 10(-7) M) from 49 +/- 4% to 63 +/- 3% maximum response and the time taken from initiation of contraction to the maximum response was reduced from 16 +/- 2 s to 9 +/- 1 s. The same contractions were not significantly potentiated by the DAG lipase inhibitor, U-57,908, 10(-5) M (51 +/- 2% control and 53 +/- 4% in the presence of U-57,908) nor was the time taken from initiation of contraction to the maximum response significantly altered (17 +/- 1 s control and 16 +/- 1 s in the presence of U-57,908). 3. Concentration-dependent contractions to noradrenaline (NA) were reduced by staurosporine (10(-7) M) and the selective protein kinase C inhibitor, calphostin C (10(-6) M) from 68 +/- 2% (NA, 3 x 10(-6) M) to 28 +/- 2% and 20 +/- 2% respectively and from 94 +/- 2% (NA, 3 x 10(-5) M) to 50 +/- 2% and 44 +/- 2% respectively. Contractions to K+ (40 +/- 2% maximum response to NA) were also significantly reduced by staurosporine (10(-7) M) (35 +/- 2%) but not by calphostin C (43 +/- 3%). 4. The phorbol ester, phorbol-12,13-dibutyrate (PDBu), produced a phasic, concentration-dependent contraction (10(-7) M - 10(-4) M) which was 41 +/- 2% of the maximum response to NA at 10(-4) M PDBu. The contraction to PDBu (10(-5) M) was reduced by calphostin C (10(-6) M) from 33 +/- 5% to 4 +/- 1% maximum response to NA. 5. Non-cumulative contractions to NA (10(-8) M - 10(-4) M) were abolished in Ca(2+)-free Krebs solution containing EGTA (1 mM) and were reduced in the presence of nifedipine (10(-6)M) in normal Krebs solution by 91 +/- 2% at 10(-4)M NA. The contraction to PDBu (10(-5)M, 33 +/- 5% maximum response to NA) was also abolished in Ca(2+)-free Krebs solution containing EGTA (1 mM) or by the presence of nifedipine (10(-6)M) in normal Krebs solution. 6. When NA (10(-4)M) was added to vasa deferentia in Ca(2+)-free Krebs solution containing EGTA (1 mM), following its wash out (and with EGTA later removed from the Krebs solution), readdition of Ca2+ (2.5 mM) to the Krebs solution produced no response. Cyclopiazonic acid (10(-5)M), which can deplete Ca2+ from intracellular stores, also produced no contraction. Therefore influx of extracellular Ca2+ is not a consequence of depletion of intracellular Ca2+ stores (capacitative Ca2+ influx). 7. Pre-incubation of tissues for 30 min with either cyclopiazonic acid (10(-5)M) or ryanodine (10(-4)M), which can both deplete intracellular Ca2+ stores, did not reduce the contractions to NA (3 x 10(-6)M). Pre-incubation of vasa deferentia with cyclopiazonic acid (1 or 3 min, when any rise in [Ca2+]i produced by cyclopiazonic acid might still exist) did not potentiate the contraction to PDBu (10(-5)M). Thus mobilization of intracellular Ca2+ may not be required for the activation of protein kinase C involved in these contractions. 8. In conclusion, the contraction of the rat epididymal vas deferens to NA mediated by alpha 1A-adrenoceptors appears to depend upon activation of protein kinase C by diacylglycerol, resulting in the influx of extracellular Ca2+ through voltage-gated Ca2+ channels. There was no evidence for a role of inositol trisphosphate in the contraction to noradrenaline in this tissue.


[Effects of moxibustion on cerebral cortical nitric oxide level and nitric oxide synthase activity in aging mice].
To explore the anti-aging effect of moxibustion of "Zusnali" (ST 36) and "Xuanzhong" (GB 39) in D-galactose induced aging mice. Thirty-three female Kunming mice (3 months old) were randomly divided into model group (n=11), saline control group (n=10), and moxibustion group (n=11). In addition, another 10 female mice (16 months old) were used as the physio-senility control (PSC) group. Senescent mouse model was established by subcutaneous injection of D-galactose (120 mg/kg x d(-1)) for 42 days. From the 13th day on after the first injection, moxibustion (3 cones/acupoint) was applied to bilateral ST36 and GB39, once every other day for one month. At the end of the treatment, the mice were killed under anesthesia for collecting cerebral cortex and cerebellar cortex separately. NO content and NOS activity were assayed by using nitrate reductase method and chemico-chromatometry respectively after homogenate and centrifugalization. Compared with saline control group, cerebral NO contents and NOS activity in physio-senility group and model group, cerebellar NO content in model group, cerebellar NOS activity in physio-senility and model groups increased considerably (P < 0.05, < 0.01). In comparison with model group, cerebral and cerebellar NO contents and NOS activity of moxibustion group lowered significantly (P < 0.05, 0.01). Moxibustion of ST36 and GB39 can significantly suppress aging induced increase of both NO content and NOS activity in cerebral and cerebellar cortical tissues in aged mice, suggesting an effective anti-aging effect of moxibustion.


Ultrastructural localization of rabies virus antigens in infected trigeminal ganglion of hamsters.
The trigeminal ganglion of hamsters infected with CVS strain of rabies virus was investigated by electron microscopy with peroxidase-labeled antibody. Major localization of virus antigens were the following three types of structures; rabies virion, cytoplasmic inclusion, and ribosomal granules consisting of Nissl body. Rabies virions in neurons were mostly found within the cluster of such ribosome-rich regions suggesting a close relationship between the two in the synthesis of virus antigen. The cytoplasmic inclusion appeared to be derived from ribosomal or allied particles with virus-specific antigens. The significance of results obtained is briefly discussed.


Surgical Indication and Approach are Associated with Transfusion in Hysterectomy for Benign Disease.
To identify pre-operative and intraoperative factors associated with the risk of red blood cell transfusion among women undergoing hysterectomy. A retrospective cohort study of hysterectomy for benign indications between January 1, 2011 - December 31, 2017. Patients receiving blood transfusion within 30 days of surgery were compared to patients who did not receive any transfusion. Multivariate logistic regression analysis was performed to identify clinical and surgical variables associated with blood transfusion. Among 171,940 women who underwent hysterectomy for benign indication, 4,667 (2.7%) required blood transfusion. The rate of transfusion was highest among patients with uterine fibroids (4.3%) and lowest in patients with genital prolapse (1.1%) (p < 0.05). Odds of blood transfusion were significantly elevated in patients undergoing hysterectomy for uterine fibroids compared to patients with genital prolapse (adjusted odds ratio [aOR] 1.36, 95% confidence interval [CI] 1.15 - 1.61). Other patient characteristics included body mass index, smoking, bleeding disorders, pre-operative sepsis, and American Society of Anesthesiologists score ≥ 2 (p < 0.05). Higher pre-operative hematocrit significantly decreased the risk of blood transfusion (aOR 0.84, 95% CI 0.84 - 0.85 per percent increase in hematocrit). Abdominal and vaginal hysterectomies were associated with greater odds of transfusion compared with laparoscopic approaches (aOR 5.06, 95% CI 4.70 - 5.44; aOR 1.87, 95% CI 1.67 - 2.10, respectively). Certain patient comorbidities, surgical indication, and approach to hysterectomy are associated with increased risk of blood transfusion. These results may have implications for pre-operative patient counseling, perioperative care, and health system planning.


Imaging findings of right cardiac amyloidosis: impact on prognosis and clinical course.
Cardiac involvement from amyloidosis is of growing interest in the overall literature. Despite cardiac amyloidosis (CA) has been considered for a long time a rare disease, the diagnostic awareness is increasing mainly thanks to the improvement of diagnostic softwares and of imaging techniques such as cardiac magnetic resonance (CMR). Some authors have observed an increase of prevalence rate of CA; moreover it's often underestimated because clinical manifestations are aspecific. The interstitial infiltration of the left ventricle has been extensively studied, while the involvement of the right ventricle (RV) has been less investigated. Involvement of the RV, even in the absence of pulmonary hypertension or clearly left ventricle infiltration, plays an important role as prognostic factor and is useful to achieve an early diagnosis. Therefore, the use of fast and low-cost diagnostic methods such as ultrasound strain of the right ventricle could be used to recognize cardiac amyloidosis early. Herein the importance of evaluating the right ventricular involvement, which can predict the most severe course of the disease also without overt clinical manifestations. The role of imaging, in particular of echocardiography, CMR, and scintigraphy is here reported.


Analysis of the presence of cutaneous and mucosal papillomavirus types in ductal lavage fluid, milk and colostrum to evaluate its role in breast carcinogenesis.
Several independent studies have presented evidence for the involvement of human papillomaviruses (HPV) in the aetiology of human breast cancer, while others have reported the opposite findings. Here, we have analysed by a high sensitive multiplex PCR-based method the prevalence of alpha mucosal and beta cutaneous HPV DNA in 90 ductal lavages, colostrum and milk. Ten of the 70 DLs analyzed (14%) contained a single or multiple beta HPV types, while DNA from mucosal high-risk HPV types was detected in only one sample (1/70). A strong reduction of HPV positivity in DL fluids was observed in 45 specimens collected after removal of the superficial layers of the nipple epidermis. All DLs were negative for the mucosal low-risk HPV types 6 and 11. Finally, HPV positivity was low in colostrum and milk. Our data show that DNA of alpha mucosa and beta cutaneous HPV types are rarely present in the breast fluids and suggest that a direct role of HPV in breast carcinogenesis is unlikely.


Preoperative quadriceps strength as a predictor of return to sports after anterior cruciate ligament reconstruction in competitive athletes.
To determine whether preoperative quadriceps strength predicts the likelihood of return to sports (RTS) following anterior cruciate ligament reconstruction (ACLR) in competitive athletes. Case-control study. Single-center. A total of 221 competitive athletes who underwent primary ACLR were followed and divided into RTS (n = 177) and non-RTS (n = 44) groups based on self-reported sports activities at one year postoperatively. Isokinetic quadriceps strength tests were performed preoperatively and at six months and one year postoperatively, and the quadriceps index (QI) was calculated. Functional performance was evaluated by the single-leg hop (SLH) test at six months postoperatively. Preoperative QI significantly predicted the likelihood of RTS (odds ratio, 1.68 per 10-unit increase; P < 0.001), with a preoperative QI cut-off of 66% (AUC: 0.74; sensitivity: 68.9%; specificity: 77.3%). Subjects with a preoperative QI < 66% had a significantly lower postoperative QI, SLH, and rates of RTS compared to those with a higher preoperative QI (P < 0.01). Preoperative quadriceps strength could predict the likelihood of RTS following ACLR, and a preoperative QI < 66% was associated with a greater risk of unsuccessful RTS at one year postoperatively. Preoperative QI should be evaluated as a predictor of RTS.


Blocking in children's causal learning depends on working memory and reasoning abilities.
A sample of 99 children completed a causal learning task that was an analogue of the food allergy paradigm used with adults. The cue competition effects of blocking and unovershadowing were assessed under forward and backward presentation conditions. Children also answered questions probing their ability to make the inference posited to be necessary for blocking by a reasoning account of cue competition. For the first time, children's working memory and general verbal ability were also measured alongside their causal learning. The magnitude of blocking and unovershadowing effects increased with age. However, analyses showed that the best predictor of both blocking and unovershadowing effects was children's performance on the reasoning questions. The magnitude of the blocking effect was also predicted by children's working memory abilities. These findings provide new evidence that cue competition effects such as blocking are underpinned by effortful reasoning processes.


Insulin Resistance: From Mechanisms to Therapeutic Strategies.
Insulin resistance is the pivotal pathogenic component of many metabolic diseases, including type 2 diabetes mellitus, and is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin. Although the underlying mechanism of insulin resistance is not fully understood, several credible theories have been proposed. In this review, we summarize the functions of insulin in glucose metabolism in typical metabolic tissues and describe the mechanisms proposed to underlie insulin resistance, that is, ectopic lipid accumulation in liver and skeletal muscle, endoplasmic reticulum stress, and inflammation. In addition, we suggest potential therapeutic strategies for addressing insulin resistance.


Successful intravenous streptokinase treatment of a child with Kawasaki disease complicated by acute myocardial infarction.
A 9-year-old boy developed ischemic cardiac symptoms 1 year after he presented with Kawasaki disease. The myocardial infarction was confirmed by the typical changes of electrocardiograms, echocardiograms, cardiac enzymes, thallium myocardial scintigrams, and angiograms. With successful intravenous streptokinase therapy, he remained well during the following 4 months.


Expression of NMDA receptor and its effect on cell proliferation in the subventricular zone of neonatal rat brain.
We investigated the involvement of N-methyl D-aspartate receptor (NMDAR) in neurogenesis of rat's subventricular zone (SVZ). For this purpose, we determined expression of the NMDAR subunits NR1, NR2A, and NR2B in SVZ of the neonatal Sprague-Dawley rats using immunohistochemical techniques. All three NMDAR subunits were expressed during postnatal day (PND)-1 to PND-28 whereas each subunit showed a distinct expression pattern. We also examined the functional effect of this receptor on cell proliferation in this region and, in this regard, the animals received either intraperitoneal injection of NMDAR agonist NMDA (2 mg/kg/day) or selective non-competitive NMDAR antagonist MK-801 (10 mg/kg) or NR2B antagonist Ro25-6981 (40 mg/kg), respectively, at PND-3. A significant developmental increase of the total cell density was observed at PND-7 (P < 0.05) while proliferating cell nuclear antigen-positive cell density was significantly increased at PND-14 (P < 0.05) and at PND-28 (P < 0.05) in the SVZ after NMDA (2 mg/kg/day) injection. Our data show that the NMDAR activation promoted the cell proliferation in SVZ during the neonatal period. We, therefore, inferred that NMDAR is expressed in SVZ of the neonatal rat brain and can promote neurogenesis, as through cell proliferation process in that region, and can thus be used as a potential therapeutic target in neurodegenerative diseases.


Polycystic disease of the kidney and liver in an adult Persian cat.
Polycystic disease of the kidney and liver was diagnosed in a 10-year-old spayed female Persian cat. Previous reports of renal and hepatic polycystic disease in dogs and cats have described only juvenile forms, with death at an early age. The cat of this report had large, fluid-filled kidney and liver cysts, compared with the relatively small, spongiform cysts of puppies and kittens. The clinicopathological findings in this adult Persian cat are comparable to the adult form of renal and hepatic polycystic disease of man.


Intraclass Difference in Pneumonia Risk with Fluticasone and Budesonide in COPD: A Systematic Review of Evidence from Direct-Comparison Studies.
Inhaled corticosteroids (ICS) are widely used and recommended to treat chronic obstructive pulmonary disease (COPD). While generally considered safe, several studies demonstrated an increased risk of pneumonia with the use of ICS in COPD patients. Although all ICS indicated for COPD carry the class labeling warning of increased pneumonia risk, evidence suggests an intraclass difference in the risk of pneumonia between inhaled budesonide and fluticasone. To date, systematic reviews of direct-comparison studies have not been performed to assess if an intraclass difference exists. This review investigated whether there is an intraclass difference in risk of pneumonia between inhaled fluticasone and budesonide, the 2 most commonly used ICS in COPD. A search of the medical literature was conducted in PubMed and Embase for the time period of 01/01/69-05/31/19. The search strategy combined terms that defined the patient/disease type, exposures, outcome, and the study/publication type. Descriptive and comparative statistics reported for fluticasone- and budesonide-containing products in each study, including data for pneumonia event subgroups, were extracted and reported by dose, seriousness, or practice setting. Controlled clinical trials and observational studies meeting the inclusion criteria were assessed for methodologic quality by using the appropriate tool from the list of study quality assessment tools developed by the National Institutes of Health. The summary relative risk (RR) ratio across 5 included studies (57,199 patients) was 1.13 (95% CI: 1.09-1.19), representing a 13.5% increased risk of pneumonia among fluticasone users compared to budesonide users. Similarly, summary RR ratio for serious pneumonia implied a 14.4% increased risk of serious pneumonia among fluticasone users compared to budesonide users (pooled RR: 1.14; 95% CI: 1.09-1.20). There is likely a clinically important intraclass difference in the risk of pneumonia between fluticasone- and budesonide-containing inhaled medications in COPD.


Scleral damage: comparison of standard and modified diathermy electrodes.
Full-thickness scleral diathermy using a standard electrode causes significant scleral damage and necrosis. Use of a modified (Jabbour's) diathermy electrode appears to cause minimal scleral damage. We evaluated the scleral changes following transscleral diathermy application using standard and modified diathermy electrodes to the peripheral retina and ciliary body. Twelve Dutch belted pigment rabbits were used in our experiment. Three eyes each were subjected to transscleral diathermy using standard and modified electrodes to produce chorioretinal scars and cyclodestruction. Eyes were examined with the slit lamp and indirect ophthalmoscope at weekly intervals for 4 weeks. Light and transmission electron microscopy was performed 1 hour after diathermy application in 4 animals and in the remaining 8 animals at 4 weeks. Chorioretinal scarring and ciliary body atrophy were successfully induced with both types of electrodes. However, scleral damage was less severe in eyes treated with the modified electrode as compared with the standard electrode.


Subretinal neovascularization in the Vogt-Koyanagi-Harada syndrome.
Two Hispanic patients with Vogt-Koyanagi-Harada (VKH) syndrome each developed a disciform lesion involving the macula of one eye several months after the onset of symptoms. Each had extraocular manifestations which included pleocytosis of the cerebrospinal fluid. The disciform lesions were associated with retinochoroidal anastomoses, a finding not previously reported in VKH syndrome. Each patient had a separate extramacular disciform lesion in the same eye. Two other Hispanic patients with diffuse bilateral intraocular inflammation had ocular findings consistent with VKH syndrome. One of these patients developed bilateral peripapillary disciform lesions and the other developed a disciform macular scar in one eye. Fluorescein angiography in each patient showed early irregular hyperfluorescence with late intense staining. The disciform detachments occurred in areas of reactive proliferation of the retinal pigment epithelium, and we postulate that growth of subretinal new vessels occurred through areas of Bruch's membrane that were damaged by the inflammation.


The effect of letrozole versus artificial hormonal endometrial preparation on pregnancy outcome after frozen-thawed embryos transfer cycles: a randomized clinical trial.
Considering that clinical trial studies are limited in polycystic ovary syndrome (PCOS) patients, and there is no consensus on an optimum endometrial preparation protocol for frozen embryo transfer (FET), the present study was designed as a randomized clinical trial to compare the reproductive outcomes following stimulated cycles with letrozole plus human menopausal gonadotropin (HMG) for endometrial preparation compared with routine AC-FET. This randomized controlled trial was carried out on infertile PCOS patients who underwent IVF/ICSI and FET cycles in Arash Women's Hospital affiliated to Tehran University of Medical Sciences between September 2018 and January 2020. PCOS diagnosis was based on the Rotterdam criteria. Eligible patients were randomly allocated into two groups: stimulated cycle with letrozole plus (HMG) (intervention group) and routine artificial hormonal endometrial preparation (control group). One hundred seventy-seven infertile patients were recruited for participation in the study. Of these, 57 women were excluded due to non-eligibility for entering the study, and a total of 120 patients were randomly assigned to two study groups. After follow up, the cycle outcomes of 57 patients in the intervention group and 59 patients in the control group were compared. The data analysis showed that the two groups did not have significant differences in fundamental and demographic characteristics. After the intervention, there were no significant differences in implantation rate, chemical, ectopic, and clinical pregnancy rates between groups. Moreover, the rates of miscarriage and ongoing pregnancy were similar between groups (P > 0.05). We found similar pregnancy outcomes with two endometrial preparation methods. Noting that each treatment centre should select the most beneficial and cost-effective method with the least adverse effects for patients, letrozole preparations for FET could be incorporated into possible options; however, establishing this approach as first-line treatment is premature in light of current evidence, and future randomized clinical trials with larger sample sizes are required for widespread application. The study was also registered in the Iranian Registry of Clinical Trials on March 20th, 2020. ( IRCT20090526001952N12 at www.irct.ir , registered retrospectively).


Role of C-C chemokine receptor type 7 and its ligands during neuroinflammation.
For decades, chemokines and their receptors have received a great deal of attention for their multiple roles in controlling leukocyte functions during inflammation and immunity. The ability of chemokines to convey remarkably versatile but context-specific signals identifies them as powerful modulators of immune responses generated in response to diverse pathogenic or non-infectious insults. A number of recent studies have speculated that the C-C chemokine receptor type 7 (CCR7), plays important roles in immune-cell trafficking in various tissue compartments during inflammation and in immune surveillance. Using computational modeling and microfluidics-based approaches, recent studies have explored leukocyte migration behavior in response to CCR7 ligands in a complex chemokine environment existing with other coexisting chemokine fields. In this review, we summarize the current understanding of the effects of soluble versus immobilized ligands and of the downstream signaling pathways of CCR7 that control leukocyte motility, directionality, and speed. This review also integrates the current knowledge about the role of CCR7 in coordinating immune responses between secondary lymphoid organs and peripheral tissue microenvironments during primary or secondary antigen encounters. CCR7 seems to influence distinct immunological events during inflammatory responses in the central nervous system (CNS) including immune-cell entry and migration, and neuroglial interactions. The clinical and pathological outcome may vary depending on its contribution in the inflamed CNS microenvironment. Understanding these mechanisms has direct implications for therapeutic developments favoring more protective and efficient immune responses.