Inverse correlation between vascular calcification and bone mineral density in human immunodeficiency virus-infected patients.
HIV-infected individuals suffer from accelerated aging, which manifests as premature cardiovascular and bone disease. However, little is known of the association of these two disorders in the HIV population. Our objective was to investigate the association between a marker of atherosclerosis (coronary artery calcium [CAC]) and low bone mineral density (BMD) in a cross-sectional cohort of HIV-infected patients. The study was conducted at the University of Modena and Reggio Emilia, Italy. A total of 636 consecutive middle-aged, HIV-infected subjects were recruited between January 2006 and December 2010. All patients underwent CAC and BMD assessment. Patients were categorized according to a CAC score <100 or >100 units based on previous literature that identified this cut-point as a marker of increased risk. Low femoral and lumbar spine BMD was defined as <25th percentile value for the study cohort. Logistic regression and bootstrap analysis were used to assess the independent association between CAC and BMD. The main outcome measure was a CAC score >100. Patients with CAC > 100 were older and more likely to be men, diabetic, and overweight. Patients with CAC < 100 had better renal function and a lower cardiovascular risk profile. After adjusting for age, sex, traditional and HIV-specific risk factors, vitamin D level, and PTH level, there was a significant association between CAC > 100 and low BMD for the femur (OR = 2.33, 95 % CI 1.09-4.99; p = 0.02) but not for the spine. Bootstrap analyses confirmed these findings. In summary, CAC was independently associated with low femoral BMD in HIV-infected patients. Future studies should test whether therapies that attenuate cardiovascular risk in HIV favorably impact bone health.


Concordant ventriculoarterial connections with parallel arterial trunks in the setting of isomerism of the right atrial appendages.
We describe an autopsied specimen, from an infant who died in 1967, in which concordant ventriculoarterial connections coexisted with parallel arterial trunks, usually described as "anatomically corrected malposition." Based on their shape, the extent of the pectinate muscles, and the absence of a coronary sinus, we diagnosed isomeric right atrial appendages. Despite this, the arrangement of the remaining thoracic and abdominal organs, as well as the patterns of venous drainage, was almost completely mirror imaged.


Inflexible Youngsters: Psychological and Psychopathological Correlates of the Avoidance and Fusion Questionnaire for Youths in Nonclinical Dutch Adolescents.
The present study examined psychological and psychopathological correlates of psychological inflexibility as measured by the Avoidance and Fusion Questionnaire for Youth (AFQ-Y) in two independent samples of nonclinical Dutch adolescents aged between 12 and 18 years (Ns being 184 and 157). Participants completed a survey containing the AFQ-Y and scales assessing mindfulness, thought suppression, self-compassion, self-worth, self-efficacy, and internalizing/externalizing symptoms. In both samples, the AFQ-Y was found to be a reliable measure of psychological inflexibility that correlated in a theoretically meaningful way with other psychological constructs. Most importantly, AFQ-Y scores correlated positively with internalizing and externalizing symptoms, and in most cases, these associations remained significant when controlling for other measures. These findings suggest that psychological inflexibility is an important factor in youth psychopathology that needs to be further investigated in future research.


Dysregulation of toll-like receptor-2 (TLR-2)-induced effects in monocytes from patients with atopic dermatitis: impact of the TLR-2 R753Q polymorphism.
Atopic dermatitis (AD) is often complicated by an enhanced susceptibility to bacterial skin infections, especially with Staphylococcus aureus. Toll-like receptors (TLR), especially TLR-2 recognizes cell wall components of S. aureus, e.g. lipoteichoic acid (LTA) and peptidoglycan (PGN). A heterozygous TLR-2 R753Q polymorphism occurs in a frequency of 11.5% in adult AD patients and has been shown to be associated with a severe phenotype of AD. The aim of this study was to investigate the impact of TLR-2 agonists (LTA, PGN and Pam3Cys) on cytokine production in human monocytes from AD patients with the TLR-2 R753Q polymorphism compared with that of AD patients with 'wild type' TLR-2 and control individuals to elucidate the functional role of the TLR-2 R753Q polymorphism. Monocytes from AD patients with the TLR-2 R753Q mutation produced significantly more IL-6 and IL-12 compared with that of AD patients with nonmutated TLR-2 upon stimulation with TLR-2 agonists. We show for the first time functional differences in TLR-2 responsiveness of monocytes from AD patients with the TLR-2 R753Q mutation compared with wild type AD patients in a ligand-dependent manner. Our data support the emerging concept that AD patients have a dysbalance in innate and acquired immunity. TLR-2 may be essential in the pathogenesis and maintenance of AD and may be involved in the enhanced susceptibility to skin infections with S. aureus and in a higher inflammatory response in patients with AD carrying the TLR-2 polymorphism.


Pharmacokinetics of prednisone and prednisolone in a case of hypothyroidism: effect of replacement therapy.
We found this particular case during the course of a clinical trial designed to assess the pharmacokinetics of oral prednisone in normal and diseased children. The plasma concentrations of prednisone, its main metabolite prednisolone, and endogenous cortisol were measured by HPLC at selected times during 8-h periods starting at 7:30 a.m. One 9.9-year-old administered prednisone 0.5mg/kg p.o. was found to be hypothyroid (TSH: 351microIU/mL; fT4: <2pg/mL; fT3: <1pg/mL); four age-matched normal boys (aged 6.6+/-4.9 years) served as a control group. In comparison with the controls, the hypothyroid boy showed a marked increase in the total AUC of prednisone (3360microg h/L versus 215+/-83microg h/L) and prednisolone (4040microg h/L versus 724+/-77microg h/L), and an altered pattern of endogenous cortisol, which is known to be impaired in hypothyroid subjects. After 6 months of thyroxine replacement therapy (75microg/day), the AUCs of prednisone and prednisolone returned to normal values (prednisone: 248microg h/L; prednisolone: 528microg h/L), as did the pattern of circadian cortisol secretion. In conclusion, our data indicate that the pharmacokinetics of prednisone and prednisolone can be profoundly altered by hypothyroidism, and subsequently restored by thyroxine replacement therapy.


Climate ripe for marketing strategies: Health promotion.
Now is the ideal time for hospitals to promote wellness in the community as part of their marketing strategies.


Advances in adult and pediatric asthma.
This review summarizes the highlights in the study of adult and pediatric asthma from October 2002 through October 2003. It is easiest to categorize this year's advances into physiologic, epidemiologic, therapeutic, and primarily pediatric developments. In physiology the identification of the ADAM33 gene as an asthma susceptibility gene has led to a new hypothesis concerning the pathogenesis of asthma. Understanding the integration of the upper and lower airways is likely to have important implications for patient management. Epidemiologic studies continue to show that asthma is a significant and costly disease, with medications comprising the most significant direct costs. Early intervention and improved management can significantly reduce the burden of illness. Research presented indicates there is an opportunity for allergist-immunologists to improve diagnostic and therapeutic approaches to asthma management. Our community has a strong commitment to health care quality, education, and delivery. The Journal will reflect this commitment with a new section devoted to these issues.


Risk factor analysis and molecular epidemiology of respiratory adenovirus infections among children in northern Taiwan, 2009-2013.
Respiratory infections caused by human adenoviruses (HAdV) are worldwide, and have significantly increased recently in Taiwan. This study aimed to clarify the molecular epidemiology and risk factors of HAdV severe infections and pneumonia among Taiwanese children. Patients with HAdV infections and hospitalized in a medical center between 2009 and 2013 were divided into severe or nonsevere HAdV infections based on whether or not they received intensive care. HAdV pneumonia was identified for comparison. The HAdV genotype was determined by sequencing the partial hexon and fiber genes. The nucleotide sequences were compared by phylogenetic analysis. The 176 patients (97 boys, 79 girls) had a median age of 3.7 years. The HAdV infections circulated year-round. HAdV B3 (54.5%) was the most common genotype, followed by HAdV C2 (21%), HAdV E4 (8%), and HAdV B7 (6.8%). Thirty-two patients needed intensive care. In multivariate analysis, the risk factors for severe HAdV infections were underlying neurologic diseases [odds ratio (OR): 164.9; p < 0.001], prematurity (OR: 10.9; p = 0.042), and HAdV B7 (OR: 39.5; p = 0.011). Twenty-nine patients had HAdV pneumonia. Patients with underlying neurologic diseases (OR 76.8; p < 0.001), airway anomaly (OR 15.1; p = 0.033), chronic lung diseases (OR 12.5; p = 0.047), weight < 3rd percentile (OR 5.5; p = 0.027), and HAdV B7 (OR 4.2; p = 0.002) had higher incidences of pneumonia. Four with underlying neurologic diseases died of acute respiratory distress syndrome. HAdV infections circulate all year-round. HAdV B7 is strongly related to severe infections and pneumonia. Underlying neurologic diseases and prematurity are risk factors for severe HAdV infections.


Study of the degradation of diphenyl-ether herbicides aclonifen and bifenox in different environmental waters.
The degradation of the diphenyl-ether herbicides aclonifen (ACL) and bifenox (BF) in water samples has been studied under different laboratory conditions, using in-tube solid-phase microextraction (IT-SPME) coupled to capillary liquid chromatography (capLC). The working conditions were selected in order to detect also bifenox acid (BFA), a compound formed as a result of the hydroxylation of BF. Samples (4 mL) were processed without any previous treatment, which allowed the detection of the herbicides at low ppt levels. The effects of temperature, light and pH on the degradation of ACL and BF have been tested using standard solutions prepared in nanopure water. The effect of the sample matrix has been evaluated by analysing different environmental waters spiked with the herbicides, namely ditch water, river water and seawater. The kinetics of the degradation have been studied and the half-life times (t1/2) have been calculated. The results obtained have demonstrated that the sample matrix is the most important parameter affecting the degradation of the tested herbicides. The degradation of both ACL and BF was much faster in ditch and river water samples, where t1/2 values of only a few days were observed. However, both compounds showed a better stability in seawater samples, where they can persist for several months. In all matrices ACL was found to be more stable than BF. In samples where BF had been substantially degraded, BFA was also detected, although the stability of this compound was also limited. Other degradation products have been detected along the study.


Medium term results following heart transplantation for end stage heart failure: A single center experience of 257 patients.
End stage heart failure is a lethal disease with a dismal 5 year survival. Heart transplantation has proven to be a highly effective modality of treatment in appropriately selected group of such patients. This is a retrospective analysis of medium term outcomes of heart transplantation in the setting of a private health facility in India. The objective of this study was two fold. The outcome of 257 heart transplants done at a single centre from October 2012 to October 2019 was analyzed. Patients with combined Heart and lung transplants and those whose complete medical records were unavailable were excluded from the study. Survival was tracked at 60 days, 90 days, one year and beyond for a maximum of 7 years. Preoperative patient risk profiles were characterized on the basis of INTERMACS category. There were 176 male and 81 female patients. The age range was from 8 months to 78 years with a mean of 32.9 years. Survival at 2 months was 87%, at 90 days was 83%, at one year was 81%, 2 years was 75%, at 3 years was 72% and at 5 years and beyond was 62% for the whole series. Strong predictors of 90 day mortality included INTERMACS category (odd's ratio 0.289, p = 0.000) and creatinine more than 1.5 mg/dl (odd's ratio 2.48, p = 0.056). Recipient pulmonary vascular resistance and donor organ ischemic times were not found to be statistically significant factors affecting outcome. Medium term survival was influenced by INTERMACS category (Hazard ratio > 3 for INTERMACS category 1 compared to INTERMACS 4 or 5, p < 0.0001) and creatinine > 1.5 mg/dl (Hazard ratio 2.15, p = 0.003). This effect of creatinine was related to the age of the recipient. Hazard ratio 1.4, p = 0.524 if age <30 and Hazard ratio 4.78, p = 0.006, if age was >50. Satisfactory medium term outcome is possible after heart transplantation even in resource constrained environment of a developing country.


Acute coronary disease Athero-Inflammation: Therapeutic approach.
Antithrombotic therapy is the cornerstone of the treatment of acute coronary syndromes, but there is now evidence which indicates that by blocking inflammation, thrombosis and thus, acute coronary events, could be lowered. The concept of athero-inflammation emerges as the meeting point of different morbidities; dyslipemia, diabetes, hypertension, obesity, immunity, infection, hyperhomocyteinemia, smoking, etc. usual named as risk factors. Thus, beside specific drugs, earliest treatment, in the stage of inflammation, using anti-inflammatory drugs, should be considered since in patients with increased risk of acute coronary process are likely to have many point of origen throughout the coronary arteries. There are a body of evidences for supporting the potential of anti-inflammatory therapy to the prevention of inflammation and atherosclerosis. COX-2 inhibition may decrease endothelial inflammation reducing monocytes infiltration improving vascular cells function, plaque stability and probably resulting in a decrease of coronary atherothrombotic events.Trials including large numbers of patients in prospective double-blind randomized studies worthwhile to confirm the efficacy of NSAID, mainly, COX-2 inhibitors, together with aspirin in the prevention of coronary events in patients with acute coronary disease.


Not Just About Faces in Context: Face-Context Relation Moderates the Impact of Contextual Threat on Facial Trustworthiness.
Recent work showed that the attribution of facial trustworthiness can be influenced by the surrounding context in which a face is embedded: contexts that convey threat make faces less trustworthy. In four studies (N = 388, three preregistered) we tested whether face-context integration is influenced by how faces and contexts are encoded relationally. In Experiments 1a to 1c, face-context integration was stronger when threatening stimuli were attributable to the human action. Faces were judged less trustworthy when shown in threatening contexts that were ascribable (vs. non-ascribable) to the human action. In Experiment 2, we manipulated face-context relations using instructions. When instructions presented facial stimuli as belonging to the "perpetrators" of the threatening contexts, no difference with the control (no-instructions) condition was found in face-context integration. Instead, the effect was reduced when faces were presented as "victims." We discussed the importance of considering relational reasoning when studying face-context integration.


Adsorption and Removal Kinetics of 2,4-Dinitroanisole and Nitrotriazolone in Contrasting Freshwater Sediments: Batch Study.
Environmental release of 2,4-dinitroanisole (DNAN) and 3-nitro-1,2,4-triazol-5-one (NTO) is of great concern due to high migration potential in the environment. In the present study we evaluated the adsorption and microbially-mediated removal kinetics of dissolved DNAN and NTO in contrasting freshwater sediments with different total organic carbon (TOC) content. River sand (low TOC), pond silt (high TOC), clay-rich lake sediment (low TOC), wetland silt (high TOC), carbonate sand (low TOC), and iron-rich clay (low TOC) were evaluated. Separate abiotic and biotic bench-top sediment slurry incubations were carried out at 23, 15, and 4 °C for DNAN and NTO. Experiments were conducted over 3 weeks. Time series aqueous samples and sediment samples collected at the end of the experiment were analyzed for DNAN and NTO concentrations. The DNAN compound equilibrated with sediment within the first 2 h after addition whereas NTO showed no adsorption. 2,4-Dinitroanisole adsorbed more onto fine-grained organic-rich sediments (Kd = 2-40 L kg-1 sed-1 ) than coarse-grained organic-poor sediments (Kd = 0.2-0.6 L kg-1 sed-1 ), and the TOC content and cation exchange capacity of sediment were reliable predictors for abiotic DNAN adsorption. Adsorption rate constants and equilibrium partitioning constants for DNAN were inversely proportional to temperature in all sediment types. The biotic removal half-life of DNAN was faster (t1/2 = 0.1-58 h) than that of NTO (t1/2 = 5-347 h) in all sediment slurries. Biotic removal rates (t1/2 = 0.1-58 h) were higher than abiotic rates (t1/2 = 0.3-107 h) for DNAN at 23 °C. Smaller grain size coupled with higher TOC content enhanced biotic NTO and DNAN removal in freshwater environments. Environ Toxicol Chem 2023;42:46-59. © 2022 SETAC.


A co-interaction model of HIV and syphilis infection among gay, bisexual and other men who have sex with men.
We developed a mathematical model to study the co-interaction of HIV and syphilis infection among gay, bisexual and other men who have sex with men (gbMSM). We qualitatively analysed the model and established necessary conditions under which disease-free and endemic equilibria are asymptotically stable. We gave analytical expressions for the reproduction number, and showed that whenever the reproduction numbers of sub-models and co-interaction model are less than unity, the epidemics die out, while epidemics persist when they are greater than unity. We presented numerical simulations of the full model and showed qualitative changes of the dynamics of the full model to changes in the transmission rates. Our numerical simulations using a set of reasonable parameter values showed that: (a) both diseases die out or co-exist whenever their reproduction number is less than or exceed unity. (b) HIV infection impacts syphilis prevalence negatively and vice versa. (c) one possibility of lowering the co-infection of HIV and syphilis among gbMSM is to increase both testing and treatment rates for syphilis and HIV infection, and decrease the rate at which HIV infected individuals go off treatment.


Spectrum of Myelodysplastic Syndrome in Patients Evaluated for Cytopenia(s). A Report from a Reference Centre in Saudi Arabia.
Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells, characterized by ineffective hematopoiesis, peripheral cytopenias along with hypercellularity of the bone marrow, and marked dysplastic features. Establishing MDS diagnosis is difficult due to nonspecific clinical presentation and imprecise morphological criteria. In anticipation to improve the diagnostic approach in this field, we aimed to characterize the clinical and morphological features of patients presented with cytopenias with a special focus on MDS. We comprehensively reviewed all medical record of patients who were referred to the hematology laboratory at KFSH-RC, Riyadh, Saudi Arabia, between January 2009 and March 2016 for evaluation of bone marrow aspirates and trephine biopsies due to severe and persistent cytopenia(s) to rule out MDS. A total of 183 patients, 155 adult and 28 pediatric, were identified. In the adult group, MDS was diagnosed in 82 (52.9%) patients, with a male-to-female (M:F) ratio of 1.6:1 and mean age at diagnosis of 50 years. According to the World Health Organization (WHO) 2017 criteria, MDS subtypes were as follows: MDS with single lineage dysplasia (SLD, 5%), MDS with ring sideroblasts and SLD (MDS-RS-SLD 7%), MDS with multilineage dysplasia (MDS-MLD 21%), MDS with deletion of chromosome 5q (MDS del(5q), 2%), MDS unclassifiable (MDS-U7%), hypoplastic MDS (h-MDS 4%), MDS with excess blasts-1 (MDS-EB1, 20%), MDS with excess blasts-2 (MDS-EB2, 28%), and therapy-related MDS (6%). Laboratory and morphological features were described. In both groups, cytogenetic abnormalities were classified according to the Revised International Prognostic Scoring System cytogenetic risk groups. In adults, the dominating cytogenetic abnormalities were monosomy 5 and monosomy 7 seen in 20.7% and 24.4% of patients, respectively. Peripheral cytopenia not due to MDS was diagnosed in 54 (34.8%) patients, with a mean age of 43 years and M:F ratio of 1:1. The cause of these cytopenias were as follows: bone marrow failure (BMF, 22%), peripheral destruction (20%), drug induced (20%), anemia of chronic disease (16%), B12 deficiency (7%), infection (7%), paroxysmal nocturnal hemoglobinuria (4%), idiopathic cytopenia of undetermined significance (2%), and idiopathic dysplasia of undetermined significance (2%). A definite diagnosis of MDS was not possible in 19 patients due to insufficient clinical data. In the pediatric group, MDS was diagnosed in 14/28 (50%) patients, with M:F ratio of 1.8:1 and mean age at diagnosis of 4 years. MDS subtypes (WHO 2017) in 14 patients were as follows: refractory cytopenia of childhood (RCC, 42.8%), MDS-EB1 (42.8%), and MDS-EB2 (14.2%). Laboratory and morphological features were described. The prevalent cytogenetic abnormality was monosomy 7 in six/14 (42.8%) patients. Cytopenias due to other causes were diagnosed in eight/28 patients (28.5%), with a mean age of 6.5 years and M:F ratio of 1.6:1. The causes of non-MDS related cytopenia were: congenital BMF (4 patients), peripheral destruction (2 patients), immune deficiency (1 patient), and viral infection (1 patient). A definite diagnosis of MDS could not be made in six/28 (21.4%) patients. MDS is the cause of cytopenia in a significant number of patients referred for evaluation of cytopenias, appears at younger age, and tends to be more aggressive than that reported in international studies. Anemia, dysplastic neutrophils in the peripheral blood, and dysplastic megakaryocytes in the bone marrow trephine biopsy are the most reliable features in distinguishing MDS from other alternative diagnoses.


Hepatogenic Supported Differentiation of Mesenchymal Stem Cells in a Lactobionic Acid-Conjugated Thermogel.
To investigate the effect of receptor substrate of target cells on stem cell differentiation, lactobionic acid-conjugated poly[(propylene glycol)-b-(ethylene glycol)-b-(propylene glycol)]-poly(l-alanine) (LB-PLX-PA) was synthesized, and then thermogelling systems consisting of LB-PLX-PA and PLX-PA in a ratio of 0/100 (LB-0), 5/95 (LB-5), and 20/80 (LB-20) were constructed as an injectable three-dimensional scaffold toward hepatogenic differentiation of tonsil-derived mesenchymal stem cells (TMSCs). Modulus of LB-0, LB-5, and LB-20 increased to 500-800 Pa at 37 °C (gel) due to the heat induced sol-to-gel transition of the systems during which TMSCs were incorporated into the gel. Based on biomarker expressions and hepatic biofunctions of the differentiated cells, the receptor substrate (LB)-conjugated bioactive thermogel provides compatible microenvironments for the differentiated cells, and thus gives pronounced positive results on the differentiation of the stem cells into target cells during three-dimensional culture, compared with a passive thermogel.


Relation between gastric emptying of albumin-dextrose meals and cholecystokinin release in man.
The effect of intragastric dextrose on albumin-stimulated cholecystokinin (CCK) release was studied in five healthy subjects and was related to gastric emptying and pancreatobiliary secretions. When combined with low concentrations of dextrose (4 g/100 ml), a 500-ml solution of albumin (7 g/100 ml) was rapidly emptied from the stomach into the duodenum (T1/2: 35 min). This rapid gastric emptying resulted in an only transient stimulation of pancreatobiliary secretion and an integrated CCK release of 278 +/- 45 pM x 180 min. When the concentration of dextrose in the albumin solution was increased from 4 g/100 ml to 21 g/100 ml, gastric emptying rate was distinctly slower (T1/2: 78 min; P < 0.01) and pancreatobiliary secretions became sustained (P < 0.01). CCK release was markedly higher (900 +/- 421 pM x 180 min; P < 0.05) after ingestion of the solution containing a high dextrose concentration. Intraduodenal infusion of 21 g/100 ml dextrose (3.1 ml/min) failed to significantly stimulate plasma CCK levels (119 +/- 38 pM x 120 min). We suggest that the higher CCK release in response to intragastrically administered albumin solution containing high concentrations of dextrose may have been induced by augmented peptic digestion of albumin due to delayed gastric emptying and by increased enteral digestion of albumin due to increased pancreatobiliary outputs.


msDNA-St85, a multicopy single-stranded DNA isolated from Salmonella enterica serovar Typhimurium LT2 with the genomic analysis of its retron.
Bacterial reverse transcriptase is responsible for the production of a small satellite DNA-RNA complex called multicopy single-stranded DNA (msDNA) that has been found in a wide variety of Gram-negative bacteria. Here we describe the isolation and characterization of a novel msDNA, msDNA-St85, from Salmonella enterica serovar Typhimurium LT2. We determined the nucleotide sequence of msDNA-St85 and the location of retron-St85 on the chromosome that is responsible for msDNA-St85 production by analyzing the complete genomic sequence of S. typhimurium LT2. It was found that the G+C content and the codon usage of retron-St85 were significantly different from those of the S. typhimurium genome, indicating that retron-St85 was probably acquired recently in this bacterium. This is the first report for identification of an msDNA in the genus Salmonella with the complete description and analysis of its retron.


Peroral xylitol increases the concentration levels of tissue iron in the rat.
The effect of xylitol feeding on the iron content of rat tissues was studied. Adult male rats were fed on the basal diet containing (g/kg) 200 glucose, or 50 or 200 xylitol, or the same diet containing no added carbohydrates for 8 weeks. Each feeding group comprised nine animals. Xylitol at 200 g/kg diet retarded the growth rate of the rats, whereas 200 g glucose/kg increased the weight gains compared with animals given no added carbohydrates. Xylitol at 50 g/kg did not affect the tissue Fe concentrations, but 200 g xylitol/kg increased the Fe content of the livers, duodenum wall, spleen, bone marrow and serum. Cadmium and lead contents of the livers were similar in all groups. Xylitol-Fe complexes are suggested to be responsible for the increased Fe absorption during xylitol feeding.


Partially unroofed coronary sinus associated with tricuspid atresia. An important associated lesion in the Fontan operation.
A case of tricuspid atresia associated with partially unroofed coronary sinus following a Fontan operation is described. A 4-year-old boy with tricuspid atresia showed persistent arterial desaturation immediately after a modified Fontan operation. At reoperation on the next day, a partially unroofed coronary sinus was recognized and repaired through a left atriotomy. Although uncommon, this associated anomaly should be kept in mind even in the absence of a persistent left superior vena cava and should be suspected if arterial desaturation occurs after a modified Fontan operation.


A comparison of male and female dually arrested domestic violence offenders.
This research provides information on dually arrested female defendants in domestic violence cases. The data comes from all heterosexual domestic violence cases resulting in a dual arrest from one large mid-South city during a 28-month period. Information on matched pairs of dually arrested male and female defendants (N = 317) came from multiple sources, including official criminal justice records (arrest reports and local criminal histories) as well as victim/offender interviews with both the arrestee and his/her partner. Comparisons were made between males and females in terms of their demographics, criminal histories, prior history of domestic violence (as both victim and offender), and behavior during the instant offense. Analyses revealed that these couples had ample contact, whether as victim or offender, with the criminal justice system. While there were no significant differences in partners' reports of minor and severe physical abuse, criminal justice date indicated that male arrestees demonstrated a significantly higher overall level of severity of violence than their female counterparts. Additionally, male arrestees had a more serious history of intimate partner and extrafamilial violence as well as other indicators of an antisocial lifestyle in comparison to female arrestees. To the extent that females in our cohort demonstrated less overall criminality and engaged in less severe domestic aggression, the idea of equivalency of violence between male and female arrestees must remain questionable.


Retroperitoneal Versus Transperitoneal Robotic Partial Nephrectomy: A Multicenter Matched-pair Analysis.
With increasing acceptance of robotic partial nephrectomy over the last decade, there is an ongoing discussion about the transperitoneal versus retroperitoneal access. To report outcomes after transperitoneal (TRPN) versus retroperitoneal (RRPN) robotic partial nephrectomy. A total of 754 patients were identified from the databases of three high-volume centers who underwent either TRPN (n = 551) or RRPN (n = 203). Perioperative data were evaluated retrospectively. A propensity score matched-pair analysis was performed with the following variables: grade of renal insufficiency, age, body mass index, tumor diameter, and preoperative aspects and dimensions used for an anatomical (PADUA) score with a subsequent subgroup analysis for tumor location. For quality outcomes, the margin, ischemia, and complications (MIC) criteria were used (negative margins, ischemia time <20 min, and no major complications). Statistical analyses included chi-square and Mann-Whitney U tests. In all, 176 patients could be matched in each group. The median tumor diameter was 28 mm with a PADUA score of 9. In 11% of RRPN versus 44% of TRPN cases, an anterior tumor location was found, and in 55% versus 30%, a posterior lesion was found (p < 0.001). Operative time (119 vs 139 min, p < 0.001) and warm ischemia time (9 vs 10 min, p = 0.003) were significantly shorter for RRPN. No significant differences were observed between intra- and postoperative complication rates, with 8% major complications in TRPN versus 3% in RRPN (p = 0.06). The MIC criteria were achieved in 90% in the RRPN versus 88% in the TRPN group, without differences for tumor location. Significant differences between TRPN and RRPN could be found for intraoperative time, while complication rates and quality outcomes were comparable. RRPN can also be a considerable alternative for anterior tumors. In this study, we demonstrate that robotic partial nephrectomy is feasible with either a transperitoneal or a retroperitoneal surgical access. The posterior approach can also be used for anterior renal tumors and may result in shorter operative time.


Assessing response to dry-off in dairy cows kept outdoors using spontaneous behaviours and infrared thermography-a pilot study.
We used spontaneous behaviours to assess response to dry-off involving abrupt dietary and milking frequency changes, followed by regrouping, after the last milking in 15 clinically healthy Holstein-Frisian cows kept outdoors. Moreover, we explored the potential of infrared thermography to detect eye temperature variations possibly induced by dry-off. On days - 1, 0, 1 and 2 relative to dry-off, we recorded whether cows vocalised during feed delivery; ate fresh feed within 5 min; and mean maximum eye temperature at approximately 1 h after feed delivery. On days 1 and 2, cows were more likely to eat fresh feed compared to days - 1 and 0. No difference in likelihood of vocalising was found. Compared to day - 1, eye temperature was substantially higher on days 0 and 2. Collectively, the results suggest that cows responded, both behaviourally and physiologically, to the abrupt dry-off management. The interpretation of the current findings deserves further investigation using larger sample sizes, more controlled environments and further behavioural, physiological, cognitive and clinical measures.


Intake of milk with added micronutrients increases the effectiveness of an energy-restricted diet to reduce body weight: a randomized controlled clinical trial in Mexican women.
Micronutrient deficiencies have been associated with an increase in fat deposition and body weight; thus, adding them to low-fat milk may facilitate weight loss when accompanied by an energy-restricted diet. The objective was to evaluate the effect of the intake of low-fat milk and low-fat milk with added micronutrients on anthropometrics, body composition, blood glucose levels, lipids profile, C-reactive protein, and blood pressure of women following an energy-restricted diet. A 16-week randomized, controlled intervention study. One hundred thirty-nine obese women (aged 34±6 years) from five rural communities in Querétaro, Mexico. Women followed an energy-restricted diet (-500 kcal) and received in addition one of the following treatments: 250 mL of low-fat milk (LFM) three times/day, 250 mL of low-fat milk with micronutrients (LFM+M) three times/day, or a no milk control group (CON). Weight, height, and hip and waist circumferences were measured at baseline and every 4 weeks. Body composition measured by dual-energy x-ray absorptiometry, blood pressure, and blood analysis were done at baseline and at the end of the 16 weeks. Changes in weight and body composition. One-factor analysis of variance, adjusted by age, baseline values, and community random effects. After the 16-week intervention, participants in the LFM+M group lost significantly more weight (-5.1 kg; 95% CI: -6.2 to -4.1) compared with LFM (-3.6 kg; 95% CI: -4.7 to -2.6) and CON (-3.2 kg; 95% CI: -4.3 to -2.2) group members (P=0.035). Body mass index change in the LFM+M group (-2.3; 95% CI: -2.7 to -1.8) was significantly greater than LFM group members (-1.5; 95% CI: -2.0 to -1.1) and CON group members (-1.4; 95% CI: -1.9 to -0.9) (P=0.022). Change in percent body fat among LFM+M group members (-2.7%; 95% CI: -3.2 to -2.1) was significantly higher than LFM group members (-1.8%; 95% CI: -2.3 to -1.3) and CON group members (-1.6%; 95% CI: -2.2 to -1.0) (P=0.019). Change in bone mineral content was significantly higher in LFM group members (29 mg; 95% CI: 15 to 44) and LFM+M group members (27 mg; 95% CI: 13 to 41) compared with CON group members (-2 mg; 95% CI: -17 to -14) (P=0.007). No differences were found between groups in glucose level, blood lipid profile, C-reactive protein level, or blood pressure. Intake of LFM+M increases the effectiveness of an energy-restricted diet to treat obesity, but had no effect on blood lipid levels, glucose levels, C-reactive protein, or blood pressure.


Effects of a Novel Web-Based Sensorimotor Exercise Program for Patients With Subacute Whiplash-Associated Disorders: Protocol for a Randomized Clinical Trial.
Whiplash-associated disorder (WAD) often becomes a persistent problem and is one of the leading causes of disability in the world. It is a costly condition for individuals, for insurance companies, and for society. Guidelines for the management of WAD have not been updated since 2014, and the use of computer-based sensorimotor exercise programs in treatment for this patient group has not been well documented. The purpose of this randomized clinical trial is to explore the degree of association between self-reported and clinical outcome measures in WAD. Individuals (n = 180) with subacute WAD grades I and II will be randomized into 3 groups using block randomization. The 2 primary intervention groups (A and B) will receive physical therapy involving manual therapy and either a remote, novel, computer-based cervical kinesthetic exercise (CKE) program starting at visit 2 (Group A) or neck exercises provided by the corresponding physical therapist (Group B). These groups will be compared to a "treatment as usual" Group C. Movement control, proprioception, and cervical range of motion will be measured. Neck disability and pain intensity, general health, self-perceived handicap, and physical, emotional, and functional difficulties due to dizziness will be measured using questionnaires. The short-term effects will be measured 10 to 12 weeks after the baseline measurements, and the long-term effects will be measured 6 to 12 months after the baseline measurements. The successful completion of this trial will help guide clinicians in the selection of outcome measures for patients with subacute WAD in the assessment of the short- and long-term effectiveness of treatment combining manual therapy with computer-based CKE compared with manual therapy and non-computer-based exercises. This trial will also demonstrate the potential of using a computer-based intervention to increase the exercise dose for this patient group and how this influences outcomes such as levels of pain and disability in the short and long term.


Are There Long-Run Effects of the Minimum Wage?
An empirical consensus suggests that there are small employment effects of minimum wage increases. This paper argues that these are short-run elasticities. Long-run elasticities, which may differ from short-run elasticities, are policy relevant. This paper develops a dynamic industry equilibrium model of labor demand. The model makes two points. First, long-run regressions have been misinterpreted because even if the short- and long-run employment elasticities differ, standard methods would not detect a difference using US variation. Second, the model offers a reconciliation of the small estimated short-run employment effects with the commonly found pass-through of minimum wage increases to product prices.


Carotid artery aneurysms in patients with human immunodeficiency virus.
Carotid artery aneurysms, although rare, are increasing in frequency due to their association with human immunodeficiency virus (HIV) disease. Our institution serves a population with a high HIV prevalence and we wished to document our growing experience with this aneurysmal pathology in a setting of an ever-increasing burden of HIV disease. Data on all patients managed at Inkosi Albert Luthuli Central Hospital in Durban, South Africa, from July 2003 to December 2009 with HIV carotid aneurysms were extracted from a prospective vascular database and their case records were examined. Twenty-two patients were identified of whom 21 had preoperative imaging and underwent some form of intervention. The initial presentation in 19 of the 22 patients was a progressively enlarging neck mass and pain. Ten patients presented with neurology with only 1 patient presenting with a hemiplegia and 1 patient with a monoplegia. Sixteen patients had an open operative repair and 5 patients had an endovascular repair performed as the initial procedure. Of the open procedure, 8 patients had an interposition graft used and 8 had ligation of the common carotid artery (CCA), external carotid artery (ECA), and/or internal carotid artery (ICA). Eighteen patients had no immediate postoperative neurological complications. The worst outcomes were from patients who underwent an endovascular procedure. These included one death, two thrombosed stents, and one endoleak. Histology showed active tuberculosis (TB) in 6 patients who were not known to have TB preoperatively. The overall mortality was 3 of 22 patients. We have noted aneurysms of the carotid artery to occur in patients who are infected with HIV and it seems to be that the incidence of such aneurysms is more common than documented. Open surgical intervention either in the form of an interposition graft or ligation seems to be the more effective treatment option as compared to endovascular stenting. Stenting should be reserved for those patients unfit for open surgery.


A study protocol for a cluster randomized pragmatic trial for comparing strategies for implementing primary HPV testing for routine cervical cancer screening in a large health care system.
Limited guidance exists regarding implementation strategies that best facilitate cancer screening practice substitution and achieve optimal stakeholder-centered outcomes. Here we describe the protocol for a randomized pragmatic trial comparing two implementation strategies to facilitate substitution of primary HPV screening for Pap and HPV co-testing to perform routine cervical cancer screening of women aged 30-65 years at Kaiser Permanente Southern California (KPSC). Twelve service areas within KPSC will be randomized to a "centrally-administered system-wide implementation + local-tailored implementation" strategy or a "centrally-administered system-wide implementation only" strategy. The centrally-administered strategy comprises clinician and staff educational activities. Sites in the local-tailored arm will then conduct a structured local needs assessment followed by site-specific selection and deployment of implementation interventions. Surveys and interviews will be conducted among women and providers from the primary care and ob/gyn departments prior to the system-wide transition, shortly after the transition, and after the completion of local-tailored interventions. A stakeholder advisory committee will assist with study design, defining stakeholder-centered outcomes, and developing data collection tools. The primary outcome of interest is uptake of primary HPV screening. Secondary provider-centered outcomes include provider knowledge, delivery of patient education, satisfaction with the practice substitution process, and resistance to primary HPV screening. Secondary patient-centered outcomes include patient knowledge, stigma, and satisfaction with the screening process. Intervention fidelity will also be measured via surveys. Findings from this study will help inform future use of a local-tailored implementation strategy for adopting primary HPV screening at large health care systems. Findings may also be applicable to other types of practice substitution.


Assessing variability in breast cancer management across the world: results of a questionnaire survey amongst global international experts in breast cancer management.
Breast cancer is the most common cancer in women worldwide with an estimated 2.3 million breast cancer cases diagnosed annually. The outcome of breast cancer management varies widely across the globe which could be due to a multitude of factors. Hence, a blanket approach in standardisation of care across the world is neither practical nor feasible. To assess the extent and type of variability in breast cancer management across the globe and to do a gap analysis of patient care pathway. An online questionnaire survey and virtual consensus meeting was carried out amongst 31 experts from 25 countries in the field of breast cancer surgical management. The questionnaire was designed to understand the variability in diagnosis and treatment of breast cancer, and potential factors contributing to this heterogeneity. The questionnaire survey shows a wide variation in breast surgical training, diagnosis and treatment pathways for breast cancer patients. There are several factors such as socioeconomic status, patient culture and preferences, lack of national screening programmes and training, and paucity of resources, which are barriers to the consistent delivery of high-quality care in different parts of the world. On-line survey platforms distributed to global experts in breast cancer care can assess gaps in the diagnosis and treatment of breast cancer patients. This survey confirms the need for an in-depth gap analysis of patient care pathways and treatments to enable the development of personalised plans and policies to standardise high quality care.


Preoperative radiation and chemotherapy for localized squamous cell carcinoma of the esophagus: a RTOG Study.
Forty-one evaluable patients with localized squamous cell carcinoma of the thoracic esophagus were treated by a course of radiation therapy (3000 cGy in 3 weeks), 5-Fluorouracil (5-FU) and Cis-platinum (Pt). This was followed by an esophagectomy in medically eligible patients who agreed to the procedure and who had no evidence of extrathoracic tumor. If tumor was found in the specimen, an added 2000 cGy of radiation therapy and additional 5-FU and Pt were given. One-year survival was 44%, 2-year survival 15%, and 3-year survival 8%. All 3-year survivors had tumor-free specimens, but one patient with tumor in the thorax and subdiaphragmatic metastasis survived 2 years.


Left Atrial Appendage Occlusion Complicated by Appendage Perforation Rescued by Device Deployment.
The Watchman device is a transcatheter left atrial appendage (LAA) occluding device used in patients with nonvalvular atrial fibrillation (NVAF) and a high CHADS2-VA2SC score who are poor long-term anticoagulation candidates. Pericardial effusion related to device deployment and perforation can be a life-threatening complication. While not common in hands of experienced operators, management may require surgical intervention. Here we present a rare case of LAA perforation, which was corrected by successful repositioning of the device foregoing the need for surgical management.


Protein Translocation Assays to Probe Protease Function and Screen for Inhibitors.
In this chapter, you will learn how to use translocation biosensors to investigate protease functions in living cells. We here present modular protein translocation biosensors tailored to investigate protease activity and protein-protein interactions. Besides the mapping of protease function, the biosensors are also applicable to identify chemicals and/or (nano)materials modulating the respective protein activities and can also be exploited for RNAi-mediated genetic screens.


The role of 3DCT for the evaluation of chop injuries in clinical forensic medicine.
As hatchet blows to the human head frequently cause fatal injuries, the forensic examination of survivors with cranial chop injuries is a rare phenomenon in forensic casework. Besides evaluation of clinical records, photographs, and medico-legal physical examination, the analysis and 3-dimensional reconstruction of pre-treatment computed tomography data (3DCT) must be considered an important and indispensable tool for the assessment of those cases because the characteristics of chopping trauma often appear masked or changed by clinical treatment. In the present article, the role of 3DCT for the evaluation of chop wounds in clinical forensic medicine is demonstrated by an illustrative case report of a young man who was attacked with a hatchet. 3DCT provides additional possibilities for supplementing missing information, such as number and direction of blows as well as weapon identification. Furthermore, 3DCT facilitates demonstration in court and understanding of medical lay people. We conclude that 3DCT is of particular value for the evaluation of survivors of life-threatening head and face injury. An increasing significance of this technique may be expected.


Bioinformaticians: the hidden heroes of the COVID-19 pandemic.
As the COVID-19 pandemic continues to evolve, we explore how bioinformatics has paved the path to this point.


[Gestational arterial hypertension: clinico-epidemiological study].
Epidemiological assessment of prevalence of blood hypertension (BH) in pregnant women. Blood pressure and urinary protein were measured in 5160 gravidae observed in female consultations in 4 cities of Russia. BH was found in 1042(20.2%) examinees. Chronic BH was diagnosed in 306 patients. The rest females had gestational BH. Essential hypertension occurred in 174 patients. A stable rise of diastolic blood pressure above 90 mm Hg is a reliable diagnostic criterion of hypertension in gravidae. Classic proteinuric forms of gestational BH are rare.


Alanyl-glutamine and glutamine supplementation improves 5-fluorouracil-induced intestinal epithelium damage in vitro.
In this study, we have examined the role of glutamine derivatives in reducing 5-fluorouracil (5-FU)-induced epithelial damage in an undifferentiated crypt intestinal cell line, IEC-6. In this model, we have investigated proliferation indirectly by detecting the enzyme-derived formazan dye from the tetrazolium salt WST-1 in viable cells at 24 and 48 h after 5-FU treatment. Migration was measured at 12 and 24 h after razor scraping of the cell monolayer. Cell death was measured by quantifying the percentage of apoptotic and necrotic figures by flow cytometry at 12 and 24 h following 5-FU challenge. Neither glutamine nor alanyl-glutamine prevented 5-FU-induced apoptosis and necrosis in IEC-6 cells at 12 and 24 h after 5-FU challenge. However, glutamine and alanyl-glutamine enhanced migration and proliferation when compared with 5-FU-treated controls (P < 0.05). These new findings support our earlier study on the benefit of oral glutamine in enhancing epithelial recovery after 5-FU challenge.


Pancytopenia due to hemophagocytic syndrome as the presenting manifestation of babesiosis.
We present a case of hemophagocytosis during infection with the intraërythrocytic protozoan Babesia microti in a 47-year-old splenectomized renal allograft recipient. After therapy with clindamycin and quinine a relapse responded to atovaquone; durable remission was not achieved until trimethoprim/sulfa was added. We postulate the severity of our patient's syndrome was due to splenectomy and chronic immunosuppression. Babesiosis should be considered when immunocompromised patients develop pancytopenia.


[The effect of a low dose of ionizing radiation and of gangliosides on the adenylate cyclase activity of the chicken thymus and thyroid in ontogeny].
Adenylate cyclase (AC) activity was studied in thymus and thyroid gland of intact chick embryos and those irradiated with a dose of 0.029 Gy prior to incubation, and newly hatched chicks in the presence of total ganglioside fractions extracted from the same organs. Gangliosides were shown to increase the enzyme activity of thymocytes and thyrocytes during the postnatal development. It is suggested that small radiation doses potentiate the stimulatory effect of ganglioside fractions on AC.


Copper-catalyzed enantioselective intramolecular alkene amination/intermolecular Heck-type coupling cascade.
Enantioselective copper-catalyzed cyclization of γ-alkenylsulfonamides and a δ-alkenylsulfonamide in the presence of a range of vinyl arenes results in variously functionalized 2-substituted chiral nitrogen heterocycles via a formal alkene C-H functionalization process. Application of this reaction to the concise synthesis of a 5-HT(7) receptor antagonist is demonstrated.


Prenatal administration of arginine vasopressin impairs memory retrieval in adult rats.
Eight pregnant female rats were chronically treated via an osmotic pump with arginine vasopressin or placebo during days 13 to 19 gestation. All offspring were tested as adults in either a discrimination task or a 25 day retention of a passive avoidance response. The results revealed that rats whose mother had been treated with vasopressin did not differ from controls on the acquisition or reversal of a brightness discrimination; however, they did require more trials to reach criterion during the ten day memory test of discrimination reversal. Further, treatment resulted in impaired memory retrieval in male rats on the 25 day memory test, while female rats were not affected. Treatment did not influence body weight. The results indicated that vasopressin administered during the prenatal period of development may have had a teratogenic effect on memory retrieval.


Distinctive clinical course and pattern of relapse in adolescents with medulloblastoma.
To report the clinical course of adolescents with medulloblastoma, with specific emphasis on prognosis and pattern of relapse. We retrospectively studied the clinical course and outcomes of children aged 10-20 years with medulloblastoma, treated at centers throughout Canada between 1986 and 2003. To better assess time to relapse, a cohort of patients aged 3-20 years at diagnosis was generated. A total of 72 adolescents were analyzed. Five-year overall survival and event-free survival rates were 78.3%+/-5.4% and 68.0%+/-6.2%, respectively. Late relapses occurred at a median of 3.0 years (range, 0.3-6.8 years). In univariate analysis, conventional risk stratification and the addition of chemotherapy to craniospinal radiation did not have prognostic significance. Female patients had improved overall survival (p=0.007). Time to relapse increased with age in a linear fashion. After relapse, patients faired poorly regardless of treatment modality. Patients who did not receive chemotherapy initially had improved progression-free survival at relapse (p=0.05). Our study suggests that adolescents with medulloblastoma might have a unique prognosis and pattern of relapse, dissimilar to those in younger children. They might benefit from different risk stratifications and prolonged follow-up. These issues should be addressed in future prospective trials.


Quantification of Myocardial Blood Flow by Machine Learning Analysis of Modified Dual Bolus MRI Examination.
Contrast-enhanced magnetic resonance imaging (MRI) is a promising method for estimating myocardial blood flow (MBF). However, it is often affected by noise from imaging artefacts, such as dark rim artefact obscuring relevant features. Machine learning enables extracting important features from such noisy data and is increasingly applied in areas where traditional approaches are limited. In this study, we investigate the capacity of machine learning, particularly support vector machines (SVM) and random forests (RF), for estimating MBF from tissue impulse response signal in an animal model. Domestic pigs (n = 5) were subjected to contrast enhanced first pass MRI (MRI-FP) and the impulse response at different regions of the myocardium (n = 24/pig) were evaluated at rest (n = 120) and stress (n = 96). Reference MBF was then measured using positron emission tomography (PET). Since the impulse response may include artefacts, classification models based on SVM and RF were developed to discriminate noisy signal. In addition, regression models based on SVM, RF and linear regression (for comparison) were developed for estimating MBF from the impulse response at rest and stress. The classification and regression models were trained on data from 4 pigs (n = 168) and tested on 1 pig (n = 48). Models based on SVM and RF outperformed linear regression, with higher correlation (R SVM 2 = 0.81, R RF 2 = 0.74, R linear_regression 2 = 0.60; ρSVM = 0.76, ρRF = 0.76, ρlinear_regression = 0.71) and lower error (RMSESVM = 0.67 mL/g/min, RMSERF = 0.77 mL/g/min, RMSElinear_regression = 0.96 mL/g/min) for predicting MBF from MRI impulse response signal. Classifier based on SVM was optimal for detecting impulse response signals with artefacts (accuracy = 92%). Modified dual bolus MRI signal, combined with machine learning, has potential for accurately estimating MBF at rest and stress states, even from signals with dark rim artefacts. This could provide a protocol for reliable and easy estimation of MBF, although further research is needed to clinically validate the approach.


The clinical significance of chromosomal changes in acute leukemia.
Clonal chromosome changes can now be detected in most cases of acute leukemia when appropriate methods of study are applied. In both acute nonlymphoblastic leukemia (ANLL) and acute lymphoblastic leukemia (ALL) identification of these chromosome abnormalities is increasingly becoming important clinically for diagnosis and prognosis, and as a result selection of therapy. This paper first briefly reviews the recurring chromosome changes now recognized in ANLL and ALL. The prognostic utility of classification of acute leukemia according to karyotype is then discussed.


Secular trend and regional differences in the stature of Italians, 1854-1980.
We present 127 years of data on the physical stature of military conscripts born in Italy during 1854-1980, as well as an analysis of regional variations in height (for birth cohorts born during 1927-1980). The height of young men has increased in all regions of Italy. The secular trend and the regional changes in stature are correlated with economic growth and a general improvement of living conditions. This is suggested by the relationship between height and various socio-economic indicators. A comparison of the 1927 birth cohort with the 1980 birth cohort shows that the mean heights for populations in Italy's southern areas, which were shorter than the national average in 1927, underwent the largest increases. In recent years, mean height has been gradually approaching an upper bound for all regions in Italy, with the exception of some central and southern regions. A multiple regression analysis evaluates the impact of living conditions on the convergence of regional heights.


Prevention and Therapeutic Effects and Mechanisms of Tanshinone IIA Sodium Sulfonate on Acute Liver Injury Mice Model.
Tanshinone IIA sodium sulfonate (TSS) is a water-soluble derivative of tanshinone IIA, which is the main pharmacologically active component of Salvia miltiorrhiza. This study aimed to verify the preventive and therapeutic effects of TSS and its combined therapeutic effects with magnesium isoglycyrrhizinate (MI) in D-galactosamine- (D-Gal-) induced acute liver injury (ALI) in mice. The potential regulatory mechanisms of TSS on ALI were also examined. Our results may provide a basis for the development of novel therapeutics for ALI.


Side effects of ofloxacin in clinical trials and in postmarketing surveillance.
Data derived from clinical trials of ofloxacin in 15,962 patients show that the incidence rate of adverse drug events was 4.27 per 100 patients. Symptoms were generally mild and related to the gastrointestinal tract, nervous system or hypersensitivity reactions in rank order. On the other hand, spontaneous reports obtained during postmarketing surveillance involving 1.5 million patients showed that the most frequent adverse drug events were related to the nervous system; next in order of frequency were hypersensitivity reactions and gastrointestinal symptoms. A comparison of the data obtained from clinical trials and postmarketing surveillance revealed no change in the favourable overall benefit:risk ratio of ofloxacin. Possible reasons for the different patterns of adverse drug events are discussed.


Esophagitis and Barrett esophagus after correction of esophageal atresia.
Gastroesophageal reflux is a frequent problem after esophageal atresia (EA) repair. Our aim was to determine the prevalence of esophagitis and Barrett esophagus more than 10 years after repair of EA. Ninety-two patients treated between 1973 and 1985 were included in this prospective study. A questionnaire was completed by 86 patients; esophagogastroscopy was performed in 49 patients. Only 36 patients had no complaints at all. Thirty-one patients complained of difficulties swallowing solid food; 23 complained of heartburn. Esophagogastroscopy revealed grade 3 esophagitis in 2 patients and a macroscopic image of Barrett esophagus in 2. Histology showed esophagitis in 30 patients, gastric metaplasia in 3, and no intestinal metaplasia (Barrett esophagus). For epidemiologic reasons, that is, the short interval of follow-up (10 years) and the low compliance of the study group, larger numbers are needed to decide if routine long-term endoscopic screening after repair of EA is necessary. For now, it cannot yet be recommended. The prevalence of symptoms of gastroesophageal reflux disease in this study group is higher than that in the general population, but we found no severe complications of gastroesophageal reflux in the pediatric age group.


The competitive NMDA receptor antagonist CPPene stimulates NREM sleep and eating in rats.
Systemic administration of noncompetitive NMDA receptor antagonists, such as MK-801, produces a period of intoxication followed by non- rapid eye movement (NREM) sleep with greatly elevated delta EEG activity. We have hypothesized that the delayed NREM delta EEG increase is a homeostatic response to the immediate elevated limbic metabolism that these drugs produce. Here we test this hypothesis by examining the sleep and EEG effects of CPPene, a competitive NMDA antagonist that does not elevate limbic metabolism. We recorded EEG in seven rats following mid-dark period systemic injections of saline and three doses of CPPene. CPPene did not produce the delayed NREM delta increase. Instead, CPPene increased eating time and dose dependently increased NREM sleep duration shortly after injection. These differences in sleep EEG response to a competitive versus the noncompetitive NMDA antagonists are consistent with the possibility that the increased NREM delta following noncompetitive antagonists is a homeostatic response to increased limbic metabolism.


Clinical Research Abstracts of the British Equine Veterinary Association Congress 2015.
Infrared imaging is becoming popular as an aid to traditional diagnostic tools, its repeatability under practically relevant conditions is still discussed. We hypothesise that time of day, ambient temperature and relative humidity affect thermography readings, and that there is no difference between values from left and right side. Repeated thermography in a convenience sample. Fifteen sound horses were thermographically imaged at 3 time points in the same day (08.00, 12.00 and 16.00 h). Images were taken of the following regions: neck, carpus, distolateral thoracic limbs (cranial and tendon areas), thoracolumbar, pelvis, hock and pelvic limb tendons. Relative humidity and ambient temperature were recorded for each session. There was a significant difference between the temperature readings during the 3 imaging sessions in all areas (Friedman and Kruskal-Wallis; all P<0.014). Ambient temperature and relative humidity correlated with thermography readings in the caudal imaging areas (P<0.008 [temperature], P<0.032 [humidity]) of the horses, with an exception of one hock reading, but not in all cranial areas (P<0.365 [temperature], P<0.992 [humidity]) (Spearman's Rho). All but 2 regions (minimum values in the carpus and thoracic tendon areas in the morning session, (P = 0.033, 0.034) did not show significant difference between left and right sides at the same time of day (all P>0.057). Time of day, ambient temperature and relative humidity must be considered when using infrared imaging. Variations between the left and right sides of the horse can occur and should be considered during the analysis of pathological asymmetry. Ethical animal research: Ethical approval was granted from the Royal Veterinary College Ethics and Welfare committee as part of the first and second author's final year research project. Funding was provided by the Royal Veterinary College as part of the first and second authors' final year research project. Competing interests: None declared.


Nutritional status and gene expression along the somatotropic axis in roach (Rutilus rutilus) infected with the tapeworm Ligula intestinalis.
The tapeworm Ligula intestinalis inhibits gametogenesis of its fish host, the roach (Rutilus rutilus). We investigated whether L. intestinalis infection makes significant demands on nutritional resources and consequently manipulates the endocrine somatotropic axis of roach. Two groups of naturally infected and uninfected roach were studied: a field group (natural feeding) and a laboratory group (ad libitum food supply). In females, no significant impact of parasitization on storage substrates (glycogen, lipids, and protein) was detected, whereas in males, either lipid content of the liver (field group) or lipid of the muscle and glycogen of the liver (laboratory group) were slightly decreased. Except for the females of the field group, higher mRNA expression of growth hormone (gh) in the pituitary of infected fish was observed. Furthermore, the expression of hypophyseal somatolactin α and β (slα, slβ) was up-regulated in infected females of the field and laboratory group, respectively. In liver and muscle, mRNA expression of insulin-like growth factors (igf1, igf2) and igf receptor (igfr) remained either unchanged or were up-regulated with infection. Parasitization showed inconsistent effects on gh receptor 1 (ghr1) expression in liver and muscle, whereas ghr2 mRNA was mostly not influenced by infection. In general, the expression profile of genes involved in the somatotropic axis as well as the content of storage substances in infected roach did not resemble that of food-deprived fish either under natural or ad libitum feeding. In conclusion, the present study does not indicate starvation of L. intestinalis infected roach, and it is suggested that the inhibition of reproduction attenuated the nutritional demand of parasitization.


Intracranial arterial duplex Doppler waveform analysis in infants.
Duplex sonography of the brain was performed on 130 pediatric patients: 53 with normal brains, 22 with intracranial hemorrhage, 15 with hypoxic-ischemic encephalopathy, 29 with hydrocephalus requiring ventricular shunting, and 11 with ventriculomegaly without hemorrhage or shunting. Doppler arterial waveforms from the Circle of Willis showed increased pulsatility in 82% of patients with intracranial hemorrhage, 53% of patients with hypoxic-ischemic change, and in only 31% of patients with hydrocephalus requiring shunt and 36% of patients with ventriculomegaly without shunt or hemorrhage. Mean pulsatility was increased (p less than 0.05) in all groups except ventriculomegaly without hemorrhage or shunt. No statistical difference was found in the diagnostic efficiency of three indices of pulsatility (frequency index profile, pulsatility index, systolic to diastolic ratio).


The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions.
Antithrombin is a member of the serine proteinase inhibitor (serpin) family which contain a flexible reactive site loop that interacts with, and is cleaved by the target proteinase. In cleaved and latent serpins, the reactive site loop is inserted into a large central beta-sheet in the same molecule, whereas in ovalbumin, a nonfunctional serpin, the reactive site loop is completely exposed and in an alpha-helical conformation. However, in neither conformation can the reactive site loop bind to target proteinases. Here we report the structure of an intact and cleaved human antithrombin complex. The intact reactive site loop is in a novel conformation that seems well suited for interaction with proteinases such as thrombin and blood coagulation factor Xa.


A new flexible design of drop-foot orthosis.
The use of polypropylene thermoplastic has caused a revolution in the design of ankle and foot orthoses in recent years. There are many variants in design to suit individual needs. A lively orthosis has been developed at this centre for those patients with weak or absent dorsiflexion of the foot and free passive ankle movements. This design overcomes problems of fatigue failure found in conventional designs and greatly enhances the dynamic cosmesis of this type of orthosis.


[Health of migrants in Calais].
Health care is provided to migrant patients in Calais (62) in a specific context: influx and mixing of populations from all four corners of the world, requirement for urgent care, adaptability of the care provision and facilities, pathologies dominated by physical and mental illness. PASS, a unit offering continuous access to health care in Calais (North), receives these patients. Their health care needs are numerous and complex, and require team work and the participation of networks and associations.


De novo and maintenance DNA methylation by a mouse plasmacytoma cell DNA methyltransferase.
A DNA methyltransferase of Mr = 140,000 that is active on both unmethylated and hemimethylated DNA substrates has been purified from the murine plasma-cytoma cell line MPC 11. The maximal rate of methylation was obtained with maintenance methylation of hemimethylated Micrococcus luteus or M13 DNAs. At low enzyme concentrations, the highest rate of de novo methylation occurred with single-stranded DNA or relatively short duplex DNA containing single-stranded regions. Strong substrate inhibition was observed with hemimethylated but not unmethylated DNA substrates. Fully methylated single-stranded M13 phage DNA inhibited neither the de novo nor the maintenance reactions, but unmethylated single-stranded M13 DNA strongly inhibited the maintenance reaction. The kinetics observed with hemimethylated and single-stranded substrates could be explained if the enzyme were to bind irreversibly to a DNA molecule and to aggregate if present in molar excess. Such aggregates would be required for activity upon hemimethylated but not single-stranded DNA. For de novo methylation of duplex DNA, single-stranded regions or large amounts of methyltransferase appear to be required. The relative substrate preference for the enzyme is hemimethylated DNA greater than fully or partially single-stranded DNA greater than fully duplex DNA.


The pharmacological potency of various AT(1) antagonists assessed by Schild regression technique in man.
A quantitative technique was used to compare the pharmacological potency in healthy volunteers of angiotensin II receptor antagonists (AIIA): candesartan cilexetil, losartan, irbesartan, valsartan, and telmisartan. In a randomised, double-blind, parallel-group (4x12 subjects) study, single oral doses of candesartan cilexetil 4, 8 and 16 mg, losartan potassium 25, 50 and 100 mg, valsartan 40, 80 and 160 mg, and irbesartan 75, 150 and 300 mg were administered on three consecutive days. Telmisartan 20, 40 and 80 mg was similarly evaluated in 12 volunteers in an open amendment. Angiotensin II (Ang II) antagonistic effects were determined in vivo from rightward shifts in Ang II dose-response curves for diastolic blood pressure (BP) and dose ratios were calculated. Apparent K(i)-doses, i.e. doses (in mg) required to induce a two-fold shift in Ang II dose-response curves (equivalent to approx. 50% blockade of receptors) were determined, using Schild regression analysis. All treatments dose-dependently attenuated increases in diastolic BP induced by infusion of exogenous Ang II. Candesartan cilexetil appeared to have a more pronounced increase in effect following cumulative dosing. At 24 hours, apparent K(i)-doses were: candesartan cilexetil 6 mg, irbesartan 123 mg, valsartan 93.5 mg, and telmisartan 54 mg. It was not possible to determine an apparent K(i)-dose for losartan at 24 hours. Consistent with results from experimental pharmacology, candesartan cilexetil displayed the highest pharmacological potency (i.e. antagonistic activity per mg substance) of the AIIAs tested. Apparent K(i)-doses at 24 hours were within the dose range recommended for clinical use in patients with hypertension.


Morphological changes in spherical E. coli induced by a DC electrical field.
Normally spherical cells of Escherichia coli C when grown on a solid minimal salts medium through which an electrical current was passed, developed as short rods, or occasionally, as longer filaments. Currents of up to 30 mA DC were used.


Chimeric flap in clinical use.
With the development of modern microsurgical reconstruction, there are several alternative methods for the complicated head and neck defect or injured extremity. The double-paddled flap, double flaps, and double flap with vascular flow-through linkage are good tools for extensive wide, composite, and three-dimensional defects. When faced with a difficult reconstruction, the expense, morbidity of the donor site, and operative time must be taken into consideration. Compared with other combined composite flaps and other methods, the chimeric flap has many advantages including: easy three-dimensional insetting, acceptable aesthetic appearance, reduced donor site morbidity, design with the least effort and operation time, and one pair of recipient vessel. The disadvantages of the chimeric flaps include: the variation of perforators, the requirement of a learning curve, and, sometimes, the need for a second venous drainage or shifting to double flaps. Overall, in selected cases, the chimeric flap is a good option for the reconstruction of extensive, composite, and three-dimensional defects.


Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial.
To investigate the efficacy and tolerability of empagliflozin as add-on to metformin and sulfonylurea in patients with type 2 diabetes. Patients inadequately controlled on metformin and sulfonylurea (HbA1c ≥7 to ≤10%) were randomized and treated with once-daily empagliflozin 10 mg (n = 225), empagliflozin 25 mg (n = 216), or placebo (n = 225) for 24 weeks. The primary end point was change from baseline in HbA1c at week 24. Key secondary end points were changes from baseline in weight and mean daily glucose (MDG) at week 24. At week 24, adjusted mean (SE) changes from baseline in HbA1c were -0.17% (0.05) for placebo vs. -0.82% (0.05) and -0.77% (0.05) for empagliflozin 10 and 25 mg, respectively (both P < 0.001). Empagliflozin significantly reduced MDG, weight, and systolic (but not diastolic) blood pressure versus placebo. Adverse events were reported in 62.7, 67.9, and 64.1% of patients on placebo and empagliflozin 10 and 25 mg, respectively. Events consistent with urinary tract infection were reported in 8.0, 10.3, and 8.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 13.3, 18.0, and 17.5%, respectively; males: 2.7, 2.7, and 0%, respectively). Events consistent with genital infection were reported in 0.9, 2.7, and 2.3% of patients on placebo and empagliflozin 10 and 25 mg, respectively (females: 0.9, 4.5, and 3.9%, respectively; males: 0.9% in each group). Empagliflozin 10 and 25 mg for 24 weeks as add-on to metformin plus sulfonylurea improved glycemic control, weight, and systolic blood pressure and were well tolerated.


Characterization of a subunit structure and stability of the recombinant porin from Neisseria gonorrhoeae.
An outer membrane PIA protein from Neisseria gonorrhoeae strain FA19 was expressed in Escherichia coli and refolded in vitro in the presence of zwitterionic detergent. Its proper folding and subunit organization was confirmed by comparison with the native counterpart. The unfolding of PIA has been investigated using fluorescence spectroscopy and analytical size-exclusion chromatography methods. Analysis of the denaturation pathway of the PIA revealed that it forms an unusually labile quaternary structure. In the presence of 1 M guanidinium chloride (GdmCl) or upon heating up to 50 degrees C, dissociation of the PIA oligomer was observed resulting in the formation of folded monomeric intermediates. Unfolding of monomers occurs at 80 degrees C or in the presence of 4.3 M GdmCl, indicating high intrinsic stability toward both GdmCl and elevated temperatures. Both oligomeric and monomeric forms of PIA exhibited affinity to the hydrophobic probe 1-anilinonaphthalene-8-sulfonic acid (ANS) and bind with Kd=80 and 130 microM, respectively. Denaturation of the PIA completely abolished affinity to ANS, suggesting that hydrophobicity is a property of the folded state of the porin.


Light-Driven Continual Oscillatory Rocking of a Polymer Film.
Achieving oscillatory motion in polymers without requiring on/off switching of stimuli is a current challenge. Hereby, a free-standing liquid crystal polymer (LCP) is demonstrated to undergo a sustained oscillatory motion when triggered by light, moving back and forth, resembling the motion of a rocking-chair. Two polymer films having different azobenzene photo-switches have been studied, revealing photoswitch requirements as well as illumination conditions necessary to sustain oscillations. The motion presented here shows how feedback loops involving light-triggered actuation, self-shadowing and a shifting center of gravity can be utilized to achieve self-sustained motion in free-standing polymers.


Hierarchical and Controlled Advancement for Continuous Collision Detection of Rigid and Articulated Models.
We present fast CCD algorithm for general rigid and articulated models based on conservative advancement. We have implemented the CCD algorithm with two different acceleration techniques which can handle rigid models, and have extended one of them to articulated models. The resulting algorithms take a few milliseconds for rigid models with tens of thousands of triangles, and a few milliseconds for articulated models with tens of links. We show that the performance of our algorithms is much faster than existing CCD algorithms for polygon-soup models and it is also comparable to competing CCD algorithms that are limited to manifold models.


The history of cryosurgery in Canada: A tale of two cities.
Although not commonly available in Canada, cryosurgery (cryoablation) for prostate cancer has been practiced in many countries. The field of cryoablation has evolved significantly over the past 30 years. Two prostate cryoablation programs were started in Canada in the early 1990s, in London, ON and Calgary, AB, focusing, respectively, on salvage therapy following radiation failure and primary local treatment. This article chronicles the development of the two programs and outlines the scientific and clinical contributions by investigators at the two centers.


On the mode of action of six putative dopamine receptor agonists on suppression of exploratory behaviour in rats.
The effects of six putative dopamine receptor agonists on exploratory behaviour in rats were assessed: pergolide, (+)- and (-)-3-PPP, bromocriptine, mesulergine and CQ 32-084. Behaviour was automatically recorded in a holeboard apparatus and the data were analysed by the novel multivariate statistical method of partial least squares. All six substances suppressed exploratory behaviour at low doses. Pergolide and (+)-3-PPP-induced stereo-typed behaviour at higher doses. The suppression of exploration induced by pergolide was completely antagonised by sulpiride, partly antagonised by metoclopramide and weakly affected by haloperidol pretreatment. The effects of a low dose of (+)-3-PPP, bromocriptine or CQ 32-084, but not (-)-3-PPP or mesulergine, were antagonised by sulpiride. These findings support the hypotheses that pergolide, (+)-3-PPP, bromocriptine and CQ 32-084 inhibit exploration via stimulation of dopamine receptors. The present data do not substantiate the hypothesis that the suppression of exploration induced by (-)-3-PPP is mediated by stimulation of dopamine autoreceptors. A detailed analysis of the dose curves for pergolide and (+)-3-PPP indicates that the latter compound may have effects in addition to those of a dopamine receptor agonist.


Measuring experience of and satisfaction with newborn care: a scoping review of tools and measures.
Standardised measures on experience of care are essential to understanding the care women and newborns receive and to designing appropriate interventions and responses. This review builds on ongoing work in the realm of maternity care and complements it by reviewing existing tools and measures to assess experience of and satisfaction with the care of the newborn. We conducted a scoping review of published literature to identify measures and tools of experience (physiological or indirect) and satisfaction with newborn care. We systematically searched five bibliographic databases from 1 January 2010 through 1 December 2022 and contacted professional networks. Using a predefined evidence template, we extracted data on the studies and the tools' characteristics. We mapped the tools and measures against the WHO quality of care frameworks to identify the most frequent measured domains of care and to highlight existing gaps. We identified 18 292 records of which 72 were eligible. An innovative finding of this review is the inclusion of newborn perspectives through behavioural responses, physiological signals, pain profiles as well as other non-verbal cues as markers of newborn experience. Domains related to parental participation and decision-making, ensuring continuity of care and receiving coordinated care, were the most measured across the included tools. Comprehensive and validated instruments measuring all aspects of care are needed. Developing a robust theoretical ground will be fundamental to the design and utilisation of standardised tools and measures. This review was registered and published on protocol.io (dx.doi.org/10.17504/protocols.io.bvk7n4zn).


A tale of dwarfs and drugs: brassinosteroids to the rescue.
Brassinosteroids (BRs), a specific class of low abundance plant steroids, are capable of eliciting strong growth responses and a variety of physiological changes through exogenous application to plants. Recently, BRs gained general acceptance as important regulators (hormones) of plant growth and development through genetic and molecular identification and characterization of genes involved in BR biosynthesis or response in Arabidopsis, pea and tomato. This major advance in the molecular genetics of BR biosynthesis and mode of action disclosed another case of amazing functional conservation of signalling molecules utilized in plants and animals, and provided a set of extremely valuable tools for the functional analysis of BRs.


Vascular properties of canine lungs perfused with Eurocollins solution and prostacyclin.
Although Eurocollins solution (ECS) is commonly used for lung preservation, its vascular effects and their time course and response to pharmacological interventions are not well understood. The effect of 4 degrees C ECS on the pulmonary circulation was assessed in excised canine left lower lobes. The roles of static oxygen inflation and prostacyclin infusion during ECS perfusion were also examined. The lobes were divided into five groups: time control (A), ECS with oxygen (B), ECS without oxygen (C), ECS with glycine buffer (D), and ECS with prostacyclin (E); group D was the control for E. Eurocollins solution had no effect on gas exchange but had a marked effect on the pulmonary circulation. Vascular conductance decreased from 22.6 to 18.9 mL/min/cm H2O and from 21.3 to 14.1 mL/min/cm H2O with average vascular closure increasing by 1.2 and 2.1 cm H2O in groups B and C, respectively. The decreased vascular conductance and increased vascular closure was associated with a reduction in vascular compliance from 1.63 to 1.25 mL/cm H2O. When prostacyclin was added to ECS, the reduction in vascular closure was much less and was associated with a decrease in vascular closure and no loss of vascular compliance. Eurocollins solution increases pressure cost for perfusion by causing both vascular obstruction and increased tone, especially when oxygen is not provided. This is significantly overcome by addition of prostacyclin infusion during ECS perfusion.


A comparison of the oximes HS-6 and HI-6 in the therapy of soman intoxication in rodents.
The bisquaternary mono-oximes HS-6 and HI-6 may both be considered as potential therapeutic agents for soman intoxication. It has been found that HI-6 was superior to an equal dose of /S-6 in the treatment of soman intoxication in mice and rats. Not only did HI-6 protect against higher levels of soman, but also fewer "delayed deaths" were seen following HI-6. In anesthetized atropinized rats, the administration of HI-6 resulted in a longer duration of spontaneous breathing and a higher degree of recovery of neuromuscular function than did the use of HS-6. HS-6 interacted with soman to alter the rate of excretion of the oxime. This problem was not encountered when HI-6 was used.


MicroRNA comparison between poplar and larch provides insight into the different mechanism of wood formation.
MiRNA transcriptome analysis of different tissues in poplar and larch suggests variant roles of miRNAs in regulating wood formation between two kinds of phyla. Poplar and larch belong to two different phyla. Both are ecological woody species and major resources for wood-related industrial applications. However, wood properties are different between these two species and the molecular basis is largely unknown. In this study, we performed high-throughput sequencing of microRNAs (miRNAs) in the three tissues, xylem, phloem and leaf of Populus alba × Populus glandulosa and Larix kaempferi. Differentially expressed miRNA (DEmiRNA) analysis identified 85 xylem-specific miRNAs in P. alba × P. glandulosa and 158 xylem-specific miRNAs in L. kaempferi. Among 36 common miRNAs, 12 were conserved between the two species. GO and KEGG analyses of the miRNA target genes showed similar metabolism in two species. Through KEGG and BLASTN, we predicted target genes of xylem differentially expressed (DEmiRNA) in the wood formation-related pathways and located DEmiRNAs in these pathways. A network was built for wood formation-related DEmiRNAs, their target genes and orthologous genes in Arabidopsis thaliana. Comparison of DEmiRNA and target gene annotation between P. alba × P. glandulosa and L. kaempferi suggested the different functions of DEmiRNAs and divergent mechanism in wood formation between two species, providing knowledge to understand wood formation mechanism in gymnosperm and angiosperm woody plants.


Combining statistical methods for detecting potential outliers in groundwater quality time series.
Quality control of large-scale monitoring networks requires the use of automatic procedures to detect potential outliers in an unambiguous and reproducible manner. This paper describes a methodology that combines existing statistical methods to accommodate for the specific characteristics of measurement data obtained from groundwater quality monitoring networks: the measurement series show a large variety of dynamics and often comprise few (< 25) measurements, the measurement data are not normally distributed, measurement series may contain several outliers, there may be trends in the series, and/or some measurements may be below detection limits. Furthermore, the detection limits may vary in time. The methodology for outlier detection described in this paper uses robust regression on order statistics (ROS) to deal with measured values below the detection limit. In addition, a biweight location estimator is applied to filter out any temporal trends from the series. The subsequent outlier detection is done in z-score space. Tuning parameters are used to attune the robustness and accuracy to the given dataset and the user requirements. The method has been applied to data from the Dutch national groundwater quality monitoring network, which consists of approximately 350 monitoring wells. It proved to work well in general, detecting outliers at the top and bottom of the regular measurement range and around the detection limit. Given the diversity exhibited by measurement series, it is to be expected that the method does not give 100% satisfactory results. Measured values identified by the method as potential outliers will therefore always need to be further assessed on the basis of expert knowledge, consistency with other measurement data and/or additional research.


Isolated lateral rectus muscle involvement as a presenting sign of euthyroid Graves disease.
A 27-year-old man who presented with diplopia and proptosis and was diagnosed with euthyroid Graves disease and restrictive strabismus. It was determined that his symptoms were caused by isolated lateral rectus muscle involvement. Diplopia resolved and ocular motility improved substantially following 6 weeks of oral corticosteroid therapy.


Identification of ICAT as an APC Inhibitor, Revealing Wnt-Dependent Inhibition of APC-Axin Interaction.
Adenomatous polyposis coli (APC) and Axin are core components of the β-catenin destruction complex. How APC's function is regulated and whether Wnt signaling influences the direct APC-Axin interaction to inhibit the β-catenin destruction complex is not clear. Through a CRISPR screen of β-catenin stability, we have identified ICAT, a polypeptide previously known to block β-catenin-TCF interaction, as a natural inhibitor of APC. ICAT blocks β-catenin-APC interaction and prevents β-catenin-mediated APC-Axin interaction, enhancing stabilization of β-catenin in cells harboring truncated APC or stimulated with Wnt, but not in cells deprived of a Wnt signal. Using ICAT as a tool to disengage β-catenin-mediated APC-Axin interaction, we demonstrate that Wnt quickly inhibits the direct interaction between APC and Axin. Our study highlights an important scaffolding function of β-catenin in the assembly of the destruction complex and suggests Wnt-inhibited APC-Axin interaction as a mechanism of Wnt-dependent inhibition of the destruction complex.


Not just an upset stomach: gastric perforation in a patient with anorexia nervosa.
Gastric perforation in patients with anorexia nervosa is a rare entity associated with high morbidity and mortality [Norris in Int J Eat Disord 49:216-237, 2016]. In cases reported in the literature, the perforation was often preceded by a binge episode, and the subsequent clinical presentation was rapid and acutely deteriorating with a fatality rate as high as 80% [Norris in Int J Eat Disord 49:216-237, 2016, Pitre in J Med Case Rep 15:61, 2021]. We present a case of gastric perforation in the context of restrictive anorexia nervosa unique both for the absence of a premorbid binge episode as well as delayed clinical manifestations of medical distress, leading to abdominal compartment syndrome.Level IV Evidence obtained from multiple time series analysis such as case studies.


Serum interferon in Navajo children with severe combined immunodeficiency disease inhibits lymphoblastogenesis.
Two Navajo Indian children with severe combined immunodeficiency disease (SCID) lost reconstituted immune function after virus infections. A serum factor which inhibited normal lymphocyte response to mitogens was found in one of them and led to the examination of sera from five other Navajos with SCID. Mean inhibition by six Navajo sera was 67%; no inhibitor was found in sera from normal adults and children. The inhibitor activity was nondialyzable and heat stable, yet partially sensitive to pH 2.0, suggesting that interferon(s) was present. Interferon (IFN) activity in patient sera ranged from 10 to 300 U/ml. Normal children had peak serum IFN levels of 100 and 30 U/ml in the acute and convalescent periods, respectively, of virus infections. IFN alpha, IFN beta, and IFN gamma were identified in SCID sera by specific antisera. Both inhibitor and IFN activities in three Navajo sera were 88-95 and 89-100%, respectively, removed with anti-IFN antisera. Similar patterns of inhibition of lymphoblastogenesis were seen with IFN standards. IFN levels in the SCID patients did not correlate with documented infections; elevated levels were present when no infections could be documented. The immunologic imbalances in some forms of SCID may be related to circulating inhibitors, possibly interferon.


miR-122-5p targets GREM2 to protect against glucocorticoid-induced endothelial damage through the BMP signaling pathway.
Glucocorticoid (GC)-induced osteonecrosis of the femoral head (ONFH) accounts for a big portion of non-traumatic ONFH; nevertheless, the pathogenesis has not yet been fully understood. GC-induced endothelial dysfunction might be a major contributor to ONFH progression. The Gene Expression Omnibus (GEO) dataset was analyzed to identify deregulated miRNAs in ONFH; among deregulated miRNAs, the physiological functions of miR-122-5p on ONFH and endothelial dysfunction remain unclear. In the present study, miR-122-5p showed to be under-expressed within GC-induced ONFH femoral head tissues and GC-stimulated bone microvascular endothelial cells (BMECs). In human umbilical vein endothelial cells (HUVECs) and BMECs, GC stimulation significantly repressed cell viability, promoted cell apoptosis and increased the mRNA expression of proinflammatory cytokines, such as TNF-α, IL-1β, and IFN-γ. After overexpressing miR-122-5p, GC-induced endothelial injuries were attenuated, as manifested by rescued cell viability, cell migration, and tube formation capacity. Regarding the BMP signaling, GC decreased the protein levels of BMP-2/6/7 and SMAD-1/5/8, whereas miR-122-5p overexpression significantly attenuated the inhibitory effects of GC on these proteins. Online tool and experimental analyses revealed the direct binding between miR-122-5p and GREM2, a specific antagonist of BMP-2. In contrast to miR-122-5p overexpression, GREM2 overexpression aggravated GC-induced endothelial injury; GREM2 silencing partially eliminated the effects of miR-122-5p inhibition on GC-stimulated HUVECs and BMECs. Finally, GREM2 silencing reversed the suppressive effects of GC on BMP-2/6/7 and SMAD-1/5/8, and attenuated the effects of miR-122-5p inhibition on these proteins upon GC stimulation. Conclusively, the present study demonstrates a miR-122-5p/GREM2 axis modulating the GC-induced endothelial damage via the BMP/SMAD signaling. Considering the critical role of endothelial function in ONFH pathogenesis, the in vivo role and clinical application of the miR-122-5p/GREM2 axis is worthy of further investigation.


Time trade-off with someone to live for: impact of having significant others on time trade-off valuations of hypothetical health states.
The TTO task involves giving up life years, i.e. living a shorter life, to avoid an undesirable health state. Despite being a hypothetical task, some respondents take other life factors into account when completing the task. This study explored the effect of having children and/or a partner on TTO valuations of hypothetical EQ-5D-5L health states in a valuation study of the general population. The study used TTO data collected in a Norwegian EQ-5D-5L valuation study in 2019-2020, by one-to-one pc-assisted interviews following the EQ-VT protocol. We used regression modelling to determine the effect of significant others (having children or a partner) on disutility per health state from the TTO valuations. 430 respondents were included [mean age 43.8 (SD 15.9) years, 58% female, 48% with children, 68% with a partner, 25% with neither children nor partner]. Having children and/or a partner was associated with lowered willingness to trade life years translating to higher elicited health state utilities (p < 0.01). Having significant others, or the lack of having significant others, was associated with respondents' valuation of hypothetical health states using TTO, more so than traditional sampling variables such as age and sex. Inadequate representativeness in terms of having significant others could bias health state preference values in valuation studies.


Femoral Neck Stress Fracture: Can MRI Grade Help Predict Return-to-Running Time?
Limited research is available regarding return-to-running (RTR) time after femoral neck stress fractures. While studies have shown the prognostic value of image-based grading scales for stress fractures at other sites, few have included femoral neck stress fractures. To determine if the grade of femoral neck stress fractures based on magnetic resonance imaging (MRI) characteristics correlates with RTR time. Cohort study; Level of evidence, 3. This study included 24 patients (mean age, 32.9 years; range, 18-51 years) who were diagnosed with 27 femoral neck stress fractures by MRI from 2009 to 2015 at a single sports medicine clinic. All fractures were compression sided and were treated nonoperatively. Charts were reviewed for patient demographics and RTR time. Images were graded from 1 to 4 using the Arendt stress fracture severity scale. Statistical analysis was performed using survival analysis and Cox proportional hazard model to compare the RTR time between grades. Cox regression was repeated, adjusted for age, bone mineral density (BMD), and body mass index (BMI). The mean (±standard error of the mean) RTR time in weeks for patients with fractures graded 1 to 4 was 7.4 ± 2.7 (range, 4-11), 13.8 ± 3.8 (range, 6-21), 14.7 ± 3.5 (range, 8.5-24), and 17.5 ± 3.4 (range, 10-32), respectively. Survival analysis indicated that there was a statistically significant effect of fracture grade on RTR time (P = .0065). The Cox model indicated a statistically significant difference in RTR time between grades 1 and 2 (P = .036), 1 and 3 (P = .014), and 1 and 4 (P = .002). The unadjusted hazard ratio was significant (P = .037). There were no statistically significant differences between the remaining grades (P = .82 for grades 2 and 3, P = .37 for grades 2 and 4, and P = .31 for grades 3 and 4). Age (P = .71) and BMD (P = .81) did not have an effect on RTR time. The hazard ratio remained significant (P = .05) after adjusting for age and BMD. BMI tended to have an effect on RTR time (P = .09). After adding BMI to the adjustment, the hazard ratio decreased in significance (P = .13), although sample size also decreased. Grade 2 to 4 femoral neck stress fractures require longer RTR time than do grade 1 injuries. Patients with lower BMI tend to require a longer RTR time.